Patent Publication Number: US-11041859-B2

Title: Methods of identifying SENP1 inhibitors

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional of U.S. patent application Ser. No. 14/247,153, filed Apr. 7, 2014, now U.S. Pat. No. 9,791,447, issued Oct. 17, 2017, which claims the benefit of U.S. Provisional Patent Applications 61/809,208, filed Apr. 5, 2013, and 61/813,832, filed Apr. 19, 2013, each of which is incorporated herein by reference in its entirety and for all purposes. 
    
    
     STATEMENT REGARDING FEDERALLY FUNDED RESEARCH 
     This invention was made with government support under NM Grant Nos. R01GM074748, R01GM086171 and R01GM102538. The government has certain rights in the invention. 
    
    
     REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII TEXT FILE 
     The Sequence Listing written in file 48440-521C01US_ST25.TXT, created on Oct. 13, 2017, 22,281 bytes, machine format IBM-PC, MS-Windows operating system, is hereby incorporated by reference. 
     BACKGROUND 
     Post-translational modifications with the small ubiquitin-like modifiers (SUMO) are initiated and removed by the activities of SUMO-specific proteases (SENPs). Unlike ubiquitylation, which has one modifier (i.e., ubiquitin) and one dominant role, namely protein degradation, SUMOylation involves three modifiers (SUMO-1, -2, and -3) and affects diverse cellular functions. There are six SENPs, organized into three families based on sequence similarity: SENP1 and 2 that catalyze maturation of SUMO precursors and removal of SUMO-1 and SUMO-2/3 conjugates; SENP3 and 5 that preferentially remove SUMO-2/3 conjugates; and SENP6 and 7 that appear to be mainly involved in editing poly-SUMO-2/3 chains. Recently, another de-SUMOylase has been discovered that does not share sequence similarity with the SENPs. 
     SENP inhibitors with cellular activity would be advantageous for elucidating the role of SUMOylation in cellular regulation and for validating SENPs as therapeutic targets. SENP1 and SENP3 are also potential targets for developing new therapeutic agents for cancer. They regulate the stability of hypoxia-inducible factor 1α (HIF1α), which is a key player in the formation of new blood vessels to support tumor growth. SENP1 is also highly expressed in human prostate cancer specimens and regulates androgen receptor (AR) activities. Androgen induces rapid and dynamic conjugation of SUMO-1 to AR, while SENP1 promotes AR-dependent transcription by cleaving SUMO-1-modified AR. SENP1 overexpression induces transformation of normal prostate gland tissue and facilitates the onset of high-grade prostatic intraepithelial neoplasia. Therefore, at least some members of the SENPs are potential targets for developing new cancer therapies. 
     SUMMARY 
     Provided herein are methods of detecting binding of an SENP1 polypeptide to a compound and methods for screening for inhibitors of SENP1. Further provided are aqueous compositions comprising SENP1 polypeptides and NMR apparatuses comprising the compositions for NMR analysis. 
     The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims. 
    
    
     
       DESCRIPTION OF DRAWINGS 
         FIG. 1  is a picture of a representative Coomassie-stained gel showing cleavage of SUMO-1 and SUMO-2 by SENP1 and SENP2 in the presence of increasing concentrations of SPI-01. YSE, fusion SUMO (S) precursors flanked by YFP (Y) and ECFP (E) at the N- and C-termini, respectively. 
         FIG. 2  is a picture of representative Coomassie-stained gel showing cleavage of SUMO-1 and SUMO-2 by SENP1 and SENP2 in the presence of increasing concentrations of SPI-07. YSE, fusion SUMO (S) precursors flanked by YFP (Y) and ECFP (E) at the N- and C-termini, respectively. 
         FIGS. 3A-3C  are graphs showing the effects of the panel of inhibitors shown in Table 1 at inhibiting SENP1, 2 and 7. In 96-well plates, SENPs (50-200 nM) were pre-treated with increasing concentrations of each compound, after which DUB-Glo (40 μM final concentration; Promega, Madison, Wis.) was added as substrate. Experiments were performed in triplicate. The amount of cleaved product is proportional to the relative light unit (RLU), which is bioluminescence produced by luciferase catalyzed reaction of luciferin that was produced by SENP cleavage of DUB-Glo. 
         FIG. 4  is a picture of a gel showing accumulation of SUMO-2/3-modified proteins in HeLa cells upon treatment with increasing doses of SPI-01. 
         FIG. 5  is a picture of a gel showing retention of SUMOylated proteins during recovery of HeLa cells from heat shock in the presence of 60 μM SPI-01 and SPI-02. 
         FIG. 6  is a graph showing superimposition of a section of the 2D  1 H- 15 N-heteronuclear single quantum coherence (HSQC) spectra of the catalytically inactive C603S mutant of human SENP1 in the absence (black cross-peaks) and presence of SPI-01 (grey cross-peaks) at 25° C. Perturbed representative cross-peaks at or near the catalytic site of SENP1 are labeled. 
         FIG. 7  is a graph showing the superimposition of a section of the 2D  1 H- 15 N-HSQC spectra of SUMO-1 precursor showing labeled peaks of the C-terminal residues when free (black) and bound to SENP1-C603S (dark grey) or both SENP1-C603S and SPI-01 (light grey) at 35° C. 
         FIG. 8  is a picture showing all SPI-01 perturbed residues on SENP1 (PDB ID: 2IY1) labeled and colored in dark grey on the surface representation of SENP1 in complex with SUMO-1 precursor. Perturbed residues that are located in the vicinity of the catalytic center of SENP1 or the C-terminus of precursor SUMO-1 are labeled in black and grey, respectively. 
         FIGS. 9A and 9B  are graphs showing enzyme kinetic measurements for SPI-01 indicating a non-competitive mode of inhibition. The data were fit to obtain the indicated kinetic parameters (α, K i  and K m ) using Graphpad Prism. Lineweaver-Burk plot analysis of the data also confirmed non-competitive inhibition. 
     
    
    
     DETAILED DESCRIPTION 
     SENP1 is a target for developing new therapeutic agents for cancer. It regulates the stability of hypoxia-inducible factor 1α (HIF1α), which is a key player in the formation of new blood vesicles to support tumor growth. SENP1 is also highly expressed in human prostate cancer specimens and regulates androgen receptor (AR) activities. SENP1 is also a target for developing anti-viral therapeutic agents for infection of viruses including, but not limited to influenza, cytomegalovirus, herpes virus, white spot syndrome virus, Epstein-Barr virus, adenovirus and HIV-1, because of the role of SUMOylation in their replication. As described in the examples below, small molecule inhibitors of SENP1 were searched for using in-silico screening in conjunction with biochemical assays. However, the data provided evidence for substrate-assisted inhibitor binding. Thus, using artificial substrates for compound screening may be misleading, as the inhibitory effects could be significantly different from using the physiological substrates. Therefore, embodiments are provided including methods and inhibitors of SENP1 that confer the non-competitive inhibitory mechanism, as shown by nuclear magnetic resonance (NMR). 
     For specific SENP proteins described herein (e.g., SENP1), the named protein includes any of the protein&#39;s naturally occurring forms, or variants that maintain the protein activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to the native protein). In some embodiments, variants have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring form. In other embodiments, the SENP1 protein is the protein as identified by its NCBI sequence reference. In other embodiments, the SENP1 protein is the protein as identified by its NCBI sequence reference or functional fragment thereof. 
     The term “SENP1” as provided herein includes any of the Sentrin-specific protease 1 (SENP1) naturally occurring forms, homologs, isoforms or variants that maintain the protease activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to the native protein). In some embodiments, variants have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring form. In embodiments, the SENP1 protein is the protein as identified by the NCBI sequence reference GI:390131988 or functional fragment thereof. In embodiments, the SENP1 protein is the protein as identified by the UniProt sequence reference Q9P0U3 or functional fragment thereof. In embodiments, the SENP1 protein includes the sequence of SEQ ID NO:1, 2, 3, 4, 5, 6, or 7. In embodiments, the SENP1 protein is encoded by a nucleic acid sequences corresponding to Gene ID: 29843. 
     As described herein, nuclear magnetic resonance (NMR) approaches have advantages over other methods previously employed on SENP1 in identifying molecules or compounds for further development. Specifically, the methods herein provide for discovery or identification of compounds or inhibitors that selectively bind SENP1 and not other SENPs. The methods also provide for identification of compounds or inhibitors that selectively bind SENP1-physiological substrate complexes and not SENP-artificial substrate complexes. Further advantages include sensitivity to binding affinities of a wide range and, thus, allowing for identification of compounds with physicochemical properties that are amenable for a greater scope for development of leads with superior ADME (absorption, distribution, metabolism, and excretion) attributes. Optionally, the test compounds are Rule-of-three (Ro3) (MW≤300, H-bond donors/acceptors≤3, c Log P≤3, rotatable bonds≤3) compliant (Congreve et al.,  Drug Discov. Today  8(19):876-7 (2003); and Erlanson,  Top Curr. Chem.  317:1-32 (2011)). 
     Nuclear magnetic resonance (NMR) studies magnetic nuclei and provide atomic resolution information on the structures of large or small molecules and their complexes. The elementary particles, neutrons and protons, composing an atomic nucleus, have the intrinsic quantum mechanical property of spin. The overall spin of the nucleus is determined by the spin quantum number I. If the number of both the protons and neutrons in a given isotope are even, then I=0. In other cases, however, the overall spin is non-zero. A non-zero spin is associated with a non-zero magnetic moment. It is this magnetic moment that is exploited in NMR. For example, nuclei that have a spin of one-half, like Hydrogen nuclei ( 1 H), a single proton, have two possible spin states (also referred to as up and down, respectively). The energies of these states are the same. Hence the populations of the two states (i.e. number of atoms in the two states) will be approximately equal at thermal equilibrium. If a nucleus is placed in a magnetic field, however, the interaction between the nuclear magnetic moment and the external magnetic field means the two states no longer have the same energy. The NMR frequency (f) is shifted by the shielding effect of the surrounding electrons. In general, this electronic shielding reduces the magnetic field at the nucleus (which is what determines the NMR frequency). As a result, the energy gap is reduced, and the frequency required to achieve resonance is also reduced. This shift of the NMR frequency due to the chemical environment is called the chemical shift, and it explains why NMR is a direct probe of chemical structure. The chemical shift in absolute terms is defined by the frequency of the resonance expressed with reference to a standard which is defined to be at 0. The scale is made manageable by expressing it in parts per million (ppm) of the standard frequency. Thus, in general, NMR spectral data are reported as chemical shift and are reported in ppm relative to either an internal standard or other baseline. A more detailed discussion of nuclear magnetic resonance may be found in, for example, C. P. Slichter, Principles of Magnetic Resonance, 3rd ed., Springer-Verlag, Berlin, pp. 1-63 (1990); J. D. Roberts, Nuclear Magnetic Resonance, Mc-Graw-Hill, N.Y., pp. 1-19 (1959); Cohen-Tannoudji et al., Quantum Mechanics, Vol. 1, New York, N.Y.: Wiley (1977); WO 2009/027973; WO 2009/029880; WO 2009/029896; Hajduk et al., “High-throughput nuclear magnetic resonance-based screening,” J. Med. Chem. 42:2315-2317 (1999); and Cavanagh et al., Protein NMR Spectroscopy: Principles and Practice Academic Press: San Diego (1996), which are incorporated by reference herein in their entireties. 
     A variety of NMR approaches have been developed to accelerate NMR data acquisition (Atreya et al., Methods Enzymol., 394:78-108 (2005)). For example, in the field of biological NMR spectroscopy (Cavanagh et al., Protein NMR Spectroscopy, Academic Press: San Diego (2007)) stable isotope ( 13 C/ 15 N) labeled biological macromolecules are now studied. The isotope labeling enables one to efficiently record three-dimensional (3D) or four-dimensional (4D) 13 C/ 15 N-resolved spectra. The most commonly used biological NMR methods are multi-dimensional and heteronuclear-edited NMR methods. See, for example, Tjandra and Bax, “Direct measurement of distances and angles in biomolecules by NMR in a dilute liquid crystalline medium,” Science 1997 278(5340):1111-4 (1997). Erratum in: Science 278(5344):1697 (1997); Clore and Gronenborn, “NMR structure determination of proteins and protein complexes larger than 20 kDa,” Curr Opin Chem Biol. October; 2(5):564-70 (1998); Mittermaier and Kay, “Observing biological dynamics at atomic resolution using NMR,” Trends Biochem Sci. 34(12):601-11 (2009); and Wüthrich, Kurt, NMR of Proteins and Nucleic Acids, John Wiley, New York, N.Y. (1986). NMR techniques further include, but are not limited to, (i) Reduced-dimensionality (RD) NMR (Szyperski et al., Proc. Natl. Acad. Sci. U.S.A., 99:8009-8014 (2002)); (ii) G-matrix FT (GFT) projection NMR (Atreya et al., J. Am. Chem. Soc., 127:4554-4555 (2005); Eletsky et al., J. Am. Chem. Soc., 127:14578-14579 (2005); Yang et al., J. Am. Chem. Soc., 127:9085-9099 (2005); Szyperski et al., Magn. Reson. Chem., 44:51-60 (2006); Atreya et al., J. Am. Chem. Soc., 129:680-692 (2007); Kupce et al., J. Am. Chem. Soc., 126:6429-40 (2004); Hiller et al., Proc. Natl. Acad. Sci. U.S.A., 102:10876-10881 (2005); and Eghbalnia et al., J. Am. Chem. Soc., 127: 12528-12536 (2005)); and (iii) Covariance NMR spectroscopy (Bruschweiler, J. Chem. Phys., 121:409-414 (2004); Zhang et al., J. Am. Chem. Soc., 126:13180-13181 (2004); and Chen et al., J. Am. Chem. Soc., 128:15564-15565 (2006)). These publications are incorporated by reference herein in their entireties. 
     Thus, as used herein, the term nuclear magnetic resonance (NMR) encompasses a variety of methods including but not limited to, one-dimensional NMR (1D-NMR), two-dimensional NMR (2D-NMR), correlation spectroscopy NMR (COSY-NMR), total correlated spectroscopy NMR (TOCSY-NMR), heteronuclear single-quantum coherence NMR (HSQC-NMR), heteronuclear multiple quantum coherence (HMQC-NMR), rotational nuclear overhauser effect spectroscopy NMR (ROESY-NMR), nuclear overhauser effect spectroscopy (NOESY-NMR), transverse relaxation optimized spectroscopy (TROSY-NMR) and combinations thereof. For more description on TROSY-NMR see Pervushin, et al., “Attenuated T 2  relaxation by mutual cancellation of dipole-dipole coupling and chemical shift anisotropy indicates an avenue to NMR structures of very large biological macromolecules in solution” PNAS 94:12366-71 (1997), which is incorporated by reference herein in its entirety. 
     As used herein, the term “chemical shift,” in nuclear magnetic resonance (NMR) spectroscopy, refers to the resonant frequency of a nucleus relative to a standard or baseline. Some atomic nuclei possess a magnetic moment (nuclear spin), which gives rise to different energy levels and resonance frequencies in a magnetic field. The electron distribution of the same type of nucleus (e.g.  1 H,  13 C,  15 N) usually varies according to the local geometry and with it the local magnetic field at each nucleus. This is reflected in the spin energy levels (and resonance frequencies). The variation of nuclear magnetic resonance frequencies of the same kind of nucleus, due to variations in the electron distribution, is called the chemical shift. The size of the chemical shift is typically given with respect to a reference frequency or reference sample usually a molecule with a barely distorted electron distribution. Typically, a  1 H- 15 N HSQC spectrum is used to obtain chemical shift values. However, as provided in the methods herein, any NMR analysis method can be used. 
     As used herein, the term “chemical shift of an amino acid” includes the chemical shift of an element within the amino acid, e.g., H, C or N. As used herein, the term “element” refers to an atom distinguished by its atomic number, which is the number of protons in its nucleus. Exemplary elements include, but are not limited to, H (hydrogen), N (nitrogen) and C (carbon). 
     Exemplary chemical shift values for certain amino acids in the SENP1 polypeptide are shown in Table 3 and exemplary chemical shift values for certain amino acids in the SENP1 polypeptide when bound to SUMO are shown in Table 4. The sample conditions that correlate to the chemical shifts listed in Table 3 are 20 mM sodium phosphate, at pH 6.8 at 25° C. The sample conditions that correlate to the chemical shifts listed in Table 4 are 20 mM sodium phosphate and containing 150 mM NaCl, at pH 7, at 35° C. The values of the chemical shifts listed in Table 3 and Table 4 may vary by as much as 1 ppm for 41, and as much as 5 ppm for  15 N and  13 C due to differences in experimental conditions such as sample pH, temperature, addition of other components (e.g., salt), or amino acid substitutions in SENP1 and/or SUMO that may affect the function of SENP1 and/or SUMO. Thus, the chemical shifts listed in Tables 3 and 4 may vary from 1 ppm for  1 H and from 5 ppm for  15 N and  13 C. 
     Thus, the peaks or chemical shifts in Tables 3 and 4 can be used by those of skill in the art to determine whether a test compound binds SENP1 by correlating experimental peaks or chemical shifts to those provided in Tables 3 and 4. For example, the peaks or chemical shifts obtained by NMR in the presence of a test compound can be compared to the corresponding peaks or chemical shifts in Tables 3 or 4 to determine whether the test compound binds SENP1. Thus, the chemical shift for an amino acid of SENP1 in Table 3 or 4 can be compared to the corresponding chemical shift obtained for the same amino acid in SENP1 in the presence of a test compound. When performing such comparisons, one of skill in the art will account for variances known to affect chemical shift values due to changes in experimental conditions, e.g., pH, temperature, addition of other components (e.g., salt), or amino acid substitutions. In some embodiments, detection of a change of greater than 5 ppm in the chemical shift for  15 N or  13 C of an amino acid of SENP1 or greater than 1 ppm in the chemical shift for  1 H of an amino acid of SENP1 indicates non-correlation of peaks. Optionally, the change is as compared to the corresponding chemical shift value for  15 N,  13 C, or  1 H of an amino acid of SENP1 in Table 3 or Table 4. 
     As used herein, the binding of a compound to SENP1 may be selective. The terms “selectively binds,” “selectively binding,” or “specifically binding” refers to the compound binding SENP1 to the partial or complete exclusion of other agents or compounds. By binding is meant a detectable binding, for example, binding above the background of the assay method. Optionally, detectable binding is evidenced by comparing baseline to experimental values, e.g., by comparing baseline NMR data (e.g., chemical shift values or digital resolution spectra) to experimental NMR data (e.g., chemical shift values or digital resolution spectra). Thus, binding can be determined by detecting changes or perturbations in an NMR measurement or spectrum for one sample, e.g., a control sample, compared to another or second sample, e.g., a sample containing a test compound. Detectable changes or perturbations in NMR signals include changes in location (chemical shift). General NMR techniques for proteins, including multidimensional NMR experiments and determination of protein-ligand interactions can be found in David G. Reid (ed.), Protein NMR Techniques, Humana Press, Totowa N.J. (1997). By way of example, detection of a perturbation or change includes detection of a difference in the chemical shift of SENP1 or SENP1-SUMO complex in the presence of a compound as compared to the chemical shift in the absence of the compound. The perturbation or change (whether increased or decreased) can include significant differences in an NMR measurement or spectrum (e.g., chemical shift) and can be greater than the experimental error or greater than the error bar range. For example, a change of at least about 1.1 times of the digital resolution of a spectrum or chemical shift for one or more amino acid residues of SENP1 in the presence of a compound can indicate the compound binds SENP1. Thus, a change of at least about 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 20 times or more of the digital resolution of an NMR measurement or spectrum, e.g., chemical shift, observed in the presence of a compound as compared to a control can indicate the compound binds SENP1. 
     The terms greater, higher, increases, elevates, or elevation refer to increases above a control. The terms low, lower, reduces, or reduction refer to any decrease below control levels. For example, control levels are levels prior to, or in the absence of, addition of a compound. 
     A “control” sample or value refers to a sample that serves as a reference, usually a known reference, for comparison to a test sample. For example, a test sample can be taken from a test condition, e.g., in the presence of a test compound, and compared to samples from known conditions, e.g., in the absence of the test compound (negative control), or in the presence of a known compound (positive control). A control can also represent an average value gathered from a number of tests or results. One of skill in the art will recognize that controls can be designed for assessment of any number of parameters. For example, a control can be devised to compare therapeutic benefit based on pharmacological data (e.g., half-life) or therapeutic measures (e.g., comparison of side effects). One of skill in the art will understand which controls are valuable in a given situation and be able to analyze data based on comparisons to control values. Controls are also valuable for determining the significance of data. For example, if values for a given parameter are widely variant in controls, variation in test samples will not be considered as significant. 
     “Nucleic acid” refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form, and complements thereof. The term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs). 
     Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al.,  Nucleic Acid Res.  19:5081 (1991); Ohtsuka et al.,  J. Biol. Chem.  260:2605-2608 (1985); Rossolini et al.,  Mol. Cell. Probes  8:91-98 (1994)). The term nucleic acid is used interchangeably with gene, cDNA, mRNA, oligonucleotide, and polynucleotide. 
     “Percentage of sequence identity” is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity. 
     The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identity over a specified region, e.g., of the entire polypeptide sequences of the invention or individual domains of the polypeptides of the invention), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Such sequences are then said to be “substantially identical.” This definition also refers to the complement of a test sequence. Optionally, the identity exists over a region that is at least about 10 to about 100, about 20 to about 75, about 30 to about 50 amino acids or nucleotides in length. Optionally, the identity exists over a region that is at least about 50 amino acids in length, or more preferably over a region that is 100 to 500 or 1000 or more amino acids in length. The present invention includes polypeptides that are substantially identical to any of SEQ ID NOs:1, 2, 3, 4, 5, 6, or 7. 
     For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Preferably, default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. 
     A “comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith &amp; Waterman,  Adv. Appl. Math.  2:482 (1981), by the homology alignment algorithm of Needleman &amp; Wunsch,  J. Mol. Biol.  48:443 (1970), by the search for similarity method of Pearson &amp; Lipman,  Proc. Nat&#39;l. Acad. Sci. USA  85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection (see, e.g.,  Current Protocols in Molecular Biology  (Ausubel et al., eds. 1995 supplement)). 
     A preferred example of algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al.,  Nuc. Acids Res.  25:3389-3402 (1977) and Altschul et al.,  J. Mol. Biol.  215:403-410 (1990), respectively. BLAST and BLAST 2.0 are used, with the parameters described herein, to determine percent sequence identity for the nucleic acids and proteins. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information, as known in the art. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always &gt;0) and N (penalty score for mismatching residues; always &lt;0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, an expectation (E) of 10, M=5, N=−4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a wordlength of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff &amp; Henikoff,  Proc. Natl. Acad. Sci. USA  89:10915 (1989)) alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and a comparison of both strands. 
     The terms “polypeptide,” “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer. 
     The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. 
     Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes. 
     An amino acid residue in a polypeptide “corresponds” to or “is corresponding to” a given residue when it occupies the same essential structural position within the polypeptide as the given residue. For example, a selected residue in a comparison polypeptide corresponds to position 603 in a polypeptide provided herein (e.g., a SENP1 polypeptide), when the selected residue occupies the same essential spatial or structural relationship to position 603 as assessed using applicable methods in the art. For example, a comparison polypeptide may be aligned for maximum sequence homology with the polypeptide provided herein and the position in the aligned comparison polypeptide that aligns with position 603 may be determined to correspond to it. Alternatively, instead of (or in addition to) a primary sequence alignment as described above, a three dimensional structural alignment can also be used, e.g., where the structure of the comparison polypeptide is aligned for maximum correspondence with a polypeptide provided herein and the overall structures compared. In this case, an amino acid that occupies the same essential position as position 603 in the structural model may be said to correspond. 
     “Conservatively modified variants” applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are “silent variations,” which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence with respect to the expression product, but not with respect to actual probe sequences. 
     As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a “conservatively modified variant” where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles. 
     The following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, e.g., Creighton,  Proteins  (1984)). 
     The “active-site” of a protein or polypeptide refers to a protein domain that is structurally, functionally, or both structurally and functionally, active. For example, the active-site of a protein can be a site that catalyzes an enzymatic reaction, i.e., a catalytically active site. An active site refers to a domain that includes amino acid residues involved in binding of a substrate for the purpose of facilitating the enzymatic reaction. Optionally, the term active site refers to a protein domain that binds to another agent, molecule or polypeptide. For example, the active sites of SENP1 include sites on SENP1 that bind to or interact with SUMO. A protein may have one or more active-sites. 
     The phrase “stringent hybridization conditions” refers to conditions under which a probe will hybridize to its target subsequence, typically in a complex mixture of nucleic acids, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures. An extensive guide to the hybridization of nucleic acids is found in Tijssen,  Techniques in Biochemistry and Molecular Biology—Hybridization with Nucleic Probes , “Overview of principles of hybridization and the strategy of nucleic acid assays” (1993). Generally, stringent conditions are selected to be about 5-10° C. lower than the thermal melting point (T m ) for the specific sequence at a defined ionic strength pH. The T m  is the temperature (under defined ionic strength, pH, and nucleic concentration) at which 50% of the probes complementary to the target hybridize to the target sequence at equilibrium (as the target sequences are present in excess, at T m , 50% of the probes are occupied at equilibrium). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide. For selective or specific hybridization, a positive signal is at least two times background, preferably 10 times background hybridization. Exemplary stringent hybridization conditions can be as following: 50% formamide, 5×SSC, and 1% SDS, incubating at 42° C., or, 5×SSC, 1% SDS, incubating at 65° C., with wash in 0.2×SSC, and 0.1% SDS at 65° C. 
     Nucleic acids that do not hybridize to each other under stringent conditions are still substantially identical if the polypeptides which they encode are substantially identical. This occurs, for example, when a copy of a nucleic acid is created using the maximum codon degeneracy permitted by the genetic code. In such cases, the nucleic acids typically hybridize under moderately stringent hybridization conditions. Exemplary “moderately stringent hybridization conditions” include a hybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37° C., and a wash in 1×SSC at 45° C. A positive hybridization is at least twice background. Those of ordinary skill will readily recognize that alternative hybridization and wash conditions can be utilized to provide conditions of similar stringency. Additional guidelines for determining hybridization parameters are provided in numerous reference, e.g., and  Current Protocols in Molecular Biology , ed. Ausubel, et al., John Wiley &amp; Sons. 
     For PCR, a temperature of about 36° C. is typical for low stringency amplification, although annealing temperatures may vary between about 32° C. and 48° C. depending on primer length. For high stringency PCR amplification, a temperature of about 62° C. is typical, although high stringency annealing temperatures can range from about 50° C. to about 65° C., depending on the primer length and specificity. Typical cycle conditions for both high and low stringency amplifications include a denaturation phase of 90° C.-95° C. for 30 sec-2 min., an annealing phase lasting 30 sec.-2 min., and an extension phase of about 72° C. for 1-2 min. Protocols and guidelines for low and high stringency amplification reactions are provided, e.g., in Innis et al. (1990)  PCR Protocols, A Guide to Methods and Applications , Academic Press, Inc. N.Y.). 
     The term “pharmaceutically acceptable salts” or “pharmaceutically acceptable carrier” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present application contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present application contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al.,  Journal of Pharmaceutical Science  66:1-19 (1977)). Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for compositions of the present application. 
     A “label” or a “detectable moiety” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include  32 P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a fluorescent label into a peptide specifically reactive with a target peptide (e.g., SENP1 polypeptide, SUMO protein or test compound). In embodiments, the label is a fluorescent label. Any method known in the art for conjugating a polypeptide to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego. 
     A “labeled protein or polypeptide” is one that is bound, either covalently, through a linker or a chemical bond, or noncovalently, through ionic, van der Waals, electrostatic, or hydrogen bonds to a label such that the presence of the labeled protein or polypeptide may be detected by detecting the presence of the label bound to the labeled protein or polypeptide. 
     Methods 
     Provided herein are methods of detecting binding of an SENP1 polypeptide to a compound. The method includes the steps of contacting an SENP1 polypeptide with a compound, allowing the compound to bind to the SENP1 polypeptide, thereby forming a SENP1-compound complex, and detecting the SENP1-compound complex using nuclear magnetic resonance, thereby detecting binding of the SENP1 polypeptide to the compound. 
     A “compound” as provided herein refers to a polypeptide, protein, amino acid, small molecule or chemical compound that is capable of binding a SENP1 polypeptide or fragment thereof. In embodiments, the compound binds a SENP1 protein of SEQ ID NO:1, 2, 3, 4, 5, 6, or 7. In embodiments, the compound is a modulator of SENP1 activity. In embodiments, the compound is an inhibitor of SENP1 activity. In embodiments, the compound is an activator of SENP1 activity. In embodiments, the compound is a small molecule. A small molecule as provided herein include, but are not limited to the compounds in Tables 1 and 2 and those described in WO 2012/064887, which is incorporated by reference herein in its entirety. As used herein, the term “small molecule” refers to an organic compound containing carbon. A small molecule is generally, but not necessarily, of low molecular weight, e.g., less than 1000 Daltons. 
     A “test compound” as provided herein refers to a compound useful for the screening methods provided herein. A test compound may be capable of binding a SENP1 polypeptide or fragment thereof as provided herein. In embodiments, the test compound binds a SENP1 polypeptide or fragment thereof. In embodiments, the binding of the test compound to the SENP1 polypeptide or fragment thereof is detected by nuclear magnetic resonance. In embodiments, the test compound does not bind a SENP1 polypeptide or fragment thereof. 
     As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a compound or protein-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the protein (e.g. decreasing gene transcription or translation) relative to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition refers to reduction of a disease or symptoms of disease (e.g., cancer). In embodiments, inhibition refers to a reduction in the activity of an enzymatic activity (e.g., SENP activity). In embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g. cell cycle). Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating transcription, translation, signal transduction or enzymatic activity or the amount of a protein (e.g. a cellular protein or a viral protein). In embodiments, inhibition refers to inhibition of SENP1. 
     The terms “inhibitor,” “repressor” or “antagonist” or “downregulator” interchangeably refer to a substance that results in a detectably lower expression or activity level as compared to a control. The inhibited expression or activity can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or less than that in a control. In certain instances, the inhibition is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more in comparison to a control. An “inhibitor” is a siRNA, (e.g., shRNA, miRNA, snoRNA), compound or small molecule that inhibits cellular function (e.g., replication) e.g., by binding, partially or totally blocking stimulation, decrease, prevent, or delay activation, or inactivate, desensitize, or down-regulate signal transduction, gene expression or enzymatic activity necessary for protein activity. Inhibition as provided herein may also include decreasing or blocking a protein activity (e.g., activity of SENP1). 
     The terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. The agonist can increase expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist. 
     Optionally, the compound is a small molecule. Optionally, the step of detecting includes detecting a perturbation in the presence of the compound relative to the absence of the compound. For example, binding of a compound to SENP1 is detected if a perturbation is detected in an NMR measurement or spectrum in the presence of the compound as compared to or relative to the absence of the compound. Optionally, the step of detecting includes determining a chemical shift for an amino acid in an active site of the SENP1 polypeptide. Binding is detected by a change in the chemical shift in the presence of the compound relative to the corresponding chemical shift in the absence of the compound. Optionally, the active site is a catalytically active site. Optionally, the active site is a site involved in SUMO binding, e.g., the active site is a site on SENP1 that binds to the SUMO protein. Thus, the step of detecting includes determining a chemical shift for an amino acid involved in binding of SENP1 polypeptide to SUMO. Optionally, the chemical shift is determined for one or more amino acids of SEQ ID NOs:3, 4, 5, 6 or 7. 
     Optionally, the chemical shift is determined for one or more amino acid residues selected from the group consisting of D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596 of SEQ ID NO:1. 
     In embodiments, the change is a change in the chemical shift of amino acid residue D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 or Q596 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue D550 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue H533 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue C603 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue W465 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue W534 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue L466 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue G531 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue C535 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue M552 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue G554 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue E469 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of amino acid residue Q596 of SEQ ID NO:1. 
     In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 or Q596 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to D550 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to H533 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to C603 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to W465 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to W534 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to L466 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to G531 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to C535 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to M552 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to G554 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to E469 of SEQ ID NO:1. In embodiments, the change is a change in the chemical shift of an amino acid residue corresponding to Q596 of SEQ ID NO:1. 
     In embodiments, the SENP1 polypeptide includes amino acid residue 603 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 603 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes amino acid residue 550 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 550 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes amino acid residue 533 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 533 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes amino acid residue 465 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 465 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes amino acid residue 534 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 534 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes amino acid residue 466 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 466 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes amino acid residue 531 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 531 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes amino acid residue 535 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 535 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes amino acid residue 552 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 552 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes amino acid residue 554 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 554 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes amino acid residue 469 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 469 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes amino acid residue 596 of SEQ ID NO:1. In embodiments, the SENP1 polypeptide includes an amino acid residue corresponding to amino acid residue 596 of SEQ ID NO:1. 
     Optionally, the chemical shift is determined for a mutation at amino acid residue 603 of SEQ ID NO:1. Optionally, the mutation is C603S. Optionally, the chemical shift is determined for one or more amino acid residues 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. Optionally, the SENP1 polypeptide or SENP1-compound complex is bound to a SUMO protein thereby forming a SENP1-SUMO complex or SENP1-SUMO-compound complex. Optionally, the SUMO protein is a truncated SUMO protein. Optionally, the compound does not interact with C603 of SEQ ID NO:1 of SENP1, e.g., the compound does not covalently modify C603 of SENP1. Thus, the provided methods optionally include detecting binding by producing an NMR spectra of the SENP-1 compound complex and identifying a change in the NMR spectra relative to the absence of the compound. Optionally, the change is a change in the chemical shift of an amino acid of SEQ ID NOs:3, 4, 5, 6 or 7. Optionally, the change is a change in the chemical shift of an amino acid selected from the group consisting of D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596. Optionally, the change is a change in the chemical shift of the amino acid S603. Optionally, the change is a change in the chemical shift of an amino acid residue 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. 
     Also provided is a method of screening for compounds that bind SENP1 including the steps of providing a first sample comprising SENP1 or an SENP1-SUMO complex, determining an NMR spectra of the first sample, providing a second sample comprising an SENP1-compound complex or an SENP1-SUMO-compound complex, and determining an NMR spectra of the second sample. Detection of a change in the NMR spectra in the second sample as compared to the first sample indicates the compound binds SENP1. 
     Provided are methods of screening for an inhibitor of SENP1. The methods include contacting a composition comprising an SENP1 polypeptide with a test compound and detecting whether the test compound binds the SENP1 polypeptide or fragment thereof by nuclear magnetic resonance. 
     Optionally, the step of detecting includes detecting a perturbation in the presence of the compound relative to the absence of the compound. For example, the test compound binds or inhibits SENP1 if a perturbation is detected in an NMR measurement or spectrum in the presence of the compound as compared to or relative to the absence of the compound. Optionally, the step of detecting comprises determining a chemical shift for one or more amino acids in the active site of the SENP1 polypeptide. The chemical shift in the presence of the compound will be changed relative to the corresponding chemical shift in the absence of the test compound if the test compound binds to SENP1. Optionally, the active site is a catalytically active site. Optionally, the active site is a site involved in SUMO binding, e.g., the active site is a site on SENP1 that binds to the SUMO protein. Thus, the step of detecting includes determining a chemical shift for an amino acid involved in binding of SENP1 polypeptide to SUMO. Optionally, the chemical shift is determined for one or more amino acids of SEQ ID NOs:3, 4, 5, 6 OR 7. Optionally, the chemical shift is determined for one or more amino acid residues selected from the group consisting of D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596 of SEQ ID NO:1. Optionally, the chemical shift is determined for a mutation at amino acid residue 603 of SEQ ID NO:1. Optionally, the mutation is C603S. Optionally, the chemical shift is determined for one or more amino acid residues 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. Optionally, the SENP1 polypeptide is bound to a SUMO protein thereby forming a SENP1-SUMO complex. Optionally, the SUMO protein is a truncated SUMO protein. Optionally, the composition comprising the SENP1 polypeptide or SENP1-SUMO complex is an aqueous solution. Optionally, the composition is at a pH from about 6.0 to about 7.5. Optionally, the pH is about 6.8. Optionally, the composition comprises a buffering agent, a reducing agent, a base or combinations thereof. Optionally, the composition comprises sodium phosphate, D 2 O, sodium azide, dithiothreitol or combinations thereof. The sodium phosphate can be present at about 20 mM. Optionally, the compound to be tested is a small molecule. Optionally, the compound does not interact with C603 numbered relative to SEQ ID NO:1 of SENP1, e.g., the compound does not covalently modify C603 of SENP1. Optionally, in the provided methods, the SENP1 binds the compound forming an SENP1-compound complex and the detecting comprises producing an NMR spectra of the SENP1-compound complex and identifying a change in the NMR spectra relative to the absence of the compound. Optionally, the change is a change in the chemical shift of an amino acid of SEQ ID NOs:3, 4, 5, 6 or 7. Optionally, the change is a change in the chemical shift of an amino acid selected from the group consisting of D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596. Optionally, the change is a change in the chemical shift of the amino acid S603. Optionally, the change is a change in the chemical shift of an amino acid residue 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. Optionally, the change is a change in the chemical shift of an amino acid in the active site of SENP1. Optionally, the active site is a catalytically active site or a site that binds to the SUMO protein. 
     Also provided are methods of identifying an SENP1 inhibitor that include combining an SENP1 polypeptide, a SUMO protein, and a test compound in a reaction vessel, allowing the SENP1 polypeptide, SUMO protein and test compound to form a SENP1-SUMO-compound complex, and detecting the SENP1-SUMO-compound complex thereby identifying the compound as a SENP1 inhibitor. A “reaction vessel” as provided herein refers to a vial, tube, flask, bottle, syringe or other container means, into which the SENP1 polypeptide, SUMO protein and test compound are combined to allow the formation of a SENP1-SUMO-compound complex. 
     Optionally, one or more of the SENP1 polypeptide, SUMO protein or test compound is labeled. Optionally, the label is a fluorescent label. Optionally, the test compound comprises a fluorescent label. Optionally, the SUMO is a truncated SUMO protein. Optionally, the SUMO comprises amino acid residues 1-92 of the SUMO protein. Optionally, the SUMO protein comprises SEQ ID NO:8 or SEQ ID NO:9. Optionally, the SENP1 polypeptide comprises SEQ ID NOs:1, 2, 3, 4, 5, 6, or 7. Optionally, the SENP1 polypeptide comprises amino acid residue 603 of SEQ ID NO:1. Optionally, the SENP1 polypeptide comprises a mutation at amino acid residue 603 of SEQ ID NO:1. Optionally, the mutation is C603S. Optionally, the SENP1 polypeptide comprises amino acid residues 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. Optionally, the test compound is a small molecule. In the provided methods, the detecting can be performed by a variety of methods known to those skilled in the art and described in the example below. See, e.g., Protein-Ligand Interactions, Vol. 1008, Methods in Molecular Biology, Humana Press, Inc., Clifton, N.J., Williams and Daviter, Eds. (2013). For example, a wide variety of assays for detecting binding can be used including labeled in vitro protein-ligand binding assays, cell based assays, immunoassays, and the like. Optionally, detecting can be performed using solution-phase binding assays, e.g., fluorescent polarization. Thus, binding can be detected by fluorescent polarization (Rossi et al.,  Nat. Protoc.  6(3):365-87 (2011)). Optionally, binding is detected by detecting a change in the thermal properties of SENP1, e.g., the thermal property can be the melting temperature of SENP1. In some embodiments, the detecting is performed using nuclear magnetic resonance. Optionally, the detecting comprises producing an NMR spectra of the SENP1-SUMO-compound complex and identifying a change in the NMR spectra relative to the absence of the test compound. Optionally, the change is a change in the chemical shift of an amino acid in an active site of the SENP1 polypeptide. The active site can be, for example, a catalytically active site or a site that binds to the SUMO protein. Optionally, the amino acid is an amino acid of SEQ ID NOs:3, 4, 5, 6 OR 7. Optionally, the amino acid is selected from the group consisting of D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596. Optionally, the amino acid is S603. Optionally, the amino acid is amino acid residue 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. 
     As used throughout, the term “SENP1 polypeptide” refers to full length SENP1 and fragments thereof. The sequence and structure of the SENP1 polypeptide is known. (See above and Protein Data Bank (PDB) accession codes 2IYC and 2IY1; Shen et al., Nat. Struct. Mol. Biol. 13(12):1069-1077 (2006); and Xu et al.,  Biochem. J.  398(3):345-52 (2006)). Optionally, the SENP1 polypeptide comprises SEQ ID NOs:1, 2, 3, 4, 5, 6, or 7. Optionally, the SENP1 polypeptide comprises amino acid residue 603 of SEQ ID NO:1. Optionally, the SENP1 polypeptide comprises a mutation at amino acid residue 603 of SEQ ID NO:1. Optionally, the mutation is C603S. Optionally, the SENP1 polypeptide comprises amino acid residues 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. 
     Optionally, in the provided methods, SENP1 is bound to SUMO or a fragment thereof, e.g., a truncated SUMO protein. Thus, optionally, the SENP1 is bound to a SUMO protein thereby forming a SENP1-SUMO complex. Optionally, the SUMO protein is a truncated SUMO protein. Optionally, the SUMO protein is SEQ ID NO:8 or 9. As used herein, the term “truncated SUMO protein” refers to a SUMO protein or polypeptide that has been manipulated to remove at least one amino acid residue relative to wild-type SUMO, e.g., a SUMO protein or polypeptide that occurs in nature. Exemplary wild-type SUMO proteins include, but are not limited to, SEQ ID NO:9 and those found at GenBank Accession Nos. AAC50996.1, NP_008868.3, NP_001005849.1, P55854.2, and NP_008867.2. Truncated SUMO proteins include, but are not limited to, SEQ ID NO:8. As used herein, the term “SUMO” refers to SUMO1, SUMO2, or SUMO3 or fragments thereof or complexes thereof, e.g., SUMO2/3. The nucleic acid and amino acid sequences for SUMO are known. See, for example, Hay, Mol. Cell 18(1):1-12 (2005); and Yeh, et al., J. Biol. Chem., 284(13):8223-7 (2009). For example, nucleic acid and amino acid sequences for SUMO-1 can be found at GenBank Accession Nos. U67122.1 and AAC50996.1. Nucleic acid and amino acid sequences for SUMO-2 can be found at GenBank Accession Nos. NM_006937.3, NM_001005849.1, NP_008868.3 and NP_001005849.1. Nucleic acid and amino acid sequences for SUMO-3 can be found at GenBank Accession Nos. NM_006936.2, P55854.2, and NP_008867.2. Optionally, the SENP1 is bound to SUMO1 to form an SENP1-SUMO1 complex. 
     The provided SENP1 polypeptides and/or SUMO polypeptides and fragments thereof may contain one or more modifications, e.g., a conservative modification. As used herein, the term “modification” refers to a modification in a nucleic acid sequence of a gene or an amino acid sequence. Modifications include, but are not limited to, insertions, substitutions and deletions. Amino acid sequence modifications typically fall into one or more of three classes: substitutional, insertional, or deletional modifications. Insertions include amino and/or terminal fusions as well as intrasequence insertions of single or multiple amino acid residues. Insertions ordinarily will be smaller insertions than those of amino or carboxyl terminal fusions, for example, on the order of one to four residues. Deletions are characterized by the removal of one or more amino acid residues from the protein sequence. Amino acid substitutions are typically of single residues, but can occur at a number of different locations at once. Substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final construct. Substitutional modifications are those in which at least one residue has been removed and a different residue inserted in its place. 
     Modifications are generated using any number of methods known in the art. For example, site directed mutagenesis can be used to modify a nucleic acid sequence. One of the most common methods of site-directed mutagenesis is oligonucleotide-directed mutagenesis. In oligonucleotide-directed mutagenesis, an oligonucleotide encoding the desired change(s) in sequence is annealed to one strand of the DNA of interest and serves as a primer for initiation of DNA synthesis. In this manner, the oligonucleotide containing the sequence change is incorporated into the newly synthesized strand. See, for example, Kunkel, 1985, Proc. Natl. Acad. Sci. USA, 82:488; Kunkel et al., 1987, Meth. Enzymol., 154:367; Lewis &amp; Thompson, 1990, Nucl. Acids Res., 18:3439; Bohnsack, 1996, Meth. Mol. Biol., 57:1; Deng &amp; Nickoloff, 1992, Anal. Biochem., 200:81; and Shimada, 1996, Meth. Mol. Biol., 57:157. Other methods are routinely used in the art to introduce a modification into a sequence. For example, modified nucleic acids are generated using PCR or chemical synthesis, or polypeptides having the desired change in amino acid sequence can be chemically synthesized. See, for example, Bang &amp; Kent, 2005, Proc. Natl. Acad. Sci. USA, 102:5014-9 and references therein. 
     Also provided herein are nucleic acids encoding the polypeptides described throughout. It is understood that the nucleic acids that can encode those peptide, polypeptide, or protein sequences, variants and fragments thereof are also disclosed. This would include all degenerate sequences related to a specific polypeptide sequence, i.e. all nucleic acids having a sequence that encodes one particular polypeptide sequence as well as all nucleic acids, including degenerate nucleic acids, encoding the disclosed variants and derivatives of the polypeptide sequences. Thus, while each particular nucleic acid sequence may not be written out herein, it is understood that each and every sequence is in fact disclosed and described herein through the disclosed polypeptide sequence. 
     Provided herein are compounds to be tested for their ability to bind and/or inhibit SENP1. As used herein, an inhibitor refers to an agent or compound that inhibits SENP1 directly or indirectly. For example, an inhibitor of SENP1 can inhibit the expression or activity of SENP1. Compounds to be tested in the provided methods include, but are not limited to, small molecules, peptides, nucleic acids and antibodies. Optionally, the compound to be tested is a small molecule. Optionally, the small molecule is an inhibitor of SENP1. Small molecule inhibitors of SENP1 include, but are not limited to the compounds in Tables 1 and 2 and those described in WO 2012/064887, which is incorporated by reference herein in its entirety. As used herein, the term “small molecule” refers to an organic compound containing carbon. A small molecule is generally, but not necessarily, of low molecular weight, e.g., less than 1000 Daltons. 
     Once a compound has been identified as binding to SENP1 and/or inhibiting SENP1, the compound can be further tested for its binding and/or inhibitory abilities using a variety of known methods including the methods described in the example below. Various assays for determining levels and activities of protein are available, such as amplification/expression methods, immunohistochemistry methods, FISH and shed antigen assays, southern blotting, or PCR techniques. Moreover, the protein expression or amplification may be evaluated using in vivo diagnostic assays. 
     Compositions and Apparatuses for NMR Analysis 
     Provided herein are compositions comprising a SENP1 polypeptide and NMR apparatuses comprising the compositions for NMR analysis. Optionally, the composition is an aqueous solution. Optionally, the aqueous solution comprises an SENP1 polypeptide at a pH from about 6.0 to about 7.5. For example, the pH can be about 6.8. The provided compositions or aqueous solutions can further include, for example, buffering agents, reducing agents, solvents, bases and combinations thereof. Buffering agents include, but are not limited to, phosphate or citrate buffers. Reducing agents include but are not limited to, dithiothreitol, and sodium borohydride. Bases include, but are not limited to, metal oxides and salts of carbanions, amides and hydrides. Solvents include, but are not limited to, dimethyl sulfoxide (DMSO) Optionally, the compositions can include sodium phosphate, DMSO, D 2 O, sodium azide, dithiothreitol or combinations thereof. By way of example, the sodium phosphate can be present at about 20 mM. Optionally, the SENP1 polypeptide is bound to a SUMO protein thereby forming a SENP1-SUMO complex. Optionally, the SENP1 polypeptide is bound to a compound thereby forming a SENP1-compound complex. Optionally, the SENP1 polypeptide is bound to a SUMO protein thereby forming a SENP1-SUMO-compound complex. Optionally, the SUMO protein is a truncated SUMO protein. Optionally, the SENP1 polypeptide comprises SEQ ID NO:1, 2, 3, 4, 5, 6, or 7. Optionally, the SENP1 polypeptide comprises amino acid residues 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 numbered relative to SEQ ID NO:1. 
     An NMR apparatus comprising an NMR sample container for NMR analysis, said NMR sample container comprising the aqueous composition or solution is also provided. NMR apparatuses are known and can be obtained from commercially available sources. Makers of NMR equipment include, but are not limited to, Bruker (Germany), Oxford Instruments (United Kingdom), General Electric (Fairfield, Conn.), Philips (Amsterdam, Netherlands), Siemens AG (Munich, Germany) and Agilent Technologies, Inc. (Santa Clara, Calif.). 
     Compositions 
     Provided herein are compositions including the inhibitors identified by the screening and binding methods provided herein. The compositions are, optionally, suitable for formulation and administration in vitro or in vivo. Optionally, the compositions comprise one or more of the provided agents and a pharmaceutically acceptable carrier. Suitable carriers and their formulations are described in  Remington: The Science and Practice of Pharmacy,  21 st  Edition, David B. Troy, ed., Lippicott Williams &amp; Wilkins (2005). By pharmaceutically acceptable carrier is meant a material that is not biologically or otherwise undesirable, i.e., the material is administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained. If administered to a subject, the carrier is optionally selected to minimize degradation of the active ingredient and to minimize adverse side effects in the subject. 
     The inhibitors are administered in accord with known methods, such as intravenous administration, e.g., as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, intratumoral or inhalation routes. The administration may be local or systemic. The compositions can be administered via any of several routes of administration, including topically, orally, parenterally, intravenously, intra-articularly, intraperitoneally, intramuscularly, subcutaneously, intracavity, transdermally, intrahepatically, intracranially, nebulization/inhalation, or by installation via bronchoscopy. Thus, the compositions are administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. 
     The compositions for administration will commonly comprise an agent as described herein (e.g. inhibitor of SENP1) dissolved in a pharmaceutically acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers can be used, e.g., buffered saline and the like. These solutions are sterile and generally free of undesirable matter. These compositions may be sterilized by conventional, well known sterilization techniques. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of active agent in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the subject&#39;s needs. 
     Pharmaceutical formulations, particularly, of the modified viruses can be prepared by mixing the modified adenovirus (or one or more nucleic acids encoding the modified adenovirus) having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers. Such formulations can be lyophilized formulations or aqueous solutions. 
     Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients or stabilizers can be acetate, phosphate, citrate, and other organic acids; antioxidants (e.g., ascorbic acid) preservatives low molecular weight polypeptides; proteins, such as serum albumin or gelatin, or hydrophilic polymers such as polyvinylpyllolidone; and amino acids, monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents; and ionic and non-ionic surfactants (e.g., polysorbate); salt-forming counter-ions such as sodium; metal complexes (e. g. Zn-protein complexes); and/or non-ionic surfactants. The modified adenovirus (or one or more nucleic acids encoding the modified adenovirus) can be formulated at any appropriate concentration of infectious units. 
     Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the modified adenovirus suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions. Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art. 
     The inhibitors of SENP1 can be made into aerosol formulations (i.e., they can be “nebulized”) to be administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. 
     Formulations suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the provided methods, compositions can be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intravesically intratumorally, or intrathecally. Parenteral administration, intratumoral administration, and intravenous administration are the preferred methods of administration. The formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials. 
     Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. Cells transduced or infected by adenovirus or transfected with nucleic acids for ex vivo therapy can also be administered intravenously or parenterally as described above. 
     The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. Thus, the pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration. For example, unit dosage forms suitable for oral administration include, but are not limited to, powder, tablets, pills, capsules and lozenges. 
     Methods of Treatment 
     The provided inhibitors of SENP1 can be administered for therapeutic or prophylactic treatments or used in the laboratory. Thus, provided is a method of treating a proliferative disorder in a subject. The method includes administering the provided inhibitors of SENP1 or compositions to the subject. As described throughout, the pharmaceutical composition is administered in any number of ways including, but not limited to, intravenously, intravascularly, intrathecally, intramuscularly, subcutaneously, intraperitoneally, or orally. Optionally, the method further comprising administering to the subject one or more additional therapeutic agents. Optionally, the therapeutic agent is a chemotherapeutic agent. 
     As described throughout, the proliferative disorder can be cancer. Optionally, the proliferative disorder is selected from the group consisting of lung cancer, prostate cancer, colorectal cancer, breast cancer, thyroid cancer, renal cancer, liver cancer and leukemia. Optionally, the proliferative disorder is metastatic. 
     In therapeutic applications, compositions are administered to a subject suffering from a proliferative disease or disorder (e.g., cancer) in a “therapeutically effective dose.” Amounts effective for this use will depend upon the severity of the disease and the general state of the patient&#39;s health. Single or multiple administrations of the compositions may be administered depending on the dosage and frequency as required and tolerated by the patient. A “patient” or “subject” includes both humans and other animals, particularly mammals. Thus the methods are applicable to both human therapy and veterinary applications. 
     Optionally, the provided methods include administering to the subject one or more additional therapeutic agents. Thus, the provided methods can be combined with other cancer therapies, radiation therapy, hormone therapy, or chemotherapy. The combined administrations contemplates coadministration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities. Combinations of agents or compositions can be administered either concomitantly (e.g., as a mixture), separately but simultaneously (e.g., via separate intravenous lines) or sequentially (e.g., one agent is administered first followed by administration of the second agent). Thus, the term combination is used to refer to concomitant, simultaneous or sequential administration of two or more agents or compositions. 
     According to the methods provided herein, the subject is administered an effective amount of one or more of the agents provided herein. The terms effective amount and effective dosage are used interchangeably. The term effective amount is defined as any amount necessary to produce a desired physiologic response (e.g., killing of a cancer cell). The dosages, however, may be varied depending upon the requirements of the subject, the severity of the condition being treated, and the compound being employed. For example, dosages can be empirically determined considering the type and stage of cancer diagnosed in a particular subject. The dose administered to a subject, in the context of the provided methods should be sufficient to affect a beneficial therapeutic response in the patient over time. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Thus, effective amounts and schedules for administering the agent may be determined empirically by one skilled in the art. The dosage ranges for administration are those large enough to produce the desired effect in which one or more symptoms of the disease or disorder are affected (e.g., reduced or delayed). The dosage should not be so large as to cause substantial adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex, type of disease, the extent of the disease or disorder, route of administration, or whether other drugs are included in the regimen, and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosages can vary and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. 
     As used herein the terms treatment, treat, or treating refers to a method of reducing the effects of one or more symptoms of a disease or condition characterized by expression of the protease or symptom of the disease or condition characterized by expression of the protease. Thus in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. Further, as used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination. 
     Kits 
     Provided herein are kits for screening for compounds that bind or inhibit SENP1. The kits include a composition comprising an SENP1 polypeptide. Optionally, the composition is an aqueous solution. Optionally, the SENP1 polypeptide comprises SEQ ID NO:1, 2, 3, 4, 5, 6, or 7. Optionally, the SENP1 polypeptide comprises amino acid residues 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 numbered relative to SEQ ID NO:1. Optionally, the aqueous composition comprising an SENP1 polypeptide is at a pH from about 6.0 to about 7.5. Optionally, the pH is about 6.8. Optionally, the compositions can further include, for example, buffering agents, reducing agents, bases and combinations thereof. Optionally, the compositions can include sodium phosphate, D 2 O, sodium azide, dithiothreitol or combinations thereof. By way of example, the sodium phosphate can be present at about 20 mM. Optionally, the SENP1 polypeptide is bound to a SUMO protein thereby forming a SENP1-SUMO complex. Optionally, the SENP1 polypeptide or SENP1-SUMO complex is bound to a compound thereby forming a SENP1-compound complex or SENP1-SUMO-compound complex. Optionally, the SUMO protein is a truncated SUMO protein. In some embodiments, the kit comprises a container including a SENP1 polypeptide or SENP1-SUMO complex and, optionally, a second container including a SENP1-compound complex or SENP-SUMO-compound complex. 
     Further provided are kits including an inhibitor of SENP1. Optionally, the kit comprises one or more doses of an effective amount of a composition comprising a SENP1 inhibitor. Optionally, the composition is present in a container (e.g., vial or packet). Optionally, the kit further includes one or more additional therapeutic agents. Optionally, the therapeutic agent is a chemotherapeutic agent. Optionally, the kit comprises a means of administering the composition, such as, for example, a syringe, needle, tubing, catheter, patch, and the like. The kit may also comprise formulations and/or materials requiring sterilization and/or dilution prior to use. 
     Disclosed are materials, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed. 
     Publications cited herein and the material for which they are cited are hereby specifically incorporated by reference in their entireties. 
     A number of embodiments have been described. Nevertheless, it will be understood that various modifications may be made. Accordingly, other embodiments are within the scope of the claims. 
     EXAMPLE 
     Example 1. Identification and Characterization of a SENP Inhibitors 
     Enzymes called SENPs catalyze both the maturation of small ubiquitin-like modifier (SUMO) precursors and removal of SUMO modifications, which regulate essential cellular functions such as cell cycle progression, DNA damage response and intracellular trafficking. Some members, such as SENP1, are potential targets for developing cancer therapeutics. A search for small molecule inhibitors of SENPs was carried out using in-silico screening in conjunction with biochemical assays, and a new chemotype of small molecule inhibitors that non-covalently inhibit SENPs was identified. The inhibitors confer the non-competitive inhibitory mechanism, as shown by nuclear magnetic resonance (NMR) and quantitative enzyme kinetic analysis. The NMR data also provided evidence for substrate-assisted inhibitor binding, which indicates the need for caution in using artificial substrates for compound screening, as the inhibitory effects could be significantly different from using the physiological substrates. 
     In this study, it was purported to identify small molecule inhibitors of SENPs through in-silico screening in conjunction with enzyme kinetic, nuclear magnetic resonance (NMR) and cellular analyses. In silico screening was performed using Protein Data Bank (PDB) accession codes 2IYC and 2IY1 and by considering hydrogen bonding and hydrophobic interactions between the C-terminus of full-length SUMO-1 and SENP1. The GLIDE program (Friesner et al.,  Journal of Medicinal Chemistry  47:1739-1749 (2004)) was used to search the 250,000 compound library provided by the Developmental Therapeutics Program (DTP) of the National Cancer Institute, using the E-model scoring function of Cvdw, which is the sum of the van der Waals (Evdw) and electrostatic interaction energy terms (Eelec). Among the top hits, the dominant scaffolds were peptidomimetics and compounds that contained 2-fold symmetry. Forty compounds (100 μM) representing the dominant scaffolds were tested for their inhibitory effects on SENP1 and SENP2 for maturation of SUMO-1 and SUMO-2 precursors. The most potent compounds contained sulfonyl-benzene groups. Additional analogues of this group were obtained from DTP, and NSC5068, hereafter referred to as SPI-01 (SUMO protease inhibitor), was found to have the highest potency (Table 1). Available analogs of SPI-01 were obtained from DTP. Five compounds in this group (Table 1, SPI-06 to SPI-10) are “half” of the other compounds (Table 1, SPI-01 to SPI-05) and allowed the exploration of the activity requirements of the two-fold symmetric structure of SPI-01 to SPI-05. The inhibitory activity of these compounds on SENP1 and SENP2 was characterized using substrates that contained precursor SUMO-1 or SUMO-2 (S) flanked by yellow fluorescent protein (Y) at the N-terminus and enhanced cyan fluorescent protein (E) at the C-terminus (YSE) (Tatham and Hay,  Methods Mol. Biol.  497:253-268 (2009)). Although the cleavage of the substrates can be detected by fluorescence resonance energy transfer (FRET), FRET could not be used because many of these compounds interfere with the FRET signal. Therefore, a gel-based assay was used to determine the inhibitory effects of all compounds on SENP1 and 2 (representative data shown in  FIGS. 1 and 2 ), and the gel bands were quantified to determine the half maximum inhibitory concentrations (IC 50 ) (Table 1). The inhibitory effects of the compounds on the endopeptidase activities were not only enzyme-dependent, but also substrate-dependent. For SENP1-mediated cleavage of SUMO-1 precursor, only four of the compounds (SPI-01 to SPI-04) had half maximal inhibitory concentrations (IC 50 ) below 60 μM. The inhibitors were more potent for inhibiting SENP2 than SENP1 for cleavage of the SUMO-1 precursor. However, for cleavage of the SUMO-2 precursor, some compounds (i.e. SPI-01 and SPI-04) had similar potency for inhibiting SENP1 and SENP2, while others (i.e. SPI-07 and SPI-10) were more potent for inhibiting SENP1 than SENP2 or vice versa (i.e. SPI-06 and SPI-09) (Table 1). In addition to the differential effects on SENP1 and SENP2, SPI-01 had more than 10 fold less potency for inhibiting a de-ubiquitin enzyme isopeptidase T than inhibiting SENP2. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Effect of inhibitors on inhibition of the maturation of SUMO precursors by SENP1 and SENP2. 
               
            
           
           
               
               
               
            
               
                 Compounds 
                 IC 50  (μM)-SUMO1 
                 IC 50  (μM)-SUMO2 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Structure 
                 Code †   
                 NCI ID ‡   
                 SENP1 
                 SENP2 
                 SENP1 
                 SENP2 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-01 
                 NSC5068 
                 32.8 ± 1.82 
                 1.42 ± 3.0 
                 1.88 ± 2.2 
                 1.1 ± 5.8 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-02 
                 NSC16224 
                 26.5 ± 1.86 
                 3.42 ± 1.6 
                 2.08 ± 2.0 
                 2.70 ± 2.1 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-03 
                 NSC8676 
                 20.27 ± 2.47 
                 5.17 ± 1.32 
                 1.86 ± 2.3 
                 3.0 ± 2.0 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-04 
                 NSC34933 
                 11.2 ± 1.7 
                 1.6 ± 2.5 
                 2.32 ± 2.6 
                 2.15 ± 2.28 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-05 
                 NSC5067 
                 &gt;60 
                 19.7 ± 1.47 
                 7.5 ± 1.6 
                 4.6 ± 1.65 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-06 
                 NSC70551 
                 &gt;60 
                 3.62 ± 1.98 
                 4.32 ± 2.2 
                 10.7 ± 1.6 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-07 
                 NSC58046 
                 &gt;60 
                 &gt;60 
                 17.54 ± 4.9 
                 28.06 ± 9.2 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-08 
                 NSC22940 
                 &gt;60 
                 4.1 ± 3.0 
                 &gt;60 
                 41.06 ± 5.2 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-09 
                 NSC42164 
                 &gt;60 
                 23.6 ± 1.6 
                 &gt;60 
                 26.6 ± 2.5 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-10 
                 NSC45551 
                 &gt;60 
                 34.21 ± 1.9 
                 11.1 ± 3.7 
                 36.44 ± 5.7 
               
               
                   
               
               
                   † Designation for our library of SUMO-protease inhibitors (SPI) 
               
               
                   ‡ Designated by the National Cancer Institute 
               
            
           
         
       
     
     To determine whether other SENPs can be inhibited by this family of inhibitors, a distant SENP member, SENP7, was tested in parallel with SENP1 and SENP2 using a pentapeptide substrate that contained the Gly-Gly motif and luciferin, known as DUB-Glo (Promega, Madison, Wis.). Cleavage of luciferin by a SENP can be detected by a coupled bioluminescent assay using luciferase. The bioluminescent reporter was chosen instead of a fluorescent reporter to avoid interference by the compounds during detection. In addition, because SENP7 has different physiological substrates than SENP1 and SENP2 (Kolli et al.,  Biochemical Journal  430:335-344 (2010); and Shen et al.,  EMBO Rep.  13(4):339-46 (2012)), an advantage of DUB-Glo is that it can act as a common substrate for all SENPs, which enabled us to rule out substrate-specific effects. The dose-dependent inhibition of each SENP by the inhibitors was determined ( FIGS. 3A-3C ), as was the IC 50  for inhibition of SENP1, 2 and 7 of all the compounds (Table 2). Most compounds had more similar inhibitory effects on SENP1 and SENP2 than on SENP7, consistent with their amino acid sequence similarities. In addition, the compounds were more potent for inhibiting SENP1 when DUB-Glo was used as a substrate than when SUMO-1 precursor was used (Tables 1 and 2). To rule out the possibility that these compounds used a promiscuous mechanism, the compounds were also tested in SUMOylation and ubiquitination reactions, which also depend on enzymes containing catalytic Cys residues. The compounds were noninhibitory in these assays. Furthermore, comparison of the DUB-Glo and the SUMO maturation assays revealed that the effect of SENP inhibitors could be highly substrate-specific. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Inhibitory effect on SENP enzymatic activity using a bioluminescent peptide substrate 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                 SENP1 
                 SENP2 
                 SENP7 
               
               
                 Structure 
                 Code †   
                 NCI ID ‡   
                 IC 50  (μM) 
                 IC 50  (μM) 
                 IC 50  (μM) 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-01 
                 NSC5068 
                 5.9 ± 1.4 
                 2.9 ± 1.6 
                 3.5 ± 1.5  
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-02 
                 NSC 16224 
                 2.1 ± 1.9 
                 2.0 ± 2.0 
                 2.7 ± 1.8 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-03 
                 NSC 8676 
                 3.8 ± 1.5 
                 2.4 ± 1.8  
                 4.8 ± 1.4  
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-04 
                 NSC 34933 
                 2.4 ± 1.8  
                 2.3 ± 1.8 
                 3.4 ± 1.5 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-05 
                 NSC 5067 
                 13.3 ± 1.3  
                 8.5 ± 1.3  
                 4.6 ± 1.5 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-06 
                 NSC 70551 
                 3.9 ± 1.4 
                 3.7 ± 1.4 
                 4.7 ± 1.7 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-07 
                 NSC 58046 
                 &gt;&gt;60  
                 &gt;&gt;60 
                 1.9 ± 2.2 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-08 
                 NSC 22940 
                 22.2 ± 1.5  
                 17.2 ± 1.5  
                 2.8 ± 1.6 
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-09  
                 NSC 42164 
                 &gt;60  
                 6.8 ± 1.3 
                 1.9 ± 2.1  
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 SPI-10 
                 NSC 45551 
                 2.4 ± 1.8 
                 2.5 ± 1.7 
                 2.0 ± 2.0 
               
               
                   
               
               
                   † Designation for our library of SUMO-protease inhibitors (SPI) 
               
               
                   ‡ Designated by the National Cancer Institute 
               
            
           
         
       
     
     The abilities of representative inhibitors were then tested to inhibit SENP in cells. HeLa cells were treated with increasing concentrations of SPI-01 for 48 hours, after which SUMOylated proteins were detected in the cells by Western blots. SUMO-2/3 conjugates accumulated in cells and this accumulation correlated with inhibitor concentration, particularly at high molecular weights ( FIG. 4 ). This result suggests that SPI-01 inhibits the isopeptidase activities of SENPs, particularly SENP6 and SENP7, which are required for SUMO chain editing. It was observed that less significant effects on the accumulation of SUMO-1 conjugates, possibly because most SENPs cleave SUMO-2/3-conjugates. It is known that heat shock triggers a dramatic increase in global SUMO-2/3 conjugations and that during recovery, the SUMOylated proteins are removed, at least in part, due to the deSUMOylation activity of SENP1 (Nefkens et al.,  J. Cell Sci.  116:513-524 (2003)). To further confirm that the inhibitors inhibited deSUMOylase activities, HeLa cells were treated with SPI-01 and SPI-02 for 2 hours at 37° C. Then, SPI-treated or untreated control HeLa cells was transferred to 42° C. for 30 minutes, followed by recovery for 4 hours at 37° C. before processing for detection of global SUMO-2/3 levels. The inhibitor-treated cells had considerably higher levels of SUMOylated proteins than did the corresponding controls that did not receive heat shock or the mock-treated cells after the recovery period ( FIG. 5 ). Thus, the results of the heat-shock experiments further confirmed that the SPI compounds had inhibitory effects on SENPs in cells. 
     NMR chemical shift perturbation (CSP) analysis was used to investigate whether this family of inhibitors binds the enzyme or the enzyme-substrate complex. CSP experiments were conducted using a  15 N-labeled C603 S mutant of the human SENP1 catalytic domain (SENP1-C603S, for which NMR chemical shift assignments have been obtained and deposited in the Biological Magnetic Resonance Bank (BMRB) with accession number 19083). Although the SENP1-C603S mutant is catalytically inactive (Xu et al.,  Biochem. J.  398:345-52 (2006)), it retains binding activity for the precursor or mature SUMO paralogs or SUMOylated substrates (Shen et al.,  Nat. Struct. Mol. Biol.  13:1069-1077 (2006)). It was observed that SPI-01 caused modest backbone amide CSP for a subset of SENP1-C603S residues. Of note, specific CSPs were observed at the canonical cysteine-protease catalytic triad residues (D550, H533, and C603), the proposed dynamic channel of conserved W465 and W534, and at several other residues located at or adjacent to the SENP catalytic center (W465, L466, G531, H533, W534, C535, M552, G554 and Q596) with only one residue located distal to this surface (E469) ( FIG. 2 ). Interestingly, M552, G554, and Q596 are clustered at the SENP1 surface that contacts the C-terminal tail of SUMO-1. Supporting the importance of this surface in SENP catalytic activity, non-conservative point mutations of Q596 in SENP1 or the equivalent residue to SENP1 M552 in SENP2 (M497) perturb SUMO processing and deconjugation (Reverter and Lima,  Nat. Struct. Mol. Biol.  13; 1060-8 (2006); and Shen et al.,  Biochem. J.  397:279-288 (2006)). Residue E469 is positioned toward the binding surface for the structured region of SUMO-1, and its CSP may be due to an alternative interaction with the compound or long-range effects. These results indicate that SPI-01 binds the surface adjacent to the catalytic center that contacts the C-terminal portion of the SUMO precursors. The residues that showed CSP are highly conserved between SENP1 and SENP2, suggesting that SPI-01 can interact with the equivalent surface on SENP2. 
     The binding of SPI-01 to the enzyme-substrate complex was investigated. CSP analysis was carried out on the 40 kDa complex of  15 N-labeled full length precursor SUMO-1-GGHSTV (SUMO-1-FL) with unlabeled SENP1-C603S. An equimolar amount of SPI-01 was added to the 1:1 enzyme-substrate complex. The only observed CSP on the  15 N-labeled precursor SUMO-1-FL was on the C-terminal residues S99 and V101 ( FIGS. 7 and 8 ) (Song et al.,  PNAS  101:14373-8 (2004)). This result indicates that SPI-01 binds the enzyme-substrate complex at the interface between SENP and the C-terminal tails of precursor SUMO-FL. X-ray crystal structures showed that the C-terminal tail of precursor SUMO sits in and projects out of the catalytic tunnel of SENPs (Shen et al.,  Nat. Struct. Mol. Biol.  13:1069-77 (2006)). In the case of SENP1, the region that interacts with the projected C-terminus is predominantly acidic and favors the C-terminus of SUMO-1, which is polar and positively charged, over that of SUMO-2, whose C-terminus is mainly hydrophobic (Shen et al.,  Nat. Struct. Mol. Biol.  13:1069-77 (2006); and Shen et al.,  The Biochemical Journal  397:279-88 (2006)). In addition, the more hydrophobic C-terminus of SUMO-2 may favor binding of aromatic inhibitors. These properties may account for the more potent inhibition of processing of the SUMO-2 precursor (Table 1). 
     To further investigate the inhibitory mechanism, enzyme kinetic experiments were conducted using the pentapeptide substrate DUB-Glo ( FIG. 9 ). The data was fit to a mixed inhibition mechanism, as described by the kinetic equation: 
     
       
         
           
             v 
             = 
             
               
                 
                   V 
                   max 
                 
                 ⁡ 
                 
                   [ 
                   S 
                   ] 
                 
               
               
                 
                   ( 
                   
                     1 
                     + 
                     
                       
                         [ 
                         I 
                         ] 
                       
                       
                         α 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         
                           K 
                           i 
                         
                       
                     
                   
                   ) 
                 
                 [ 
                 
                   
                     
                       
                         K 
                         m 
                       
                       ( 
                       
                         1 
                         + 
                         
                           
                             [ 
                             I 
                             ] 
                           
                           
                             K 
                             i 
                           
                         
                       
                       ) 
                     
                     
                       1 
                       + 
                       
                         
                           [ 
                           I 
                           ] 
                         
                         
                           α 
                           ⁢ 
                           
                               
                           
                           ⁢ 
                           
                             K 
                             i 
                           
                         
                       
                     
                   
                   + 
                   
                     [ 
                     S 
                     ] 
                   
                 
                 ] 
               
             
           
         
       
     
     in which the value of “α” indicates the mechanism of inhibition (Segel,  Enzyme Kinetics  John Wiley &amp; Sons (1993)). For both SENP1 and SENP2, the “α” values indicated that the inhibitory mechanism is mainly noncompetitive and suggests that the inhibitor binds to the enzyme and the enzyme-substrate complex to inhibit chemical conversion. This finding is consistent with the NMR binding analysis indicating that the inhibitor binds both the enzyme and the enzyme-substrate complex as discussed above. 
     In conclusion, this study has identified SENP inhibitors that do not covalently modify the catalytic Cys residue. This study has also provided the first mechanistic insights into how a small molecule inhibitor of SENPs that does not covalently modify the catalytic Cys can inhibit the enzymes. The substrate-assisted inhibitor binding indicates the need for caution in designing high throughput screening assays that use fluorogenic or chemiluminescent artificial substrates, as the results could be significantly different from using the physiological substrates. The substrate-dependent inhibitory effect suggests the possibility of designing SENP inhibitors that are tuned for substrate-specificity. 
     Materials and Methods 
     Protein Purification. The catalytic domains of SENP1, 2, and 7 were expressed as His-tagged protein in  E. coli  (DE3) and purified using nickel affinity chromatography (Namanja et al.,  The Journal of Biological Chemistry  287:3231-3240 (2012)). The pET11 expression plasmids for SENP1 and 2 contained a cDNA insert coding for the catalytic domain of human SENP1-WT (419-644) and SENP2-WT (364-589). The expression plasmid for the SENP1 active site point mutant C603 S was generated using the QuikChange mutagenesis kit (Agilent Technologies, San Diego, Calif.). The expression plasmid for the catalytic domain of SENP7 has been described (Mikolajczyk et al.,  Journal of Biological Chemistry  282:26217-26224 (2007)). 
     SUMO Cleavage Assays. SUMO cleavage assays were performed by incubating SENPs with various concentrations of the inhibitor (0-60 μM) at room temperature for 10 min in assay buffer (50 mM Tris, pH 7.4, 100 mM NaCl, 10 mM DTT). SENP concentrations were 32-50 nM when 50 μg/ml of the final substrate YFP-SUMO-ECFP (YSE) fusion protein was added. The mixture was incubated (37° C., 15 min), followed by SDS-PAGE and Coomassie staining for visualization. For cellular SENP inhibition experiments, HeLa cells cultured in DMEM plus 10% FBS, 100 units/ml penicillin, 100 mg/ml streptomycin, and 0.2 M glutamine were treated for 48 hours with SPI compounds. For heat shock experiment, HeLa cells were treated with SPI compounds or mock treated (2 h, 37° C.), after which cells were transferred to 42° C. for 30 min. After heat shock, the cells were allowed to recover (4-5 hours) before being harvested and lysed. Proteins were separated by SDS-PAGE and immunoblotted to determine global SUMO-2/3 levels. 
     DUB-Glo Assay. The luciferase substrate assay (DUB-Glo, Promega, Madison, Wis.) was performed according to the manufacturer&#39;s instructions. Briefly, SENPs (final concentration 50-100 nM) in Tris buffer (50 mM Tris, pH 8.0, 100 mM NaCl, 10 mM DTT) were pre-incubated (10 min, room temperature) with increasing concentrations of inhibitor (0-60 μM final concentration) followed by addition of the luciferase substrate. Luciferase output was recorded 30 min after addition of the luciferase substrate. Values are the averages of experiments performed in triplicate. 
     NMR Experiments. Samples used for NMR titration or chemical shift perturbation analyses were  15 N or  15 N/ 13 C-labeled; the titrant protein or SPI-01 was not labeled. The  15 N/ 13 C SUMO-1-FL sample was used to extend the backbone assignments of mature SUMO-1 to the HSTV tail by using 2D- 15 N- 1 H-HSQC, 3D-HNCA, 3D-HNCOCA, and 3D-HNCACB. Additionally, comparison of  15 N- 1 H-HSQC between precursor and mature SUMO quickly identified the resonances of the HSTV tail. For SENP1 assignments, a full suite of triple-resonance NMR experiments were acquired on  15 N/ 13 C/ 2 H or  15 N/13C samples: HNCA, HNCOCA, HNCACB, HNCOCACB, HNCO, HNCACO, and NOESY-HSQC. All samples were dissolved in the NMR buffer: 20 mM sodium phosphate (pH 6.8), 10% D2O, 0.03% sodium azide and 10 mM d10-dithiothreitol. Purified perdeuterated SENP1 samples were unfolded and refolded into NMR buffer. 
     For titration of SENP1-C603S with SPI-01, 270 μM  15 N-labeled sample was titrated with the inhibitor that was prepared by diluting a 10 mM stock in 100% DMSO-d 6  to a concentration of 1.7 mM in the NMR buffer. The 2D  1 H- 15 N-HSQC spectra of SENP1 were recorded at each incremental addition of 5 μl of SPI-01 into 250 μl of SENP1. The chemical shift perturbation (CSP) analysis compared the spectra of SENP1 in the absence or the presence of equimolar SPI-01. A separate DMSO control titration was performed to account for DMSO-induced CSP. NMR resonance assignments for SUMO samples at 35° C. were transferred from those obtained at 25° C. by spectral acquisition at 2.5° C. incremental increases. All data were acquired on a 600 MHz Bruker Avance NMR spectrometer equipped with a TXI Cryoprobe. 
     
       
         
           
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Free SENP1 NMR Chemical Shifts Values. 
               
               
                 Chemical Shift Ambiguity Index Value Definitions 
               
               
                 The values other than 1 are used for those atoms with 
               
               
                 different chemical shifts that cannot be assigned to 
               
               
                 stereospecific atoms or to specific residues or chains. 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Index 
                   
               
               
                 Value 
                 Definition 
               
               
                   
               
               
                 1 
                 Unique (including isolated methyl protons 
               
               
                   
                 germinal atoms, and geminal methyl groups with 
               
               
                   
                 identical chemical shifts 
               
               
                   
                 (e.g. ILE HD11, HD12, HD13 protons) 
               
               
                 2 
                 Ambiguity of geminal atoms or geminal methyl 
               
               
                   
                 proton groups (e.g. ASP HB2 and HB3 protons, 
               
               
                   
                 LEU CD1 and CD2 carbons, or LEU HD11, HD12, 
               
               
                   
                 HD13 and HD21, HD22, HD23 methyl protons) 
               
               
                 3 
                 Aromatic atoms on opposite sides of symmetrical 
               
               
                   
                 rings (e.g. TYR HE1 and HE2 protons) 
               
               
                 4 
                 Intraresidue ambiguities (e.g. LYS HG and HD 
               
               
                   
                 protons or TRP HZ2 and HZ3 protons) 
               
               
                 5 
                 Interresidue ambiguities (LYS 12 vs. LYS 27) 
               
               
                 6 
                 Intermolecular ambiguities (e.g. ASP 31 CA in 
               
               
                   
                 monomer 1 and ASP 31 CA in monomer 2 of an 
               
               
                   
                 asymmetrical homodimer, duplex DNA assignments, 
               
               
                   
                 or other assignments that may apply to atoms 
               
               
                   
                 in one or more molecule in the molecular assembly) 
               
               
                 9 
                 Ambiguous, specific ambiguity not defined 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Chemical 
                   
               
               
                 Atom 
                 Residue 
                 Amino 
                 Atom 
                 Atom 
                 Iso- 
                 shift 
                 Unique- 
               
               
                 number 
                 number 
                 acid 
                 context 
                 type 
                 type 
                 (ppm)* 
                 ness 
               
               
                   
               
               
                 1 
                 419 
                 E 
                 CA 
                 C 
                 13 
                 56.635 
                 1 
               
               
                 2 
                 419 
                 E 
                 CB 
                 C 
                 13 
                 29.326 
                 1 
               
               
                 3 
                 419 
                 E 
                 CO 
                 C 
                 13 
                 175.803 
                 1 
               
               
                 4 
                 419 
                 E 
                 H 
                 H 
                 1 
                 8.056 
                 1 
               
               
                 5 
                 419 
                 E 
                 N 
                 N 
                 15 
                 120.257 
                 1 
               
               
                 6 
                 420 
                 F 
                 CA 
                 C 
                 13 
                 54.951 
                 1 
               
               
                 7 
                 420 
                 F 
                 CB 
                 C 
                 13 
                 37.882 
                 1 
               
               
                 8 
                 420 
                 F 
                 CO 
                 C 
                 13 
                 173.207 
                 1 
               
               
                 9 
                 420 
                 F 
                 H 
                 H 
                 1 
                 8.035 
                 1 
               
               
                 10 
                 420 
                 F 
                 N 
                 N 
                 15 
                 118.648 
                 1 
               
               
                 11 
                 422 
                 E 
                 CA 
                 C 
                 13 
                 56.498 
                 1 
               
               
                 12 
                 422 
                 E 
                 CB 
                 C 
                 13 
                 29.476 
                 1 
               
               
                 13 
                 422 
                 E 
                 CO 
                 C 
                 13 
                 176.111 
                 1 
               
               
                 14 
                 422 
                 E 
                 H 
                 H 
                 1 
                 8.637 
                 1 
               
               
                 15 
                 422 
                 E 
                 N 
                 N 
                 15 
                 124.065 
                 1 
               
               
                 16 
                 423 
                 I 
                 CA 
                 C 
                 13 
                 60.725 
                 1 
               
               
                 17 
                 423 
                 I 
                 CB 
                 C 
                 13 
                 35.427 
                 1 
               
               
                 18 
                 423 
                 I 
                 CO 
                 C 
                 13 
                 176.659 
                 1 
               
               
                 19 
                 423 
                 I 
                 H 
                 H 
                 1 
                 8.522 
                 1 
               
               
                 20 
                 423 
                 I 
                 N 
                 N 
                 15 
                 122.041 
                 1 
               
               
                 21 
                 424 
                 T 
                 CB 
                 C 
                 13 
                 70.292 
                 1 
               
               
                 22 
                 424 
                 T 
                 CO 
                 C 
                 13 
                 174.725 
                 1 
               
               
                 23 
                 424 
                 T 
                 H 
                 H 
                 1 
                 7.633 
                 1 
               
               
                 24 
                 424 
                 T 
                 N 
                 N 
                 15 
                 121.188 
                 1 
               
               
                 25 
                 425 
                 E 
                 CA 
                 C 
                 13 
                 59.696 
                 1 
               
               
                 26 
                 425 
                 E 
                 CB 
                 C 
                 13 
                 28.462 
                 1 
               
               
                 27 
                 425 
                 E 
                 H 
                 H 
                 1 
                 8.913 
                 1 
               
               
                 28 
                 425 
                 E 
                 N 
                 N 
                 15 
                 120.9 
                 1 
               
               
                 29 
                 426 
                 E 
                 CA 
                 C 
                 13 
                 59.444 
                 1 
               
               
                 30 
                 426 
                 E 
                 CO 
                 C 
                 13 
                 179.787 
                 1 
               
               
                 31 
                 426 
                 E 
                 H 
                 H 
                 1 
                 8.419 
                 1 
               
               
                 32 
                 426 
                 E 
                 N 
                 N 
                 15 
                 118.024 
                 1 
               
               
                 33 
                 427 
                 M 
                 CB 
                 C 
                 13 
                 33.371 
                 1 
               
               
                 34 
                 427 
                 M 
                 CO 
                 C 
                 13 
                 177.912 
                 1 
               
               
                 35 
                 427 
                 M 
                 H 
                 H 
                 1 
                 7.366 
                 1 
               
               
                 36 
                 427 
                 M 
                 N 
                 N 
                 15 
                 119.301 
                 1 
               
               
                 37 
                 428 
                 E 
                 CB 
                 C 
                 13 
                 28.41 
                 1 
               
               
                 38 
                 428 
                 E 
                 CO 
                 C 
                 13 
                 178.828 
                 1 
               
               
                 39 
                 428 
                 E 
                 H 
                 H 
                 1 
                 8.605 
                 1 
               
               
                 40 
                 428 
                 E 
                 N 
                 N 
                 15 
                 118.58 
                 1 
               
               
                 41 
                 429 
                 K 
                 CA 
                 C 
                 13 
                 59.488 
                 1 
               
               
                 42 
                 429 
                 K 
                 CB 
                 C 
                 13 
                 31.407 
                 1 
               
               
                 43 
                 429 
                 K 
                 CO 
                 C 
                 13 
                 178.978 
                 1 
               
               
                 44 
                 429 
                 K 
                 H 
                 H 
                 1 
                 7.858 
                 1 
               
               
                 45 
                 429 
                 K 
                 N 
                 N 
                 15 
                 118.101 
                 1 
               
               
                 46 
                 430 
                 E 
                 CB 
                 C 
                 13 
                 29.584 
                 1 
               
               
                 47 
                 430 
                 E 
                 CO 
                 C 
                 13 
                 179.111 
                 1 
               
               
                 48 
                 430 
                 E 
                 H 
                 H 
                 1 
                 7.356 
                 1 
               
               
                 49 
                 430 
                 E 
                 N 
                 N 
                 15 
                 119.087 
                 1 
               
               
                 50 
                 431 
                 I 
                 CA 
                 C 
                 13 
                 64.567 
                 1 
               
               
                 51 
                 431 
                 I 
                 CB 
                 C 
                 13 
                 38.123 
                 1 
               
               
                 52 
                 431 
                 I 
                 CO 
                 C 
                 13 
                 176.796 
                 1 
               
               
                 53 
                 431 
                 I 
                 H 
                 H 
                 1 
                 8.075 
                 1 
               
               
                 54 
                 431 
                 I 
                 N 
                 N 
                 15 
                 119.774 
                 1 
               
               
                 55 
                 432 
                 K 
                 CA 
                 C 
                 13 
                 59.195 
                 1 
               
               
                 56 
                 432 
                 K 
                 CB 
                 C 
                 13 
                 31.197 
                 1 
               
               
                 57 
                 432 
                 K 
                 CO 
                 C 
                 13 
                 180.185 
                 1 
               
               
                 58 
                 432 
                 K 
                 H 
                 H 
                 1 
                 8.32 
                 1 
               
               
                 59 
                 432 
                 K 
                 N 
                 N 
                 15 
                 116.686 
                 1 
               
               
                 60 
                 433 
                 N 
                 CA 
                 C 
                 13 
                 55.822 
                 1 
               
               
                 61 
                 433 
                 N 
                 CB 
                 C 
                 13 
                 37.95 
                 1 
               
               
                 62 
                 433 
                 N 
                 CO 
                 C 
                 13 
                 178.466 
                 1 
               
               
                 63 
                 433 
                 N 
                 H 
                 H 
                 1 
                 7.635 
                 1 
               
               
                 64 
                 433 
                 N 
                 N 
                 N 
                 15 
                 114.913 
                 1 
               
               
                 65 
                 434 
                 V 
                 CA 
                 C 
                 13 
                 64.189 
                 1 
               
               
                 66 
                 434 
                 V 
                 CB 
                 C 
                 13 
                 30.396 
                 1 
               
               
                 67 
                 434 
                 V 
                 CG1 
                 C 
                 13 
                 22.475 
                 1 
               
               
                 68 
                 434 
                 V 
                 CG2 
                 C 
                 13 
                 21.674 
                 1 
               
               
                 69 
                 434 
                 V 
                 CO 
                 C 
                 13 
                 176.412 
                 1 
               
               
                 70 
                 434 
                 V 
                 H 
                 H 
                 1 
                 7.548 
                 1 
               
               
                 71 
                 434 
                 V 
                 HG1 
                 H 
                 1 
                 0.724 
                 1 
               
               
                 72 
                 434 
                 V 
                 HG2 
                 H 
                 1 
                 0.725 
                 1 
               
               
                 73 
                 434 
                 V 
                 N 
                 N 
                 15 
                 114.74 
                 1 
               
               
                 74 
                 435 
                 F 
                 CA 
                 C 
                 13 
                 55.321 
                 1 
               
               
                 75 
                 435 
                 F 
                 CB 
                 C 
                 13 
                 37.701 
                 1 
               
               
                 76 
                 435 
                 F 
                 CO 
                 C 
                 13 
                 177.18 
                 1 
               
               
                 77 
                 435 
                 F 
                 H 
                 H 
                 1 
                 7.344 
                 1 
               
               
                 78 
                 435 
                 F 
                 N 
                 N 
                 15 
                 117.562 
                 1 
               
               
                 79 
                 436 
                 R 
                 CA 
                 C 
                 13 
                 56.384 
                 1 
               
               
                 80 
                 436 
                 R 
                 CB 
                 C 
                 13 
                 30.009 
                 1 
               
               
                 81 
                 436 
                 R 
                 CO 
                 C 
                 13 
                 176.099 
                 1 
               
               
                 82 
                 436 
                 R 
                 H 
                 H 
                 1 
                 7.225 
                 1 
               
               
                 83 
                 436 
                 R 
                 N 
                 N 
                 15 
                 118.73 
                 1 
               
               
                 84 
                 437 
                 N 
                 CA 
                 C 
                 13 
                 53.605 
                 1 
               
               
                 85 
                 437 
                 N 
                 CB 
                 C 
                 13 
                 38.193 
                 1 
               
               
                 86 
                 437 
                 N 
                 H 
                 H 
                 1 
                 8.252 
                 1 
               
               
                 87 
                 437 
                 N 
                 N 
                 N 
                 15 
                 119.685 
                 1 
               
               
                 88 
                 438 
                 G 
                 CA 
                 C 
                 13 
                 44.807 
                 1 
               
               
                 89 
                 438 
                 G 
                 CO 
                 C 
                 13 
                 172.725 
                 1 
               
               
                 90 
                 438 
                 G 
                 H 
                 H 
                 1 
                 8.08 
                 1 
               
               
                 91 
                 438 
                 G 
                 N 
                 N 
                 15 
                 109.481 
                 1 
               
               
                 92 
                 439 
                 N 
                 CA 
                 C 
                 13 
                 52.847 
                 1 
               
               
                 93 
                 439 
                 N 
                 CB 
                 C 
                 13 
                 37.175 
                 1 
               
               
                 94 
                 439 
                 N 
                 H 
                 H 
                 1 
                 8.737 
                 1 
               
               
                 95 
                 439 
                 N 
                 N 
                 N 
                 15 
                 120.443 
                 1 
               
               
                 96 
                 440 
                 Q 
                 CA 
                 C 
                 13 
                 58.04 
                 1 
               
               
                 97 
                 440 
                 Q 
                 CB 
                 C 
                 13 
                 28.495 
                 1 
               
               
                 98 
                 440 
                 Q 
                 CO 
                 C 
                 13 
                 175.605 
                 1 
               
               
                 99 
                 440 
                 Q 
                 H 
                 H 
                 1 
                 9.022 
                 1 
               
               
                 100 
                 440 
                 Q 
                 N 
                 N 
                 15 
                 125.59 
                 1 
               
               
                 101 
                 441 
                 D 
                 CA 
                 C 
                 13 
                 53.428 
                 1 
               
               
                 102 
                 441 
                 D 
                 CB 
                 C 
                 13 
                 40.409 
                 1 
               
               
                 103 
                 441 
                 D 
                 CO 
                 C 
                 13 
                 175.45 
                 1 
               
               
                 104 
                 441 
                 D 
                 H 
                 H 
                 1 
                 7.969 
                 1 
               
               
                 105 
                 441 
                 D 
                 N 
                 N 
                 15 
                 114.845 
                 1 
               
               
                 106 
                 442 
                 E 
                 CA 
                 C 
                 13 
                 56.501 
                 1 
               
               
                 107 
                 442 
                 E 
                 CB 
                 C 
                 13 
                 30.044 
                 1 
               
               
                 108 
                 442 
                 E 
                 CO 
                 C 
                 13 
                 175.905 
                 1 
               
               
                 109 
                 442 
                 E 
                 H 
                 H 
                 1 
                 7.143 
                 1 
               
               
                 110 
                 442 
                 E 
                 N 
                 N 
                 15 
                 121.501 
                 1 
               
               
                 111 
                 443 
                 V 
                 CA 
                 C 
                 13 
                 64.02 
                 1 
               
               
                 112 
                 443 
                 V 
                 CB 
                 C 
                 13 
                 31.155 
                 1 
               
               
                 113 
                 443 
                 V 
                 CG1 
                 C 
                 13 
                 21.487 
                 1 
               
               
                 114 
                 443 
                 V 
                 CG2 
                 C 
                 13 
                 21.844 
                 1 
               
               
                 115 
                 443 
                 V 
                 H 
                 H 
                 1 
                 8.65 
                 1 
               
               
                 116 
                 443 
                 V 
                 HG1 
                 H 
                 1 
                 0.721 
                 1 
               
               
                 117 
                 443 
                 V 
                 HG2 
                 H 
                 1 
                 0.882 
                 1 
               
               
                 118 
                 443 
                 V 
                 N 
                 N 
                 15 
                 127.026 
                 1 
               
               
                 119 
                 444 
                 L 
                 CA 
                 C 
                 13 
                 54.051 
                 1 
               
               
                 120 
                 444 
                 L 
                 CB 
                 C 
                 13 
                 43.293 
                 1 
               
               
                 121 
                 444 
                 L 
                 CD1 
                 C 
                 13 
                 27.029 
                 1 
               
               
                 122 
                 444 
                 L 
                 CD2 
                 C 
                 13 
                 21.807 
                 1 
               
               
                 123 
                 444 
                 L 
                 CO 
                 C 
                 13 
                 176.79 
                 1 
               
               
                 124 
                 444 
                 L 
                 H 
                 H 
                 1 
                 9.012 
                 1 
               
               
                 125 
                 444 
                 L 
                 HD1 
                 H 
                 1 
                 0.59 
                 1 
               
               
                 126 
                 444 
                 L 
                 HD2 
                 H 
                 1 
                 0.597 
                 1 
               
               
                 127 
                 444 
                 L 
                 N 
                 N 
                 15 
                 127.296 
                 1 
               
               
                 128 
                 445 
                 S 
                 CA 
                 C 
                 13 
                 57.432 
                 1 
               
               
                 129 
                 445 
                 S 
                 CB 
                 C 
                 13 
                 64.093 
                 1 
               
               
                 130 
                 445 
                 S 
                 CO 
                 C 
                 13 
                 172 
                 1 
               
               
                 131 
                 445 
                 S 
                 H 
                 H 
                 1 
                 7.412 
                 1 
               
               
                 132 
                 445 
                 S 
                 N 
                 N 
                 15 
                 111.726 
                 1 
               
               
                 133 
                 446 
                 E 
                 CA 
                 C 
                 13 
                 55.317 
                 1 
               
               
                 134 
                 446 
                 E 
                 CB 
                 C 
                 13 
                 31.965 
                 1 
               
               
                 135 
                 446 
                 E 
                 CO 
                 C 
                 13 
                 174.257 
                 1 
               
               
                 136 
                 446 
                 E 
                 H 
                 H 
                 1 
                 7.933 
                 1 
               
               
                 137 
                 446 
                 E 
                 N 
                 N 
                 15 
                 125.063 
                 1 
               
               
                 138 
                 447 
                 A 
                 CA 
                 C 
                 13 
                 51.875 
                 1 
               
               
                 139 
                 447 
                 A 
                 CB 
                 C 
                 13 
                 18.979 
                 1 
               
               
                 140 
                 447 
                 A 
                 CO 
                 C 
                 13 
                 176.087 
                 1 
               
               
                 141 
                 447 
                 A 
                 H 
                 H 
                 1 
                 8.286 
                 1 
               
               
                 142 
                 447 
                 A 
                 N 
                 N 
                 15 
                 124.213 
                 1 
               
               
                 143 
                 448 
                 F 
                 CA 
                 C 
                 13 
                 56.316 
                 1 
               
               
                 144 
                 448 
                 F 
                 CB 
                 C 
                 13 
                 36.029 
                 1 
               
               
                 145 
                 448 
                 F 
                 CO 
                 C 
                 13 
                 175.788 
                 1 
               
               
                 146 
                 448 
                 F 
                 H 
                 H 
                 1 
                 8.61 
                 1 
               
               
                 147 
                 448 
                 F 
                 N 
                 N 
                 15 
                 115.367 
                 1 
               
               
                 148 
                 449 
                 R 
                 CA 
                 C 
                 13 
                 57.675 
                 1 
               
               
                 149 
                 449 
                 R 
                 CB 
                 C 
                 13 
                 26.229 
                 1 
               
               
                 150 
                 449 
                 R 
                 CO 
                 C 
                 13 
                 175.491 
                 1 
               
               
                 151 
                 449 
                 R 
                 H 
                 H 
                 1 
                 8.484 
                 1 
               
               
                 152 
                 449 
                 R 
                 N 
                 N 
                 15 
                 110.844 
                 1 
               
               
                 153 
                 450 
                 L 
                 CA 
                 C 
                 13 
                 53.763 
                 1 
               
               
                 154 
                 450 
                 L 
                 CB 
                 C 
                 13 
                 44.035 
                 1 
               
               
                 155 
                 450 
                 L 
                 CD1 
                 C 
                 13 
                 25.813 
                 1 
               
               
                 156 
                 450 
                 L 
                 CD2 
                 C 
                 13 
                 22.437 
                 1 
               
               
                 157 
                 450 
                 L 
                 CO 
                 C 
                 13 
                 176.645 
                 1 
               
               
                 158 
                 450 
                 L 
                 H 
                 H 
                 1 
                 8.389 
                 1 
               
               
                 159 
                 450 
                 L 
                 HD1 
                 H 
                 1 
                 0.89 
                 1 
               
               
                 160 
                 450 
                 L 
                 HD2 
                 H 
                 1 
                 0.948 
                 1 
               
               
                 161 
                 450 
                 L 
                 N 
                 N 
                 15 
                 121.623 
                 1 
               
               
                 162 
                 451 
                 T 
                 CA 
                 C 
                 13 
                 60.834 
                 1 
               
               
                 163 
                 451 
                 T 
                 CB 
                 C 
                 13 
                 71.178 
                 1 
               
               
                 164 
                 451 
                 T 
                 CO 
                 C 
                 13 
                 173.407 
                 1 
               
               
                 165 
                 451 
                 T 
                 H 
                 H 
                 1 
                 8.315 
                 1 
               
               
                 166 
                 451 
                 T 
                 N 
                 N 
                 15 
                 113.296 
                 1 
               
               
                 167 
                 452 
                 I 
                 CA 
                 C 
                 13 
                 56.522 
                 1 
               
               
                 168 
                 452 
                 I 
                 CB 
                 C 
                 13 
                 36.082 
                 1 
               
               
                 169 
                 452 
                 I 
                 CO 
                 C 
                 13 
                 176.082 
                 1 
               
               
                 170 
                 452 
                 I 
                 H 
                 H 
                 1 
                 8.521 
                 1 
               
               
                 171 
                 452 
                 I 
                 N 
                 N 
                 15 
                 124.173 
                 1 
               
               
                 172 
                 453 
                 T 
                 CA 
                 C 
                 13 
                 59.709 
                 1 
               
               
                 173 
                 453 
                 T 
                 CB 
                 C 
                 13 
                 72.939 
                 1 
               
               
                 174 
                 453 
                 T 
                 H 
                 H 
                 1 
                 9.811 
                 1 
               
               
                 175 
                 453 
                 T 
                 N 
                 N 
                 15 
                 119.807 
                 1 
               
               
                 176 
                 454 
                 R 
                 CA 
                 C 
                 13 
                 60.137 
                 1 
               
               
                 177 
                 454 
                 R 
                 CB 
                 C 
                 13 
                 28.989 
                 1 
               
               
                 178 
                 454 
                 R 
                 CO 
                 C 
                 13 
                 177.392 
                 1 
               
               
                 179 
                 454 
                 R 
                 H 
                 H 
                 1 
                 8.211 
                 1 
               
               
                 180 
                 454 
                 R 
                 N 
                 N 
                 15 
                 122.061 
                 1 
               
               
                 181 
                 455 
                 K 
                 CA 
                 C 
                 13 
                 59.289 
                 1 
               
               
                 182 
                 455 
                 K 
                 CB 
                 C 
                 13 
                 31.114 
                 1 
               
               
                 183 
                 455 
                 K 
                 CO 
                 C 
                 13 
                 178.628 
                 1 
               
               
                 184 
                 455 
                 K 
                 H 
                 H 
                 1 
                 8.504 
                 1 
               
               
                 185 
                 455 
                 K 
                 N 
                 N 
                 15 
                 119.122 
                 1 
               
               
                 186 
                 456 
                 D 
                 CA 
                 C 
                 13 
                 57.369 
                 1 
               
               
                 187 
                 456 
                 D 
                 CB 
                 C 
                 13 
                 40.809 
                 1 
               
               
                 188 
                 456 
                 D 
                 H 
                 H 
                 1 
                 7.271 
                 1 
               
               
                 189 
                 456 
                 D 
                 N 
                 N 
                 15 
                 117.779 
                 1 
               
               
                 190 
                 457 
                 I 
                 CA 
                 C 
                 13 
                 62.392 
                 1 
               
               
                 191 
                 457 
                 I 
                 CB 
                 C 
                 13 
                 37.06 
                 1 
               
               
                 192 
                 457 
                 I 
                 H 
                 H 
                 1 
                 8.159 
                 1 
               
               
                 193 
                 457 
                 I 
                 N 
                 N 
                 15 
                 121.588 
                 1 
               
               
                 194 
                 458 
                 Q 
                 CA 
                 C 
                 13 
                 57.804 
                 1 
               
               
                 195 
                 458 
                 Q 
                 CB 
                 C 
                 13 
                 26.567 
                 1 
               
               
                 196 
                 458 
                 Q 
                 CO 
                 C 
                 13 
                 178.732 
                 1 
               
               
                 197 
                 458 
                 Q 
                 H 
                 H 
                 1 
                 7.923 
                 1 
               
               
                 198 
                 458 
                 Q 
                 N 
                 N 
                 15 
                 117.897 
                 1 
               
               
                 199 
                 459 
                 T 
                 CA 
                 C 
                 13 
                 65.051 
                 1 
               
               
                 200 
                 459 
                 T 
                 CB 
                 C 
                 13 
                 67.395 
                 1 
               
               
                 201 
                 459 
                 T 
                 H 
                 H 
                 1 
                 7.897 
                 1 
               
               
                 202 
                 459 
                 T 
                 N 
                 N 
                 15 
                 113.263 
                 1 
               
               
                 203 
                 460 
                 L 
                 CA 
                 C 
                 13 
                 54.923 
                 1 
               
               
                 204 
                 460 
                 L 
                 CB 
                 C 
                 13 
                 41.723 
                 1 
               
               
                 205 
                 460 
                 L 
                 CD1 
                 C 
                 13 
                 25.968 
                 1 
               
               
                 206 
                 460 
                 L 
                 CD2 
                 C 
                 13 
                 25.889 
                 1 
               
               
                 207 
                 460 
                 L 
                 CO 
                 C 
                 13 
                 179.644 
                 1 
               
               
                 208 
                 460 
                 L 
                 H 
                 H 
                 1 
                 7.253 
                 1 
               
               
                 209 
                 460 
                 L 
                 HD1 
                 H 
                 1 
                 0.82 
                 1 
               
               
                 210 
                 460 
                 L 
                 HD2 
                 H 
                 1 
                 0.925 
                 1 
               
               
                 211 
                 460 
                 L 
                 N 
                 N 
                 15 
                 115.083 
                 1 
               
               
                 212 
                 461 
                 N 
                 CA 
                 C 
                 13 
                 51.888 
                 1 
               
               
                 213 
                 461 
                 N 
                 CB 
                 C 
                 13 
                 37.194 
                 1 
               
               
                 214 
                 461 
                 N 
                 H 
                 H 
                 1 
                 7.421 
                 1 
               
               
                 215 
                 461 
                 N 
                 N 
                 N 
                 15 
                 119.845 
                 1 
               
               
                 216 
                 462 
                 H 
                 CA 
                 C 
                 13 
                 57.014 
                 1 
               
               
                 217 
                 462 
                 H 
                 CB 
                 C 
                 13 
                 28.992 
                 1 
               
               
                 218 
                 462 
                 H 
                 H 
                 H 
                 1 
                 7.773 
                 1 
               
               
                 219 
                 462 
                 H 
                 N 
                 N 
                 15 
                 119.821 
                 1 
               
               
                 220 
                 465 
                 W 
                 CA 
                 C 
                 13 
                 56.901 
                 1 
               
               
                 221 
                 465 
                 W 
                 CB 
                 C 
                 13 
                 27.801 
                 1 
               
               
                 222 
                 465 
                 W 
                 H 
                 H 
                 1 
                 8.319 
                 1 
               
               
                 223 
                 465 
                 W 
                 HE1 
                 H 
                 1 
                 10.206 
                 1 
               
               
                 224 
                 465 
                 W 
                 N 
                 N 
                 15 
                 120.321 
                 1 
               
               
                 225 
                 465 
                 W 
                 NE1 
                 N 
                 15 
                 130.435 
                 1 
               
               
                 226 
                 466 
                 L 
                 CA 
                 C 
                 13 
                 57.74 
                 1 
               
               
                 227 
                 466 
                 L 
                 CB 
                 C 
                 13 
                 41.916 
                 1 
               
               
                 228 
                 466 
                 L 
                 CD1 
                 C 
                 13 
                 25.446 
                 1 
               
               
                 229 
                 466 
                 L 
                 CD2 
                 C 
                 13 
                 23.298 
                 1 
               
               
                 230 
                 466 
                 L 
                 H 
                 H 
                 1 
                 7.644 
                 1 
               
               
                 231 
                 466 
                 L 
                 HD1 
                 H 
                 1 
                 0.634 
                 1 
               
               
                 232 
                 466 
                 L 
                 HD2 
                 H 
                 1 
                 0.563 
                 1 
               
               
                 233 
                 466 
                 L 
                 N 
                 N 
                 15 
                 125.508 
                 1 
               
               
                 234 
                 467 
                 N 
                 CA 
                 C 
                 13 
                 50.295 
                 1 
               
               
                 235 
                 467 
                 N 
                 CB 
                 C 
                 13 
                 39.556 
                 1 
               
               
                 236 
                 467 
                 N 
                 CO 
                 C 
                 13 
                 174.619 
                 1 
               
               
                 237 
                 467 
                 N 
                 H 
                 H 
                 1 
                 7.164 
                 1 
               
               
                 238 
                 467 
                 N 
                 N 
                 N 
                 15 
                 116.901 
                 1 
               
               
                 239 
                 468 
                 D 
                 CA 
                 C 
                 13 
                 57.481 
                 1 
               
               
                 240 
                 468 
                 D 
                 CB 
                 C 
                 13 
                 40.531 
                 1 
               
               
                 241 
                 468 
                 D 
                 H 
                 H 
                 1 
                 8.246 
                 1 
               
               
                 242 
                 468 
                 D 
                 N 
                 N 
                 15 
                 115.434 
                 1 
               
               
                 243 
                 469 
                 E 
                 CA 
                 C 
                 13 
                 60.578 
                 1 
               
               
                 244 
                 469 
                 E 
                 CB 
                 C 
                 13 
                 27.414 
                 1 
               
               
                 245 
                 469 
                 E 
                 CO 
                 C 
                 13 
                 179.948 
                 1 
               
               
                 246 
                 469 
                 E 
                 H 
                 H 
                 1 
                 8.991 
                 1 
               
               
                 247 
                 469 
                 E 
                 N 
                 N 
                 15 
                 119.089 
                 1 
               
               
                 248 
                 470 
                 I 
                 CA 
                 C 
                 13 
                 61.231 
                 1 
               
               
                 249 
                 470 
                 I 
                 CB 
                 C 
                 13 
                 34.744 
                 1 
               
               
                 250 
                 470 
                 I 
                 CO 
                 C 
                 13 
                 177.04 
                 1 
               
               
                 251 
                 470 
                 I 
                 H 
                 H 
                 1 
                 7.753 
                 1 
               
               
                 252 
                 470 
                 I 
                 N 
                 N 
                 15 
                 117.845 
                 1 
               
               
                 253 
                 471 
                 I 
                 CA 
                 C 
                 13 
                 64.903 
                 1 
               
               
                 254 
                 471 
                 I 
                 H 
                 H 
                 1 
                 6.974 
                 1 
               
               
                 255 
                 471 
                 I 
                 N 
                 N 
                 15 
                 117.941 
                 1 
               
               
                 256 
                 472 
                 N 
                 CA 
                 C 
                 13 
                 56.07 
                 1 
               
               
                 257 
                 472 
                 N 
                 CB 
                 C 
                 13 
                 37.624 
                 1 
               
               
                 258 
                 472 
                 N 
                 CO 
                 C 
                 13 
                 178.288 
                 1 
               
               
                 259 
                 472 
                 N 
                 H 
                 H 
                 1 
                 9.03 
                 1 
               
               
                 260 
                 472 
                 N 
                 N 
                 N 
                 15 
                 115.254 
                 1 
               
               
                 261 
                 473 
                 F 
                 CA 
                 C 
                 13 
                 62.584 
                 1 
               
               
                 262 
                 473 
                 F 
                 CB 
                 C 
                 13 
                 39.667 
                 1 
               
               
                 263 
                 473 
                 F 
                 CO 
                 C 
                 13 
                 177.436 
                 1 
               
               
                 264 
                 473 
                 F 
                 H 
                 H 
                 1 
                 8.304 
                 1 
               
               
                 265 
                 473 
                 F 
                 N 
                 N 
                 15 
                 123.63 
                 1 
               
               
                 266 
                 474 
                 Y 
                 CA 
                 C 
                 13 
                 62.784 
                 1 
               
               
                 267 
                 474 
                 Y 
                 CB 
                 C 
                 13 
                 38.335 
                 1 
               
               
                 268 
                 474 
                 Y 
                 CO 
                 C 
                 13 
                 178.151 
                 1 
               
               
                 269 
                 474 
                 Y 
                 H 
                 H 
                 1 
                 8.774 
                 1 
               
               
                 270 
                 474 
                 Y 
                 N 
                 N 
                 15 
                 120.467 
                 1 
               
               
                 271 
                 475 
                 M 
                 CA 
                 C 
                 13 
                 57.325 
                 1 
               
               
                 272 
                 475 
                 M 
                 CB 
                 C 
                 13 
                 31.041 
                 1 
               
               
                 273 
                 475 
                 M 
                 CO 
                 C 
                 13 
                 179.367 
                 1 
               
               
                 274 
                 475 
                 M 
                 H 
                 H 
                 1 
                 8.709 
                 1 
               
               
                 275 
                 475 
                 M 
                 N 
                 N 
                 15 
                 115.346 
                 1 
               
               
                 276 
                 476 
                 N 
                 CA 
                 C 
                 13 
                 56.292 
                 1 
               
               
                 277 
                 476 
                 N 
                 CB 
                 C 
                 13 
                 37.912 
                 1 
               
               
                 278 
                 476 
                 N 
                 CO 
                 C 
                 13 
                 177.604 
                 1 
               
               
                 279 
                 476 
                 N 
                 H 
                 H 
                 1 
                 7.371 
                 1 
               
               
                 280 
                 476 
                 N 
                 N 
                 N 
                 15 
                 117.074 
                 1 
               
               
                 281 
                 477 
                 M 
                 CA 
                 C 
                 13 
                 59.952 
                 1 
               
               
                 282 
                 477 
                 M 
                 CB 
                 C 
                 13 
                 31.504 
                 1 
               
               
                 283 
                 477 
                 M 
                 CO 
                 C 
                 13 
                 179.545 
                 1 
               
               
                 284 
                 477 
                 M 
                 H 
                 H 
                 1 
                 7.664 
                 1 
               
               
                 285 
                 477 
                 M 
                 N 
                 N 
                 15 
                 121.465 
                 1 
               
               
                 286 
                 478 
                 L 
                 CA 
                 C 
                 13 
                 57.471 
                 1 
               
               
                 287 
                 478 
                 L 
                 CB 
                 C 
                 13 
                 39.79 
                 1 
               
               
                 288 
                 478 
                 L 
                 CD1 
                 C 
                 13 
                 27.34 
                 1 
               
               
                 289 
                 478 
                 L 
                 CD2 
                 C 
                 13 
                 22.112 
                 1 
               
               
                 290 
                 478 
                 L 
                 CO 
                 C 
                 13 
                 180.857 
                 1 
               
               
                 291 
                 478 
                 L 
                 H 
                 H 
                 1 
                 7.767 
                 1 
               
               
                 292 
                 478 
                 L 
                 HD1 
                 H 
                 1 
                 0.658 
                 1 
               
               
                 293 
                 478 
                 L 
                 HD2 
                 H 
                 1 
                 0.411 
                 1 
               
               
                 294 
                 478 
                 L 
                 N 
                 N 
                 15 
                 119.925 
                 1 
               
               
                 295 
                 479 
                 M 
                 CA 
                 C 
                 13 
                 59.413 
                 1 
               
               
                 296 
                 479 
                 M 
                 CB 
                 C 
                 13 
                 32.433 
                 1 
               
               
                 297 
                 479 
                 M 
                 CO 
                 C 
                 13 
                 179.134 
                 1 
               
               
                 298 
                 479 
                 M 
                 H 
                 H 
                 1 
                 7.603 
                 1 
               
               
                 299 
                 479 
                 M 
                 N 
                 N 
                 15 
                 118.957 
                 1 
               
               
                 300 
                 480 
                 E 
                 CA 
                 C 
                 13 
                 59.225 
                 1 
               
               
                 301 
                 480 
                 E 
                 CB 
                 C 
                 13 
                 28.37 
                 1 
               
               
                 302 
                 480 
                 E 
                 H 
                 H 
                 1 
                 8.059 
                 1 
               
               
                 303 
                 480 
                 E 
                 N 
                 N 
                 15 
                 122.932 
                 1 
               
               
                 304 
                 481 
                 R 
                 CA 
                 C 
                 13 
                 58.251 
                 1 
               
               
                 305 
                 481 
                 R 
                 CB 
                 C 
                 13 
                 28.749 
                 1 
               
               
                 306 
                 481 
                 R 
                 CO 
                 C 
                 13 
                 176.421 
                 1 
               
               
                 307 
                 481 
                 R 
                 H 
                 H 
                 1 
                 7.917 
                 1 
               
               
                 308 
                 481 
                 R 
                 N 
                 N 
                 15 
                 120.662 
                 1 
               
               
                 309 
                 482 
                 S 
                 CA 
                 C 
                 13 
                 60.255 
                 1 
               
               
                 310 
                 482 
                 S 
                 CB 
                 C 
                 13 
                 63.102 
                 1 
               
               
                 311 
                 482 
                 S 
                 CO 
                 C 
                 13 
                 172.394 
                 1 
               
               
                 312 
                 482 
                 S 
                 H 
                 H 
                 1 
                 7.201 
                 1 
               
               
                 313 
                 482 
                 S 
                 N 
                 N 
                 15 
                 113.273 
                 1 
               
               
                 314 
                 483 
                 K 
                 CA 
                 C 
                 13 
                 56.793 
                 1 
               
               
                 315 
                 483 
                 K 
                 CB 
                 C 
                 13 
                 31.687 
                 1 
               
               
                 316 
                 483 
                 K 
                 CO 
                 C 
                 13 
                 178.176 
                 1 
               
               
                 317 
                 483 
                 K 
                 H 
                 H 
                 1 
                 6.968 
                 1 
               
               
                 318 
                 483 
                 K 
                 N 
                 N 
                 15 
                 118.755 
                 1 
               
               
                 319 
                 484 
                 E 
                 CB 
                 C 
                 13 
                 29.049 
                 1 
               
               
                 320 
                 484 
                 E 
                 CO 
                 C 
                 13 
                 176.653 
                 1 
               
               
                 321 
                 484 
                 E 
                 H 
                 H 
                 1 
                 8.114 
                 1 
               
               
                 322 
                 484 
                 E 
                 N 
                 N 
                 15 
                 121.011 
                 1 
               
               
                 323 
                 485 
                 K 
                 CA 
                 C 
                 13 
                 57.55 
                 1 
               
               
                 324 
                 485 
                 K 
                 CB 
                 C 
                 13 
                 31.154 
                 1 
               
               
                 325 
                 485 
                 K 
                 CO 
                 C 
                 13 
                 177.924 
                 1 
               
               
                 326 
                 485 
                 K 
                 H 
                 H 
                 1 
                 8.263 
                 1 
               
               
                 327 
                 485 
                 K 
                 N 
                 N 
                 15 
                 121.725 
                 1 
               
               
                 328 
                 486 
                 G 
                 CA 
                 C 
                 13 
                 44.731 
                 1 
               
               
                 329 
                 486 
                 G 
                 CO 
                 C 
                 13 
                 173.993 
                 1 
               
               
                 330 
                 486 
                 G 
                 H 
                 H 
                 1 
                 8.738 
                 1 
               
               
                 331 
                 486 
                 G 
                 N 
                 N 
                 15 
                 111.446 
                 1 
               
               
                 332 
                 487 
                 L 
                 CA 
                 C 
                 13 
                 52.224 
                 1 
               
               
                 333 
                 487 
                 L 
                 CB 
                 C 
                 13 
                 40.075 
                 1 
               
               
                 334 
                 487 
                 L 
                 CD1 
                 C 
                 13 
                 25.797 
                 1 
               
               
                 335 
                 487 
                 L 
                 CD2 
                 C 
                 13 
                 23.228 
                 1 
               
               
                 336 
                 487 
                 L 
                 CO 
                 C 
                 13 
                 174.966 
                 1 
               
               
                 337 
                 487 
                 L 
                 H 
                 H 
                 1 
                 7.357 
                 1 
               
               
                 338 
                 487 
                 L 
                 HD1 
                 H 
                 1 
                 0.778 
                 1 
               
               
                 339 
                 487 
                 L 
                 HD2 
                 H 
                 1 
                 0.829 
                 1 
               
               
                 340 
                 487 
                 L 
                 N 
                 N 
                 15 
                 121.648 
                 1 
               
               
                 341 
                 489 
                 S 
                 CA 
                 C 
                 13 
                 57.732 
                 1 
               
               
                 342 
                 489 
                 S 
                 CB 
                 C 
                 13 
                 63.976 
                 1 
               
               
                 343 
                 489 
                 S 
                 CO 
                 C 
                 13 
                 175.307 
                 1 
               
               
                 344 
                 489 
                 S 
                 H 
                 H 
                 1 
                 9.146 
                 1 
               
               
                 345 
                 489 
                 S 
                 N 
                 N 
                 15 
                 117.954 
                 1 
               
               
                 346 
                 490 
                 V 
                 CA 
                 C 
                 13 
                 59.96 
                 1 
               
               
                 347 
                 490 
                 V 
                 CB 
                 C 
                 13 
                 36.725 
                 1 
               
               
                 348 
                 490 
                 V 
                 CG1 
                 C 
                 13 
                 21.034 
                 1 
               
               
                 349 
                 490 
                 V 
                 CG2 
                 C 
                 13 
                 23.035 
                 1 
               
               
                 350 
                 490 
                 V 
                 CO 
                 C 
                 13 
                 175.445 
                 1 
               
               
                 351 
                 490 
                 V 
                 H 
                 H 
                 1 
                 7.378 
                 1 
               
               
                 352 
                 490 
                 V 
                 HG1 
                 H 
                 1 
                 0.555 
                 1 
               
               
                 353 
                 490 
                 V 
                 HG2 
                 H 
                 1 
                 0.885 
                 1 
               
               
                 354 
                 490 
                 V 
                 N 
                 N 
                 15 
                 118.616 
                 1 
               
               
                 355 
                 491 
                 H 
                 CA 
                 C 
                 13 
                 56.457 
                 1 
               
               
                 356 
                 491 
                 H 
                 CB 
                 C 
                 13 
                 33.175 
                 1 
               
               
                 357 
                 491 
                 H 
                 CO 
                 C 
                 13 
                 172.689 
                 1 
               
               
                 358 
                 491 
                 H 
                 H 
                 H 
                 1 
                 8.824 
                 1 
               
               
                 359 
                 491 
                 H 
                 N 
                 N 
                 15 
                 124.16 
                 1 
               
               
                 360 
                 492 
                 A 
                 CA 
                 C 
                 13 
                 48.933 
                 1 
               
               
                 361 
                 492 
                 A 
                 CB 
                 C 
                 13 
                 20.637 
                 1 
               
               
                 362 
                 492 
                 A 
                 CO 
                 C 
                 13 
                 175.149 
                 1 
               
               
                 363 
                 492 
                 A 
                 H 
                 H 
                 1 
                 7.475 
                 1 
               
               
                 364 
                 492 
                 A 
                 N 
                 N 
                 15 
                 129.587 
                 1 
               
               
                 365 
                 493 
                 F 
                 CA 
                 C 
                 13 
                 57.443 
                 1 
               
               
                 366 
                 493 
                 F 
                 CB 
                 C 
                 13 
                 40.032 
                 1 
               
               
                 367 
                 493 
                 F 
                 H 
                 H 
                 1 
                 8.075 
                 1 
               
               
                 368 
                 493 
                 F 
                 N 
                 N 
                 15 
                 120.292 
                 1 
               
               
                 369 
                 494 
                 N 
                 CA 
                 C 
                 13 
                 52.612 
                 1 
               
               
                 370 
                 494 
                 N 
                 CB 
                 C 
                 13 
                 39.014 
                 1 
               
               
                 371 
                 494 
                 N 
                 CO 
                 C 
                 13 
                 177.042 
                 1 
               
               
                 372 
                 494 
                 N 
                 H 
                 H 
                 1 
                 8.614 
                 1 
               
               
                 373 
                 494 
                 N 
                 N 
                 N 
                 15 
                 116.324 
                 1 
               
               
                 374 
                 495 
                 T 
                 CA 
                 C 
                 13 
                 65.108 
                 1 
               
               
                 375 
                 495 
                 T 
                 CB 
                 C 
                 13 
                 67.954 
                 1 
               
               
                 376 
                 495 
                 T 
                 H 
                 H 
                 1 
                 8.712 
                 1 
               
               
                 377 
                 495 
                 T 
                 N 
                 N 
                 15 
                 111.881 
                 1 
               
               
                 378 
                 496 
                 F 
                 CA 
                 C 
                 13 
                 57.589 
                 1 
               
               
                 379 
                 496 
                 F 
                 CB 
                 C 
                 13 
                 38.722 
                 1 
               
               
                 380 
                 496 
                 F 
                 CO 
                 C 
                 13 
                 176.791 
                 1 
               
               
                 381 
                 496 
                 F 
                 H 
                 H 
                 1 
                 8.441 
                 1 
               
               
                 382 
                 496 
                 F 
                 N 
                 N 
                 15 
                 120.392 
                 1 
               
               
                 383 
                 497 
                 F 
                 CA 
                 C 
                 13 
                 61.468 
                 1 
               
               
                 384 
                 497 
                 F 
                 CB 
                 C 
                 13 
                 38.442 
                 1 
               
               
                 385 
                 497 
                 F 
                 CO 
                 C 
                 13 
                 175.62 
                 1 
               
               
                 386 
                 497 
                 F 
                 H 
                 H 
                 1 
                 7.951 
                 1 
               
               
                 387 
                 497 
                 F 
                 N 
                 N 
                 15 
                 121.386 
                 1 
               
               
                 388 
                 498 
                 F 
                 CA 
                 C 
                 13 
                 62.45 
                 1 
               
               
                 389 
                 498 
                 F 
                 CB 
                 C 
                 13 
                 37.649 
                 1 
               
               
                 390 
                 498 
                 F 
                 CO 
                 C 
                 13 
                 176.151 
                 1 
               
               
                 391 
                 498 
                 F 
                 H 
                 H 
                 1 
                 10.059 
                 1 
               
               
                 392 
                 498 
                 F 
                 N 
                 N 
                 15 
                 120.473 
                 1 
               
               
                 393 
                 499 
                 T 
                 CA 
                 C 
                 13 
                 65.751 
                 1 
               
               
                 394 
                 499 
                 T 
                 CB 
                 C 
                 13 
                 68.656 
                 1 
               
               
                 395 
                 499 
                 T 
                 H 
                 H 
                 1 
                 7.099 
                 1 
               
               
                 396 
                 499 
                 T 
                 N 
                 N 
                 15 
                 111.797 
                 1 
               
               
                 397 
                 500 
                 K 
                 CA 
                 C 
                 13 
                 58.082 
                 1 
               
               
                 398 
                 500 
                 K 
                 CB 
                 C 
                 13 
                 30.293 
                 1 
               
               
                 399 
                 500 
                 K 
                 CO 
                 C 
                 13 
                 177.17 
                 1 
               
               
                 400 
                 500 
                 K 
                 H 
                 H 
                 1 
                 7.805 
                 1 
               
               
                 401 
                 500 
                 K 
                 N 
                 N 
                 15 
                 122.907 
                 1 
               
               
                 402 
                 501 
                 L 
                 CA 
                 C 
                 13 
                 56.922 
                 1 
               
               
                 403 
                 501 
                 L 
                 CB 
                 C 
                 13 
                 40.32 
                 1 
               
               
                 404 
                 501 
                 L 
                 CD1 
                 C 
                 13 
                 21.344 
                 1 
               
               
                 405 
                 501 
                 L 
                 CD2 
                 C 
                 13 
                 26.13 
                 1 
               
               
                 406 
                 501 
                 L 
                 H 
                 H 
                 1 
                 8.04 
                 1 
               
               
                 407 
                 501 
                 L 
                 HD1 
                 H 
                 1 
                 0.619 
                 1 
               
               
                 408 
                 501 
                 L 
                 HD2 
                 H 
                 1 
                 0.269 
                 1 
               
               
                 409 
                 501 
                 L 
                 N 
                 N 
                 15 
                 120.722 
                 1 
               
               
                 410 
                 502 
                 K 
                 CA 
                 C 
                 13 
                 58.359 
                 1 
               
               
                 411 
                 502 
                 K 
                 CB 
                 C 
                 13 
                 31.117 
                 1 
               
               
                 412 
                 502 
                 K 
                 CO 
                 C 
                 13 
                 177.542 
                 1 
               
               
                 413 
                 502 
                 K 
                 H 
                 H 
                 1 
                 8.113 
                 1 
               
               
                 414 
                 502 
                 K 
                 N 
                 N 
                 15 
                 117.113 
                 1 
               
               
                 415 
                 503 
                 T 
                 CA 
                 C 
                 13 
                 63.65 
                 1 
               
               
                 416 
                 503 
                 T 
                 CB 
                 C 
                 13 
                 69.641 
                 1 
               
               
                 417 
                 503 
                 T 
                 CO 
                 C 
                 13 
                 175.362 
                 1 
               
               
                 418 
                 503 
                 T 
                 H 
                 H 
                 1 
                 7.521 
                 1 
               
               
                 419 
                 503 
                 T 
                 N 
                 N 
                 15 
                 108.626 
                 1 
               
               
                 420 
                 504 
                 A 
                 CA 
                 C 
                 13 
                 51.681 
                 1 
               
               
                 421 
                 504 
                 A 
                 CB 
                 C 
                 13 
                 19.982 
                 1 
               
               
                 422 
                 504 
                 A 
                 CO 
                 C 
                 13 
                 177.923 
                 1 
               
               
                 423 
                 504 
                 A 
                 H 
                 H 
                 1 
                 8.417 
                 1 
               
               
                 424 
                 504 
                 A 
                 N 
                 N 
                 15 
                 124.229 
                 1 
               
               
                 425 
                 505 
                 G 
                 CA 
                 C 
                 13 
                 44.062 
                 1 
               
               
                 426 
                 505 
                 G 
                 CO 
                 C 
                 13 
                 173.703 
                 1 
               
               
                 427 
                 505 
                 G 
                 H 
                 H 
                 1 
                 7.404 
                 1 
               
               
                 428 
                 505 
                 G 
                 N 
                 N 
                 15 
                 108.216 
                 1 
               
               
                 429 
                 506 
                 Y 
                 CA 
                 C 
                 13 
                 61.372 
                 1 
               
               
                 430 
                 506 
                 Y 
                 CB 
                 C 
                 13 
                 38.185 
                 1 
               
               
                 431 
                 506 
                 Y 
                 CO 
                 C 
                 13 
                 177.707 
                 1 
               
               
                 432 
                 506 
                 Y 
                 H 
                 H 
                 1 
                 8.506 
                 1 
               
               
                 433 
                 506 
                 Y 
                 N 
                 N 
                 15 
                 118.015 
                 1 
               
               
                 434 
                 507 
                 Q 
                 CA 
                 C 
                 13 
                 58.073 
                 1 
               
               
                 435 
                 507 
                 Q 
                 CB 
                 C 
                 13 
                 26.321 
                 1 
               
               
                 436 
                 507 
                 Q 
                 CO 
                 C 
                 13 
                 177.318 
                 1 
               
               
                 437 
                 507 
                 Q 
                 H 
                 H 
                 1 
                 8.677 
                 1 
               
               
                 438 
                 507 
                 Q 
                 N 
                 N 
                 15 
                 113.949 
                 1 
               
               
                 439 
                 508 
                 A 
                 CA 
                 C 
                 13 
                 53.059 
                 1 
               
               
                 440 
                 508 
                 A 
                 CB 
                 C 
                 13 
                 19.41 
                 1 
               
               
                 441 
                 508 
                 A 
                 CO 
                 C 
                 13 
                 178.474 
                 1 
               
               
                 442 
                 508 
                 A 
                 H 
                 H 
                 1 
                 7.193 
                 1 
               
               
                 443 
                 508 
                 A 
                 N 
                 N 
                 15 
                 117.81 
                 1 
               
               
                 444 
                 509 
                 V 
                 CA 
                 C 
                 13 
                 59.584 
                 1 
               
               
                 445 
                 509 
                 V 
                 CB 
                 C 
                 13 
                 32.636 
                 1 
               
               
                 446 
                 509 
                 V 
                 CG1 
                 C 
                 13 
                 19.036 
                 1 
               
               
                 447 
                 509 
                 V 
                 CG2 
                 C 
                 13 
                 20.077 
                 1 
               
               
                 448 
                 509 
                 V 
                 CO 
                 C 
                 13 
                 178.833 
                 1 
               
               
                 449 
                 509 
                 V 
                 H 
                 H 
                 1 
                 6.99 
                 1 
               
               
                 450 
                 509 
                 V 
                 HG1 
                 H 
                 1 
                 0.152 
                 1 
               
               
                 451 
                 509 
                 V 
                 HG2 
                 H 
                 1 
                 0.505 
                 1 
               
               
                 452 
                 509 
                 V 
                 N 
                 N 
                 15 
                 104.928 
                 1 
               
               
                 453 
                 510 
                 K 
                 CA 
                 C 
                 13 
                 59.235 
                 1 
               
               
                 454 
                 510 
                 K 
                 CB 
                 C 
                 13 
                 30.396 
                 1 
               
               
                 455 
                 510 
                 K 
                 CO 
                 C 
                 13 
                 178.002 
                 1 
               
               
                 456 
                 510 
                 K 
                 H 
                 H 
                 1 
                 7.252 
                 1 
               
               
                 457 
                 510 
                 K 
                 N 
                 N 
                 15 
                 126.565 
                 1 
               
               
                 458 
                 511 
                 R 
                 CA 
                 C 
                 13 
                 56.969 
                 1 
               
               
                 459 
                 511 
                 R 
                 CB 
                 C 
                 13 
                 28.393 
                 1 
               
               
                 460 
                 511 
                 R 
                 H 
                 H 
                 1 
                 8.593 
                 1 
               
               
                 461 
                 511 
                 R 
                 N 
                 N 
                 15 
                 116.236 
                 1 
               
               
                 462 
                 512 
                 W 
                 CA 
                 C 
                 13 
                 59.154 
                 1 
               
               
                 463 
                 512 
                 W 
                 CB 
                 C 
                 13 
                 27.825 
                 1 
               
               
                 464 
                 512 
                 W 
                 CO 
                 C 
                 13 
                 178.179 
                 1 
               
               
                 465 
                 512 
                 W 
                 H 
                 H 
                 1 
                 8.477 
                 1 
               
               
                 466 
                 512 
                 W 
                 HE1 
                 H 
                 1 
                 10.293 
                 1 
               
               
                 467 
                 512 
                 W 
                 N 
                 N 
                 15 
                 120.092 
                 1 
               
               
                 468 
                 512 
                 W 
                 NE1 
                 N 
                 15 
                 129.338 
                 1 
               
               
                 469 
                 513 
                 T 
                 CA 
                 C 
                 13 
                 60 
                 1 
               
               
                 470 
                 513 
                 T 
                 CB 
                 C 
                 13 
                 65.562 
                 1 
               
               
                 471 
                 513 
                 T 
                 CO 
                 C 
                 13 
                 174.181 
                 1 
               
               
                 472 
                 513 
                 T 
                 H 
                 H 
                 1 
                 7.356 
                 1 
               
               
                 473 
                 513 
                 T 
                 N 
                 N 
                 15 
                 105.836 
                 1 
               
               
                 474 
                 514 
                 K 
                 CA 
                 C 
                 13 
                 59.285 
                 1 
               
               
                 475 
                 514 
                 K 
                 CB 
                 C 
                 13 
                 31.488 
                 1 
               
               
                 476 
                 514 
                 K 
                 CO 
                 C 
                 13 
                 177.271 
                 1 
               
               
                 477 
                 514 
                 K 
                 H 
                 H 
                 1 
                 7.187 
                 1 
               
               
                 478 
                 514 
                 K 
                 N 
                 N 
                 15 
                 120.77 
                 1 
               
               
                 479 
                 515 
                 K 
                 CA 
                 C 
                 13 
                 55.075 
                 1 
               
               
                 480 
                 515 
                 K 
                 CB 
                 C 
                 13 
                 31.34 
                 1 
               
               
                 481 
                 515 
                 K 
                 CO 
                 C 
                 13 
                 175.55 
                 1 
               
               
                 482 
                 515 
                 K 
                 H 
                 H 
                 1 
                 8.52 
                 1 
               
               
                 483 
                 515 
                 K 
                 N 
                 N 
                 15 
                 115.267 
                 1 
               
               
                 484 
                 516 
                 V 
                 CA 
                 C 
                 13 
                 60.315 
                 1 
               
               
                 485 
                 516 
                 V 
                 CB 
                 C 
                 13 
                 34.794 
                 1 
               
               
                 486 
                 516 
                 V 
                 CG1 
                 C 
                 13 
                 22.213 
                 1 
               
               
                 487 
                 516 
                 V 
                 CG2 
                 C 
                 13 
                 19.431 
                 1 
               
               
                 488 
                 516 
                 V 
                 CO 
                 C 
                 13 
                 173.373 
                 1 
               
               
                 489 
                 516 
                 V 
                 H 
                 H 
                 1 
                 7.346 
                 1 
               
               
                 490 
                 516 
                 V 
                 HG1 
                 H 
                 1 
                 1.035 
                 1 
               
               
                 491 
                 516 
                 V 
                 HG2 
                 H 
                 1 
                 0.828 
                 1 
               
               
                 492 
                 516 
                 V 
                 N 
                 N 
                 15 
                 118.521 
                 1 
               
               
                 493 
                 517 
                 D 
                 CA 
                 C 
                 13 
                 50.719 
                 1 
               
               
                 494 
                 517 
                 D 
                 CB 
                 C 
                 13 
                 39.298 
                 1 
               
               
                 495 
                 517 
                 D 
                 CO 
                 C 
                 13 
                 178.171 
                 1 
               
               
                 496 
                 517 
                 D 
                 H 
                 H 
                 1 
                 8.502 
                 1 
               
               
                 497 
                 517 
                 D 
                 N 
                 N 
                 15 
                 124.325 
                 1 
               
               
                 498 
                 518 
                 V 
                 CA 
                 C 
                 13 
                 64.12 
                 1 
               
               
                 499 
                 518 
                 V 
                 CB 
                 C 
                 13 
                 30.53 
                 1 
               
               
                 500 
                 518 
                 V 
                 CG1 
                 C 
                 13 
                 21.974 
                 1 
               
               
                 501 
                 518 
                 V 
                 CG2 
                 C 
                 13 
                 17.74 
                 1 
               
               
                 502 
                 518 
                 V 
                 CO 
                 C 
                 13 
                 173.205 
                 1 
               
               
                 503 
                 518 
                 V 
                 H 
                 H 
                 1 
                 8.909 
                 1 
               
               
                 504 
                 518 
                 V 
                 HG1 
                 H 
                 1 
                 0.709 
                 1 
               
               
                 505 
                 518 
                 V 
                 HG2 
                 H 
                 1 
                 0.246 
                 1 
               
               
                 506 
                 518 
                 V 
                 N 
                 N 
                 15 
                 121.419 
                 1 
               
               
                 507 
                 519 
                 F 
                 CA 
                 C 
                 13 
                 57.9 
                 1 
               
               
                 508 
                 519 
                 F 
                 CB 
                 C 
                 13 
                 36.872 
                 1 
               
               
                 509 
                 519 
                 F 
                 CO 
                 C 
                 13 
                 176.5 
                 1 
               
               
                 510 
                 519 
                 F 
                 H 
                 H 
                 1 
                 7.223 
                 1 
               
               
                 511 
                 519 
                 F 
                 N 
                 N 
                 15 
                 110.893 
                 1 
               
               
                 512 
                 520 
                 S 
                 CB 
                 C 
                 13 
                 64.082 
                 1 
               
               
                 513 
                 520 
                 S 
                 CO 
                 C 
                 13 
                 173.635 
                 1 
               
               
                 514 
                 520 
                 S 
                 H 
                 H 
                 1 
                 7.457 
                 1 
               
               
                 515 
                 520 
                 S 
                 N 
                 N 
                 15 
                 113.527 
                 1 
               
               
                 516 
                 521 
                 V 
                 CA 
                 C 
                 13 
                 58.421 
                 1 
               
               
                 517 
                 521 
                 V 
                 CB 
                 C 
                 13 
                 33.049 
                 1 
               
               
                 518 
                 521 
                 V 
                 CG1 
                 C 
                 13 
                 21.474 
                 1 
               
               
                 519 
                 521 
                 V 
                 CG2 
                 C 
                 13 
                 19.203 
                 1 
               
               
                 520 
                 521 
                 V 
                 CO 
                 C 
                 13 
                 174.363 
                 1 
               
               
                 521 
                 521 
                 V 
                 H 
                 H 
                 1 
                 6.675 
                 1 
               
               
                 522 
                 521 
                 V 
                 HG1 
                 H 
                 1 
                 0.677 
                 1 
               
               
                 523 
                 521 
                 V 
                 HG2 
                 H 
                 1 
                 0.736 
                 1 
               
               
                 524 
                 521 
                 V 
                 N 
                 N 
                 15 
                 114.244 
                 1 
               
               
                 525 
                 522 
                 D 
                 CA 
                 C 
                 13 
                 57.671 
                 1 
               
               
                 526 
                 522 
                 D 
                 CB 
                 C 
                 13 
                 42.241 
                 1 
               
               
                 527 
                 522 
                 D 
                 H 
                 H 
                 1 
                 8.177 
                 1 
               
               
                 528 
                 522 
                 D 
                 N 
                 N 
                 15 
                 120.102 
                 1 
               
               
                 529 
                 523 
                 I 
                 CA 
                 C 
                 13 
                 59.234 
                 1 
               
               
                 530 
                 523 
                 I 
                 H 
                 H 
                 1 
                 8.209 
                 1 
               
               
                 531 
                 523 
                 I 
                 N 
                 N 
                 15 
                 117.31 
                 1 
               
               
                 532 
                 524 
                 L 
                 CA 
                 C 
                 13 
                 51.912 
                 1 
               
               
                 533 
                 524 
                 L 
                 CB 
                 C 
                 13 
                 42.117 
                 1 
               
               
                 534 
                 524 
                 L 
                 CD1 
                 C 
                 13 
                 24.261 
                 2 
               
               
                 535 
                 524 
                 L 
                 CD2 
                 C 
                 13 
                 24.458 
                 2 
               
               
                 536 
                 524 
                 L 
                 H 
                 H 
                 1 
                 9.357 
                 1 
               
               
                 537 
                 524 
                 L 
                 HD1 
                 H 
                 1 
                 0.826 
                 2 
               
               
                 538 
                 524 
                 L 
                 HD2 
                 H 
                 1 
                 0.873 
                 2 
               
               
                 539 
                 524 
                 L 
                 N 
                 N 
                 15 
                 121.905 
                 1 
               
               
                 540 
                 525 
                 L 
                 CA 
                 C 
                 13 
                 53.109 
                 1 
               
               
                 541 
                 525 
                 L 
                 CB 
                 C 
                 13 
                 43.667 
                 1 
               
               
                 542 
                 525 
                 L 
                 CD1 
                 C 
                 13 
                 27.473 
                 1 
               
               
                 543 
                 525 
                 L 
                 CD2 
                 C 
                 13 
                 23.613 
                 1 
               
               
                 544 
                 525 
                 L 
                 H 
                 H 
                 1 
                 8.708 
                 1 
               
               
                 545 
                 525 
                 L 
                 HD1 
                 H 
                 1 
                 0.737 
                 1 
               
               
                 546 
                 525 
                 L 
                 HD2 
                 H 
                 1 
                 0.713 
                 1 
               
               
                 547 
                 525 
                 L 
                 N 
                 N 
                 15 
                 120.45 
                 1 
               
               
                 548 
                 526 
                 V 
                 CA 
                 C 
                 13 
                 59.564 
                 1 
               
               
                 549 
                 526 
                 V 
                 CB 
                 C 
                 13 
                 32.337 
                 1 
               
               
                 550 
                 526 
                 V 
                 CG1 
                 C 
                 13 
                 20.681 
                 1 
               
               
                 551 
                 526 
                 V 
                 CG2 
                 C 
                 13 
                 19.401 
                 1 
               
               
                 552 
                 526 
                 V 
                 H 
                 H 
                 1 
                 8.925 
                 1 
               
               
                 553 
                 526 
                 V 
                 HG1 
                 H 
                 1 
                 −0.236 
                 1 
               
               
                 554 
                 526 
                 V 
                 HG2 
                 H 
                 1 
                 0.488 
                 1 
               
               
                 555 
                 526 
                 V 
                 N 
                 N 
                 15 
                 120.847 
                 1 
               
               
                 556 
                 528 
                 I 
                 CA 
                 C 
                 13 
                 60.95 
                 1 
               
               
                 557 
                 528 
                 I 
                 CB 
                 C 
                 13 
                 39.801 
                 1 
               
               
                 558 
                 528 
                 I 
                 H 
                 H 
                 1 
                 8.737 
                 1 
               
               
                 559 
                 528 
                 I 
                 N 
                 N 
                 15 
                 125.023 
                 1 
               
               
                 560 
                 529 
                 H 
                 CA 
                 C 
                 13 
                 50.979 
                 1 
               
               
                 561 
                 529 
                 H 
                 CB 
                 C 
                 13 
                 29.375 
                 1 
               
               
                 562 
                 529 
                 H 
                 CO 
                 C 
                 13 
                 174.067 
                 1 
               
               
                 563 
                 529 
                 H 
                 H 
                 H 
                 1 
                 9.036 
                 1 
               
               
                 564 
                 529 
                 H 
                 N 
                 N 
                 15 
                 129.849 
                 1 
               
               
                 565 
                 530 
                 L 
                 CA 
                 C 
                 13 
                 52.799 
                 1 
               
               
                 566 
                 530 
                 L 
                 CB 
                 C 
                 13 
                 41.01 
                 1 
               
               
                 567 
                 530 
                 L 
                 CD1 
                 C 
                 13 
                 25.841 
                 1 
               
               
                 568 
                 530 
                 L 
                 CD2 
                 C 
                 13 
                 23.767 
                 1 
               
               
                 569 
                 530 
                 L 
                 CO 
                 C 
                 13 
                 176.318 
                 1 
               
               
                 570 
                 530 
                 L 
                 H 
                 H 
                 1 
                 8.525 
                 1 
               
               
                 571 
                 530 
                 L 
                 HD1 
                 H 
                 1 
                 0.874 
                 1 
               
               
                 572 
                 530 
                 L 
                 HD2 
                 H 
                 1 
                 0.77 
                 1 
               
               
                 573 
                 530 
                 L 
                 N 
                 N 
                 15 
                 130.501 
                 1 
               
               
                 574 
                 531 
                 G 
                 CA 
                 C 
                 13 
                 46.001 
                 1 
               
               
                 575 
                 531 
                 G 
                 CO 
                 C 
                 13 
                 174.79 
                 1 
               
               
                 576 
                 531 
                 G 
                 H 
                 H 
                 1 
                 8.157 
                 1 
               
               
                 577 
                 531 
                 G 
                 N 
                 N 
                 15 
                 115.336 
                 1 
               
               
                 578 
                 532 
                 V 
                 CA 
                 C 
                 13 
                 61.094 
                 1 
               
               
                 579 
                 532 
                 V 
                 CB 
                 C 
                 13 
                 30.784 
                 1 
               
               
                 580 
                 532 
                 V 
                 CG1 
                 C 
                 13 
                 20.964 
                 1 
               
               
                 581 
                 532 
                 V 
                 CG2 
                 C 
                 13 
                 18.117 
                 1 
               
               
                 582 
                 532 
                 V 
                 CO 
                 C 
                 13 
                 175.461 
                 1 
               
               
                 583 
                 532 
                 V 
                 H 
                 H 
                 1 
                 8.198 
                 1 
               
               
                 584 
                 532 
                 V 
                 HG1 
                 H 
                 1 
                 0.532 
                 1 
               
               
                 585 
                 532 
                 V 
                 HG2 
                 H 
                 1 
                 0.584 
                 1 
               
               
                 586 
                 532 
                 V 
                 N 
                 N 
                 15 
                 119.81 
                 1 
               
               
                 587 
                 533 
                 H 
                 CA 
                 C 
                 13 
                 55.28 
                 1 
               
               
                 588 
                 533 
                 H 
                 CB 
                 C 
                 13 
                 32.996 
                 1 
               
               
                 589 
                 533 
                 H 
                 CO 
                 C 
                 13 
                 174.498 
                 1 
               
               
                 590 
                 533 
                 H 
                 H 
                 H 
                 1 
                 7.803 
                 1 
               
               
                 591 
                 533 
                 H 
                 N 
                 N 
                 15 
                 121.771 
                 1 
               
               
                 592 
                 534 
                 W 
                 CA 
                 C 
                 13 
                 55.915 
                 1 
               
               
                 593 
                 534 
                 W 
                 CB 
                 C 
                 13 
                 32.49 
                 1 
               
               
                 594 
                 534 
                 W 
                 H 
                 H 
                 1 
                 6.407 
                 1 
               
               
                 595 
                 534 
                 W 
                 HE1 
                 H 
                 1 
                 9.377 
                 1 
               
               
                 596 
                 534 
                 W 
                 N 
                 N 
                 15 
                 125.3 
                 1 
               
               
                 597 
                 534 
                 W 
                 NE1 
                 N 
                 15 
                 128.192 
                 1 
               
               
                 598 
                 535 
                 C 
                 CA 
                 C 
                 13 
                 56.548 
                 1 
               
               
                 599 
                 535 
                 C 
                 CB 
                 C 
                 13 
                 30.615 
                 1 
               
               
                 600 
                 535 
                 C 
                 CO 
                 C 
                 13 
                 171.965 
                 1 
               
               
                 601 
                 535 
                 C 
                 H 
                 H 
                 1 
                 9.461 
                 1 
               
               
                 602 
                 535 
                 C 
                 N 
                 N 
                 15 
                 117.22 
                 1 
               
               
                 603 
                 536 
                 L 
                 CA 
                 C 
                 13 
                 54.008 
                 1 
               
               
                 604 
                 536 
                 L 
                 CB 
                 C 
                 13 
                 46.487 
                 1 
               
               
                 605 
                 536 
                 L 
                 CD1 
                 C 
                 13 
                 22.301 
                 1 
               
               
                 606 
                 536 
                 L 
                 CD2 
                 C 
                 13 
                 26.282 
                 1 
               
               
                 607 
                 536 
                 L 
                 H 
                 H 
                 1 
                 7.905 
                 1 
               
               
                 608 
                 536 
                 L 
                 HD1 
                 H 
                 1 
                 0.679 
                 1 
               
               
                 609 
                 536 
                 L 
                 HD2 
                 H 
                 1 
                 0.597 
                 1 
               
               
                 610 
                 536 
                 L 
                 N 
                 N 
                 15 
                 120.825 
                 1 
               
               
                 611 
                 537 
                 A 
                 CA 
                 C 
                 13 
                 49.576 
                 1 
               
               
                 612 
                 537 
                 A 
                 CB 
                 C 
                 13 
                 20.964 
                 1 
               
               
                 613 
                 537 
                 A 
                 H 
                 H 
                 1 
                 8.835 
                 1 
               
               
                 614 
                 537 
                 A 
                 N 
                 N 
                 15 
                 126.773 
                 1 
               
               
                 615 
                 538 
                 V 
                 CA 
                 C 
                 13 
                 60.449 
                 1 
               
               
                 616 
                 538 
                 V 
                 CB 
                 C 
                 13 
                 35.413 
                 1 
               
               
                 617 
                 538 
                 V 
                 CG1 
                 C 
                 13 
                 21.698 
                 1 
               
               
                 618 
                 538 
                 V 
                 CG2 
                 C 
                 13 
                 21.913 
                 1 
               
               
                 619 
                 538 
                 V 
                 CO 
                 C 
                 13 
                 174.727 
                 1 
               
               
                 620 
                 538 
                 V 
                 H 
                 H 
                 1 
                 9.071 
                 1 
               
               
                 621 
                 538 
                 V 
                 HG1 
                 H 
                 1 
                 0.87 
                 1 
               
               
                 622 
                 538 
                 V 
                 HG2 
                 H 
                 1 
                 0.809 
                 1 
               
               
                 623 
                 538 
                 V 
                 N 
                 N 
                 15 
                 119.546 
                 1 
               
               
                 624 
                 539 
                 V 
                 CA 
                 C 
                 13 
                 60.873 
                 1 
               
               
                 625 
                 539 
                 V 
                 CB 
                 C 
                 13 
                 32.053 
                 1 
               
               
                 626 
                 539 
                 V 
                 CG1 
                 C 
                 13 
                 20.502 
                 1 
               
               
                 627 
                 539 
                 V 
                 CG2 
                 C 
                 13 
                 19.475 
                 1 
               
               
                 628 
                 539 
                 V 
                 H 
                 H 
                 1 
                 9.402 
                 1 
               
               
                 629 
                 539 
                 V 
                 HG1 
                 H 
                 1 
                 0.441 
                 1 
               
               
                 630 
                 539 
                 V 
                 HG2 
                 H 
                 1 
                 0.881 
                 1 
               
               
                 631 
                 539 
                 V 
                 N 
                 N 
                 15 
                 130.501 
                 1 
               
               
                 632 
                 540 
                 D 
                 CA 
                 C 
                 13 
                 51.922 
                 1 
               
               
                 633 
                 540 
                 D 
                 CB 
                 C 
                 13 
                 41.816 
                 1 
               
               
                 634 
                 540 
                 D 
                 H 
                 H 
                 1 
                 8.954 
                 1 
               
               
                 635 
                 540 
                 D 
                 N 
                 N 
                 15 
                 126.546 
                 1 
               
               
                 636 
                 541 
                 F 
                 CA 
                 C 
                 13 
                 62.022 
                 1 
               
               
                 637 
                 541 
                 F 
                 CB 
                 C 
                 13 
                 39.187 
                 1 
               
               
                 638 
                 541 
                 F 
                 H 
                 H 
                 1 
                 9.479 
                 1 
               
               
                 639 
                 541 
                 F 
                 N 
                 N 
                 15 
                 123.936 
                 1 
               
               
                 640 
                 542 
                 R 
                 CA 
                 C 
                 13 
                 57.3 
                 1 
               
               
                 641 
                 542 
                 R 
                 CB 
                 C 
                 13 
                 28.607 
                 1 
               
               
                 642 
                 542 
                 R 
                 CO 
                 C 
                 13 
                 179.074 
                 1 
               
               
                 643 
                 542 
                 R 
                 H 
                 H 
                 1 
                 8.714 
                 1 
               
               
                 644 
                 542 
                 R 
                 N 
                 N 
                 15 
                 117.561 
                 1 
               
               
                 645 
                 543 
                 K 
                 CA 
                 C 
                 13 
                 54.808 
                 1 
               
               
                 646 
                 543 
                 K 
                 CB 
                 C 
                 13 
                 33.288 
                 1 
               
               
                 647 
                 543 
                 K 
                 CO 
                 C 
                 13 
                 175.221 
                 1 
               
               
                 648 
                 543 
                 K 
                 H 
                 H 
                 1 
                 6.749 
                 1 
               
               
                 649 
                 543 
                 K 
                 N 
                 N 
                 15 
                 114.224 
                 1 
               
               
                 650 
                 544 
                 K 
                 CA 
                 C 
                 13 
                 55.562 
                 1 
               
               
                 651 
                 544 
                 K 
                 CB 
                 C 
                 13 
                 27.641 
                 1 
               
               
                 652 
                 544 
                 K 
                 CO 
                 C 
                 13 
                 175.247 
                 1 
               
               
                 653 
                 544 
                 K 
                 H 
                 H 
                 1 
                 7.423 
                 1 
               
               
                 654 
                 544 
                 K 
                 N 
                 N 
                 15 
                 115.776 
                 1 
               
               
                 655 
                 545 
                 N 
                 CA 
                 C 
                 13 
                 51.023 
                 1 
               
               
                 656 
                 545 
                 N 
                 CB 
                 C 
                 13 
                 42.123 
                 1 
               
               
                 657 
                 545 
                 N 
                 CO 
                 C 
                 13 
                 173.859 
                 1 
               
               
                 658 
                 545 
                 N 
                 H 
                 H 
                 1 
                 7.23 
                 1 
               
               
                 659 
                 545 
                 N 
                 N 
                 N 
                 15 
                 113.498 
                 1 
               
               
                 660 
                 546 
                 I 
                 CA 
                 C 
                 13 
                 61.517 
                 1 
               
               
                 661 
                 546 
                 I 
                 H 
                 H 
                 1 
                 8.432 
                 1 
               
               
                 662 
                 546 
                 I 
                 N 
                 N 
                 15 
                 120.288 
                 1 
               
               
                 663 
                 547 
                 T 
                 CA 
                 C 
                 13 
                 60.921 
                 1 
               
               
                 664 
                 547 
                 T 
                 CB 
                 C 
                 13 
                 70.493 
                 1 
               
               
                 665 
                 547 
                 T 
                 H 
                 H 
                 1 
                 8.781 
                 1 
               
               
                 666 
                 547 
                 T 
                 N 
                 N 
                 15 
                 121.352 
                 1 
               
               
                 667 
                 548 
                 Y 
                 CA 
                 C 
                 13 
                 57.227 
                 1 
               
               
                 668 
                 548 
                 Y 
                 CB 
                 C 
                 13 
                 40.796 
                 1 
               
               
                 669 
                 548 
                 Y 
                 H 
                 H 
                 1 
                 8.727 
                 1 
               
               
                 670 
                 548 
                 Y 
                 N 
                 N 
                 15 
                 128.981 
                 1 
               
               
                 671 
                 549 
                 Y 
                 CB 
                 C 
                 13 
                 40.072 
                 1 
               
               
                 672 
                 549 
                 Y 
                 H 
                 H 
                 1 
                 9.079 
                 1 
               
               
                 673 
                 549 
                 Y 
                 N 
                 N 
                 15 
                 125.239 
                 1 
               
               
                 674 
                 550 
                 D 
                 CA 
                 C 
                 13 
                 52.549 
                 1 
               
               
                 675 
                 550 
                 D 
                 CB 
                 C 
                 13 
                 43.937 
                 1 
               
               
                 676 
                 550 
                 D 
                 CO 
                 C 
                 13 
                 177.444 
                 1 
               
               
                 677 
                 550 
                 D 
                 H 
                 H 
                 1 
                 8.116 
                 1 
               
               
                 678 
                 550 
                 D 
                 N 
                 N 
                 15 
                 123.169 
                 1 
               
               
                 679 
                 551 
                 S 
                 CA 
                 C 
                 13 
                 60.463 
                 1 
               
               
                 680 
                 551 
                 S 
                 CB 
                 C 
                 13 
                 62.962 
                 1 
               
               
                 681 
                 551 
                 S 
                 CO 
                 C 
                 13 
                 174.422 
                 1 
               
               
                 682 
                 551 
                 S 
                 H 
                 H 
                 1 
                 9.519 
                 1 
               
               
                 683 
                 551 
                 S 
                 N 
                 N 
                 15 
                 122.969 
                 1 
               
               
                 684 
                 552 
                 M 
                 CA 
                 C 
                 13 
                 54.901 
                 1 
               
               
                 685 
                 552 
                 M 
                 CB 
                 C 
                 13 
                 34.489 
                 1 
               
               
                 686 
                 552 
                 M 
                 CO 
                 C 
                 13 
                 178.972 
                 1 
               
               
                 687 
                 552 
                 M 
                 H 
                 H 
                 1 
                 9.32 
                 1 
               
               
                 688 
                 552 
                 M 
                 N 
                 N 
                 15 
                 122.574 
                 1 
               
               
                 689 
                 553 
                 G 
                 CA 
                 C 
                 13 
                 46.475 
                 1 
               
               
                 690 
                 553 
                 G 
                 CO 
                 C 
                 13 
                 175.385 
                 1 
               
               
                 691 
                 553 
                 G 
                 H 
                 H 
                 1 
                 7.89 
                 1 
               
               
                 692 
                 553 
                 G 
                 N 
                 N 
                 15 
                 109.507 
                 1 
               
               
                 693 
                 554 
                 G 
                 CA 
                 C 
                 13 
                 44.928 
                 1 
               
               
                 694 
                 554 
                 G 
                 CO 
                 C 
                 13 
                 171.658 
                 1 
               
               
                 695 
                 554 
                 G 
                 H 
                 H 
                 1 
                 7.51 
                 1 
               
               
                 696 
                 554 
                 G 
                 N 
                 N 
                 15 
                 107.555 
                 1 
               
               
                 697 
                 555 
                 I 
                 CA 
                 C 
                 13 
                 59.215 
                 1 
               
               
                 698 
                 555 
                 I 
                 CB 
                 C 
                 13 
                 37.955 
                 1 
               
               
                 699 
                 555 
                 I 
                 CO 
                 C 
                 13 
                 176.285 
                 1 
               
               
                 700 
                 555 
                 I 
                 H 
                 H 
                 1 
                 8.05 
                 1 
               
               
                 701 
                 555 
                 I 
                 N 
                 N 
                 15 
                 118.138 
                 1 
               
               
                 702 
                 556 
                 N 
                 CA 
                 C 
                 13 
                 50.688 
                 1 
               
               
                 703 
                 556 
                 N 
                 CB 
                 C 
                 13 
                 36.209 
                 1 
               
               
                 704 
                 556 
                 N 
                 H 
                 H 
                 1 
                 7.762 
                 1 
               
               
                 705 
                 556 
                 N 
                 N 
                 N 
                 15 
                 124.106 
                 1 
               
               
                 706 
                 557 
                 N 
                 CA 
                 C 
                 13 
                 55.66 
                 1 
               
               
                 707 
                 557 
                 N 
                 CB 
                 C 
                 13 
                 37.225 
                 1 
               
               
                 708 
                 557 
                 N 
                 H 
                 H 
                 1 
                 8.339 
                 1 
               
               
                 709 
                 557 
                 N 
                 N 
                 N 
                 15 
                 121.312 
                 1 
               
               
                 710 
                 558 
                 E 
                 CA 
                 C 
                 13 
                 59.21 
                 1 
               
               
                 711 
                 558 
                 E 
                 CB 
                 C 
                 13 
                 28.223 
                 1 
               
               
                 712 
                 558 
                 E 
                 H 
                 H 
                 1 
                 8.531 
                 1 
               
               
                 713 
                 558 
                 E 
                 N 
                 N 
                 15 
                 120.721 
                 1 
               
               
                 714 
                 559 
                 A 
                 CA 
                 C 
                 13 
                 55.072 
                 1 
               
               
                 715 
                 559 
                 A 
                 CB 
                 C 
                 13 
                 17.209 
                 1 
               
               
                 716 
                 559 
                 A 
                 CO 
                 C 
                 13 
                 179.228 
                 1 
               
               
                 717 
                 559 
                 A 
                 H 
                 H 
                 1 
                 7.491 
                 1 
               
               
                 718 
                 559 
                 A 
                 N 
                 N 
                 15 
                 120.499 
                 1 
               
               
                 719 
                 560 
                 C 
                 CA 
                 C 
                 13 
                 61.861 
                 1 
               
               
                 720 
                 560 
                 C 
                 CB 
                 C 
                 13 
                 26.362 
                 1 
               
               
                 721 
                 560 
                 C 
                 CO 
                 C 
                 13 
                 176.152 
                 1 
               
               
                 722 
                 560 
                 C 
                 H 
                 H 
                 1 
                 6.803 
                 1 
               
               
                 723 
                 560 
                 C 
                 N 
                 N 
                 15 
                 111.946 
                 1 
               
               
                 724 
                 561 
                 R 
                 CA 
                 C 
                 13 
                 59.736 
                 1 
               
               
                 725 
                 561 
                 R 
                 CB 
                 C 
                 13 
                 29.122 
                 1 
               
               
                 726 
                 561 
                 R 
                 CO 
                 C 
                 13 
                 179.458 
                 1 
               
               
                 727 
                 561 
                 R 
                 H 
                 H 
                 1 
                 8.077 
                 1 
               
               
                 728 
                 561 
                 R 
                 N 
                 N 
                 15 
                 120.238 
                 1 
               
               
                 729 
                 562 
                 I 
                 CA 
                 C 
                 13 
                 64.773 
                 1 
               
               
                 730 
                 562 
                 I 
                 CB 
                 C 
                 13 
                 36.965 
                 1 
               
               
                 731 
                 562 
                 I 
                 CO 
                 C 
                 13 
                 179.283 
                 1 
               
               
                 732 
                 562 
                 I 
                 H 
                 H 
                 1 
                 8.583 
                 1 
               
               
                 733 
                 562 
                 I 
                 N 
                 N 
                 15 
                 120.588 
                 1 
               
               
                 734 
                 563 
                 L 
                 CA 
                 C 
                 13 
                 56.989 
                 1 
               
               
                 735 
                 563 
                 L 
                 CB 
                 C 
                 13 
                 41.139 
                 1 
               
               
                 736 
                 563 
                 L 
                 CD1 
                 C 
                 13 
                 26.07 
                 1 
               
               
                 737 
                 563 
                 L 
                 CD2 
                 C 
                 13 
                 22.794 
                 1 
               
               
                 738 
                 563 
                 L 
                 CO 
                 C 
                 13 
                 177.668 
                 1 
               
               
                 739 
                 563 
                 L 
                 H 
                 H 
                 1 
                 7.58 
                 1 
               
               
                 740 
                 563 
                 L 
                 HD1 
                 H 
                 1 
                 0.714 
                 1 
               
               
                 741 
                 563 
                 L 
                 HD2 
                 H 
                 1 
                 0.791 
                 1 
               
               
                 742 
                 563 
                 L 
                 N 
                 N 
                 15 
                 120.645 
                 1 
               
               
                 743 
                 564 
                 L 
                 CA 
                 C 
                 13 
                 57.863 
                 1 
               
               
                 744 
                 564 
                 L 
                 CB 
                 C 
                 13 
                 40.586 
                 1 
               
               
                 745 
                 564 
                 L 
                 CD1 
                 C 
                 13 
                 23.029 
                 1 
               
               
                 746 
                 564 
                 L 
                 CD2 
                 C 
                 13 
                 25.722 
                 1 
               
               
                 747 
                 564 
                 L 
                 H 
                 H 
                 1 
                 7.989 
                 1 
               
               
                 748 
                 564 
                 L 
                 HD1 
                 H 
                 1 
                 0.503 
                 1 
               
               
                 749 
                 564 
                 L 
                 HD2 
                 H 
                 1 
                 0.873 
                 1 
               
               
                 750 
                 564 
                 L 
                 N 
                 N 
                 15 
                 122.277 
                 1 
               
               
                 751 
                 565 
                 Q 
                 CB 
                 C 
                 13 
                 27.023 
                 1 
               
               
                 752 
                 565 
                 Q 
                 CO 
                 C 
                 13 
                 178.554 
                 1 
               
               
                 753 
                 565 
                 Q 
                 H 
                 H 
                 1 
                 7.945 
                 1 
               
               
                 754 
                 565 
                 Q 
                 N 
                 N 
                 15 
                 116.169 
                 1 
               
               
                 755 
                 566 
                 Y 
                 CA 
                 C 
                 13 
                 61.262 
                 1 
               
               
                 756 
                 566 
                 Y 
                 CB 
                 C 
                 13 
                 36.89 
                 1 
               
               
                 757 
                 566 
                 Y 
                 H 
                 H 
                 1 
                 8.147 
                 1 
               
               
                 758 
                 566 
                 Y 
                 N 
                 N 
                 15 
                 121.414 
                 1 
               
               
                 759 
                 567 
                 L 
                 CA 
                 C 
                 13 
                 57.69 
                 1 
               
               
                 760 
                 567 
                 L 
                 CB 
                 C 
                 13 
                 39.693 
                 1 
               
               
                 761 
                 567 
                 L 
                 CD1 
                 C 
                 13 
                 26.027 
                 1 
               
               
                 762 
                 567 
                 L 
                 CD2 
                 C 
                 13 
                 21.698 
                 1 
               
               
                 763 
                 567 
                 L 
                 H 
                 H 
                 1 
                 7.756 
                 1 
               
               
                 764 
                 567 
                 L 
                 HD1 
                 H 
                 1 
                 0.298 
                 1 
               
               
                 765 
                 567 
                 L 
                 HD2 
                 H 
                 1 
                 0.574 
                 1 
               
               
                 766 
                 567 
                 L 
                 N 
                 N 
                 15 
                 118.927 
                 1 
               
               
                 767 
                 568 
                 K 
                 CA 
                 C 
                 13 
                 59.666 
                 1 
               
               
                 768 
                 568 
                 K 
                 CB 
                 C 
                 13 
                 31.072 
                 1 
               
               
                 769 
                 568 
                 K 
                 CO 
                 C 
                 13 
                 180.159 
                 1 
               
               
                 770 
                 568 
                 K 
                 H 
                 H 
                 1 
                 7.436 
                 1 
               
               
                 771 
                 568 
                 K 
                 N 
                 N 
                 15 
                 116.321 
                 1 
               
               
                 772 
                 569 
                 Q 
                 CA 
                 C 
                 13 
                 58.376 
                 1 
               
               
                 773 
                 569 
                 Q 
                 CB 
                 C 
                 13 
                 26.837 
                 1 
               
               
                 774 
                 569 
                 Q 
                 CO 
                 C 
                 13 
                 178.121 
                 1 
               
               
                 775 
                 569 
                 Q 
                 H 
                 H 
                 1 
                 7.71 
                 1 
               
               
                 776 
                 569 
                 Q 
                 N 
                 N 
                 15 
                 119.281 
                 1 
               
               
                 777 
                 570 
                 E 
                 CA 
                 C 
                 13 
                 57.248 
                 1 
               
               
                 778 
                 570 
                 E 
                 CB 
                 C 
                 13 
                 27.85 
                 1 
               
               
                 779 
                 570 
                 E 
                 CO 
                 C 
                 13 
                 178.511 
                 1 
               
               
                 780 
                 570 
                 E 
                 H 
                 H 
                 1 
                 8.874 
                 1 
               
               
                 781 
                 570 
                 E 
                 N 
                 N 
                 15 
                 123.757 
                 1 
               
               
                 782 
                 571 
                 S 
                 CA 
                 C 
                 13 
                 61.824 
                 1 
               
               
                 783 
                 571 
                 S 
                 CB 
                 C 
                 13 
                 63.591 
                 1 
               
               
                 784 
                 571 
                 S 
                 H 
                 H 
                 1 
                 8.112 
                 1 
               
               
                 785 
                 571 
                 S 
                 N 
                 N 
                 15 
                 113.072 
                 1 
               
               
                 786 
                 572 
                 I 
                 CA 
                 C 
                 13 
                 64.046 
                 1 
               
               
                 787 
                 572 
                 I 
                 CB 
                 C 
                 13 
                 36.762 
                 1 
               
               
                 788 
                 572 
                 I 
                 CO 
                 C 
                 13 
                 178.898 
                 1 
               
               
                 789 
                 572 
                 I 
                 H 
                 H 
                 1 
                 7.085 
                 1 
               
               
                 790 
                 572 
                 I 
                 N 
                 N 
                 15 
                 120.025 
                 1 
               
               
                 791 
                 573 
                 D 
                 CA 
                 C 
                 13 
                 58.589 
                 1 
               
               
                 792 
                 573 
                 D 
                 CB 
                 C 
                 13 
                 45.295 
                 1 
               
               
                 793 
                 573 
                 D 
                 H 
                 H 
                 1 
                 8.267 
                 1 
               
               
                 794 
                 573 
                 D 
                 N 
                 N 
                 15 
                 119.596 
                 1 
               
               
                 795 
                 574 
                 K 
                 CA 
                 C 
                 13 
                 55.261 
                 1 
               
               
                 796 
                 574 
                 K 
                 H 
                 H 
                 1 
                 8.537 
                 1 
               
               
                 797 
                 574 
                 K 
                 N 
                 N 
                 15 
                 110.111 
                 1 
               
               
                 798 
                 575 
                 K 
                 CA 
                 C 
                 13 
                 53.6 
                 1 
               
               
                 799 
                 575 
                 K 
                 H 
                 H 
                 1 
                 7.814 
                 1 
               
               
                 800 
                 575 
                 K 
                 N 
                 N 
                 15 
                 114.921 
                 1 
               
               
                 801 
                 580 
                 D 
                 CA 
                 C 
                 13 
                 53.108 
                 1 
               
               
                 802 
                 580 
                 D 
                 CO 
                 C 
                 13 
                 175.974 
                 1 
               
               
                 803 
                 580 
                 D 
                 H 
                 H 
                 1 
                 8.008 
                 1 
               
               
                 804 
                 580 
                 D 
                 N 
                 N 
                 15 
                 128.24 
                 1 
               
               
                 805 
                 581 
                 T 
                 CA 
                 C 
                 13 
                 61.607 
                 1 
               
               
                 806 
                 581 
                 T 
                 CB 
                 C 
                 13 
                 67.992 
                 1 
               
               
                 807 
                 581 
                 T 
                 CO 
                 C 
                 13 
                 176.37 
                 1 
               
               
                 808 
                 581 
                 T 
                 H 
                 H 
                 1 
                 8.005 
                 1 
               
               
                 809 
                 581 
                 T 
                 N 
                 N 
                 15 
                 114.488 
                 1 
               
               
                 810 
                 582 
                 N 
                 CA 
                 C 
                 13 
                 55.671 
                 1 
               
               
                 811 
                 582 
                 N 
                 CB 
                 C 
                 13 
                 37.704 
                 1 
               
               
                 812 
                 582 
                 N 
                 CO 
                 C 
                 13 
                 177.026 
                 1 
               
               
                 813 
                 582 
                 N 
                 H 
                 H 
                 1 
                 8.559 
                 1 
               
               
                 814 
                 582 
                 N 
                 N 
                 N 
                 15 
                 124.721 
                 1 
               
               
                 815 
                 583 
                 G 
                 CA 
                 C 
                 13 
                 45.005 
                 1 
               
               
                 816 
                 583 
                 G 
                 CO 
                 C 
                 13 
                 174.64 
                 1 
               
               
                 817 
                 583 
                 G 
                 H 
                 H 
                 1 
                 8.964 
                 1 
               
               
                 818 
                 583 
                 G 
                 N 
                 N 
                 15 
                 113.066 
                 1 
               
               
                 819 
                 584 
                 W 
                 CA 
                 C 
                 13 
                 58.735 
                 1 
               
               
                 820 
                 584 
                 W 
                 CB 
                 C 
                 13 
                 27.343 
                 1 
               
               
                 821 
                 584 
                 W 
                 CO 
                 C 
                 13 
                 177.331 
                 1 
               
               
                 822 
                 584 
                 W 
                 H 
                 H 
                 1 
                 7.891 
                 1 
               
               
                 823 
                 584 
                 W 
                 HE1 
                 H 
                 1 
                 10.207 
                 1 
               
               
                 824 
                 584 
                 W 
                 N 
                 N 
                 15 
                 120.551 
                 1 
               
               
                 825 
                 584 
                 W 
                 NE1 
                 N 
                 15 
                 130.072 
                 1 
               
               
                 826 
                 585 
                 Q 
                 CA 
                 C 
                 13 
                 54.336 
                 1 
               
               
                 827 
                 585 
                 Q 
                 CB 
                 C 
                 13 
                 32.617 
                 1 
               
               
                 828 
                 585 
                 Q 
                 CO 
                 C 
                 13 
                 173.396 
                 1 
               
               
                 829 
                 585 
                 Q 
                 H 
                 H 
                 1 
                 8.32 
                 1 
               
               
                 830 
                 585 
                 Q 
                 N 
                 N 
                 15 
                 120.47 
                 1 
               
               
                 831 
                 586 
                 L 
                 CA 
                 C 
                 13 
                 52.787 
                 1 
               
               
                 832 
                 586 
                 L 
                 CB 
                 C 
                 13 
                 41.572 
                 1 
               
               
                 833 
                 586 
                 L 
                 CD1 
                 C 
                 13 
                 24.58 
                 1 
               
               
                 834 
                 586 
                 L 
                 CD2 
                 C 
                 13 
                 24.177 
                 1 
               
               
                 835 
                 586 
                 L 
                 CO 
                 C 
                 13 
                 176.073 
                 1 
               
               
                 836 
                 586 
                 L 
                 H 
                 H 
                 1 
                 8.257 
                 1 
               
               
                 837 
                 586 
                 L 
                 HD1 
                 H 
                 1 
                 0.875 
                 1 
               
               
                 838 
                 586 
                 L 
                 HD2 
                 H 
                 1 
                 1.06 
                 1 
               
               
                 839 
                 586 
                 L 
                 N 
                 N 
                 15 
                 122.471 
                 1 
               
               
                 840 
                 587 
                 F 
                 CA 
                 C 
                 13 
                 56.274 
                 1 
               
               
                 841 
                 587 
                 F 
                 CB 
                 C 
                 13 
                 41.98 
                 1 
               
               
                 842 
                 587 
                 F 
                 CO 
                 C 
                 13 
                 174.71 
                 1 
               
               
                 843 
                 587 
                 F 
                 H 
                 H 
                 1 
                 9.007 
                 1 
               
               
                 844 
                 587 
                 F 
                 N 
                 N 
                 15 
                 119.628 
                 1 
               
               
                 845 
                 588 
                 S 
                 CA 
                 C 
                 13 
                 57.584 
                 1 
               
               
                 846 
                 588 
                 S 
                 CB 
                 C 
                 13 
                 64.741 
                 1 
               
               
                 847 
                 588 
                 S 
                 CO 
                 C 
                 13 
                 174.522 
                 1 
               
               
                 848 
                 588 
                 S 
                 H 
                 H 
                 1 
                 8.55 
                 1 
               
               
                 849 
                 588 
                 S 
                 N 
                 N 
                 15 
                 115.508 
                 1 
               
               
                 850 
                 589 
                 K 
                 CA 
                 C 
                 13 
                 54.504 
                 1 
               
               
                 851 
                 589 
                 K 
                 CB 
                 C 
                 13 
                 30.677 
                 1 
               
               
                 852 
                 589 
                 K 
                 CO 
                 C 
                 13 
                 176.928 
                 1 
               
               
                 853 
                 589 
                 K 
                 H 
                 H 
                 1 
                 8.375 
                 1 
               
               
                 854 
                 589 
                 K 
                 N 
                 N 
                 15 
                 123.879 
                 1 
               
               
                 855 
                 590 
                 K 
                 CA 
                 C 
                 13 
                 55.59 
                 1 
               
               
                 856 
                 590 
                 K 
                 CB 
                 C 
                 13 
                 32.654 
                 1 
               
               
                 857 
                 590 
                 K 
                 CO 
                 C 
                 13 
                 178.646 
                 1 
               
               
                 858 
                 590 
                 K 
                 H 
                 H 
                 1 
                 9.16 
                 1 
               
               
                 859 
                 590 
                 K 
                 N 
                 N 
                 15 
                 124.442 
                 1 
               
               
                 860 
                 591 
                 S 
                 CA 
                 C 
                 13 
                 60.73 
                 1 
               
               
                 861 
                 591 
                 S 
                 CB 
                 C 
                 13 
                 62.469 
                 1 
               
               
                 862 
                 591 
                 S 
                 CO 
                 C 
                 13 
                 175.07 
                 1 
               
               
                 863 
                 591 
                 S 
                 H 
                 H 
                 1 
                 8.771 
                 1 
               
               
                 864 
                 591 
                 S 
                 N 
                 N 
                 15 
                 116.878 
                 1 
               
               
                 865 
                 592 
                 Q 
                 CA 
                 C 
                 13 
                 56.481 
                 1 
               
               
                 866 
                 592 
                 Q 
                 CB 
                 C 
                 13 
                 27.319 
                 1 
               
               
                 867 
                 592 
                 Q 
                 CO 
                 C 
                 13 
                 177.119 
                 1 
               
               
                 868 
                 592 
                 Q 
                 H 
                 H 
                 1 
                 7.787 
                 1 
               
               
                 869 
                 592 
                 Q 
                 N 
                 N 
                 15 
                 114.421 
                 1 
               
               
                 870 
                 593 
                 E 
                 CA 
                 C 
                 13 
                 56.788 
                 1 
               
               
                 871 
                 593 
                 E 
                 CB 
                 C 
                 13 
                 31.514 
                 1 
               
               
                 872 
                 593 
                 E 
                 CO 
                 C 
                 13 
                 176.185 
                 1 
               
               
                 873 
                 593 
                 E 
                 H 
                 H 
                 1 
                 8.147 
                 1 
               
               
                 874 
                 593 
                 E 
                 N 
                 N 
                 15 
                 116.571 
                 1 
               
               
                 875 
                 594 
                 I 
                 CA 
                 C 
                 13 
                 57.233 
                 1 
               
               
                 876 
                 594 
                 I 
                 CB 
                 C 
                 13 
                 39.464 
                 1 
               
               
                 877 
                 594 
                 I 
                 H 
                 H 
                 1 
                 7.099 
                 1 
               
               
                 878 
                 594 
                 I 
                 N 
                 N 
                 15 
                 111.638 
                 1 
               
               
                 879 
                 596 
                 Q 
                 CA 
                 C 
                 13 
                 52.641 
                 1 
               
               
                 880 
                 596 
                 Q 
                 CB 
                 C 
                 13 
                 31.367 
                 1 
               
               
                 881 
                 596 
                 Q 
                 CO 
                 C 
                 13 
                 176.998 
                 1 
               
               
                 882 
                 596 
                 Q 
                 H 
                 H 
                 1 
                 8.568 
                 1 
               
               
                 883 
                 596 
                 Q 
                 N 
                 N 
                 15 
                 119.776 
                 1 
               
               
                 884 
                 597 
                 Q 
                 CA 
                 C 
                 13 
                 53.866 
                 1 
               
               
                 885 
                 597 
                 Q 
                 CB 
                 C 
                 13 
                 28.195 
                 1 
               
               
                 886 
                 597 
                 Q 
                 CO 
                 C 
                 13 
                 175.677 
                 1 
               
               
                 887 
                 597 
                 Q 
                 H 
                 H 
                 1 
                 8.67 
                 1 
               
               
                 888 
                 597 
                 Q 
                 N 
                 N 
                 15 
                 118.265 
                 1 
               
               
                 889 
                 598 
                 M 
                 CA 
                 C 
                 13 
                 55.496 
                 1 
               
               
                 890 
                 598 
                 M 
                 CB 
                 C 
                 13 
                 33.978 
                 1 
               
               
                 891 
                 598 
                 M 
                 CO 
                 C 
                 13 
                 175.887 
                 1 
               
               
                 892 
                 598 
                 M 
                 H 
                 H 
                 1 
                 9.45 
                 1 
               
               
                 893 
                 598 
                 M 
                 N 
                 N 
                 15 
                 118.496 
                 1 
               
               
                 894 
                 599 
                 N 
                 CA 
                 C 
                 13 
                 51.768 
                 1 
               
               
                 895 
                 599 
                 N 
                 CB 
                 C 
                 13 
                 39.114 
                 1 
               
               
                 896 
                 599 
                 N 
                 H 
                 H 
                 1 
                 7.565 
                 1 
               
               
                 897 
                 599 
                 N 
                 N 
                 N 
                 15 
                 117.184 
                 1 
               
               
                 898 
                 600 
                 G 
                 H 
                 H 
                 1 
                 9.054 
                 1 
               
               
                 899 
                 600 
                 G 
                 N 
                 N 
                 15 
                 114.081 
                 1 
               
               
                 900 
                 601 
                 S 
                 CA 
                 C 
                 13 
                 58.424 
                 1 
               
               
                 901 
                 601 
                 S 
                 CB 
                 C 
                 13 
                 60.647 
                 1 
               
               
                 902 
                 601 
                 S 
                 H 
                 H 
                 1 
                 7.855 
                 1 
               
               
                 903 
                 601 
                 S 
                 N 
                 N 
                 15 
                 114.866 
                 1 
               
               
                 904 
                 602 
                 D 
                 CA 
                 C 
                 13 
                 55.181 
                 1 
               
               
                 905 
                 602 
                 D 
                 CB 
                 C 
                 13 
                 40.81 
                 1 
               
               
                 906 
                 602 
                 D 
                 CO 
                 C 
                 13 
                 178.539 
                 1 
               
               
                 907 
                 602 
                 D 
                 H 
                 H 
                 1 
                 7.257 
                 1 
               
               
                 908 
                 602 
                 D 
                 N 
                 N 
                 15 
                 118.282 
                 1 
               
               
                 909 
                 603 
                 C 
                 CA 
                 C 
                 13 
                 60.678 
                 1 
               
               
                 910 
                 603 
                 C 
                 CB 
                 C 
                 13 
                 28.27 
                 1 
               
               
                 911 
                 603 
                 C 
                 CO 
                 C 
                 13 
                 175.783 
                 1 
               
               
                 912 
                 603 
                 C 
                 H 
                 H 
                 1 
                 7.715 
                 1 
               
               
                 913 
                 603 
                 C 
                 N 
                 N 
                 15 
                 121.968 
                 1 
               
               
                 914 
                 604 
                 G 
                 CA 
                 C 
                 13 
                 46.862 
                 1 
               
               
                 915 
                 604 
                 G 
                 CO 
                 C 
                 13 
                 175.076 
                 1 
               
               
                 916 
                 604 
                 G 
                 H 
                 H 
                 1 
                 8.736 
                 1 
               
               
                 917 
                 604 
                 G 
                 N 
                 N 
                 15 
                 109.643 
                 1 
               
               
                 918 
                 605 
                 M 
                 CA 
                 C 
                 13 
                 54.421 
                 1 
               
               
                 919 
                 605 
                 M 
                 CB 
                 C 
                 13 
                 28.885 
                 1 
               
               
                 920 
                 605 
                 M 
                 CO 
                 C 
                 13 
                 178.831 
                 1 
               
               
                 921 
                 605 
                 M 
                 H 
                 H 
                 1 
                 6.973 
                 1 
               
               
                 922 
                 605 
                 M 
                 N 
                 N 
                 15 
                 118.381 
                 1 
               
               
                 923 
                 606 
                 F 
                 CA 
                 C 
                 13 
                 63.186 
                 1 
               
               
                 924 
                 606 
                 F 
                 CB 
                 C 
                 13 
                 37.346 
                 1 
               
               
                 925 
                 606 
                 F 
                 CO 
                 C 
                 13 
                 175.928 
                 1 
               
               
                 926 
                 606 
                 F 
                 H 
                 H 
                 1 
                 8.265 
                 1 
               
               
                 927 
                 606 
                 F 
                 N 
                 N 
                 15 
                 118.962 
                 1 
               
               
                 928 
                 607 
                 A 
                 CA 
                 C 
                 13 
                 55.826 
                 1 
               
               
                 929 
                 607 
                 A 
                 CB 
                 C 
                 13 
                 15.841 
                 1 
               
               
                 930 
                 607 
                 A 
                 CO 
                 C 
                 13 
                 179.705 
                 1 
               
               
                 931 
                 607 
                 A 
                 H 
                 H 
                 1 
                 7.745 
                 1 
               
               
                 932 
                 607 
                 A 
                 N 
                 N 
                 15 
                 118.262 
                 1 
               
               
                 933 
                 608 
                 C 
                 CA 
                 C 
                 13 
                 64.555 
                 1 
               
               
                 934 
                 608 
                 C 
                 CB 
                 C 
                 13 
                 26.489 
                 1 
               
               
                 935 
                 608 
                 C 
                 CO 
                 C 
                 13 
                 176.344 
                 1 
               
               
                 936 
                 608 
                 C 
                 H 
                 H 
                 1 
                 7.15 
                 1 
               
               
                 937 
                 608 
                 C 
                 N 
                 N 
                 15 
                 111.327 
                 1 
               
               
                 938 
                 609 
                 K 
                 CA 
                 C 
                 13 
                 55.983 
                 1 
               
               
                 939 
                 609 
                 K 
                 CB 
                 C 
                 13 
                 28.003 
                 1 
               
               
                 940 
                 609 
                 K 
                 CO 
                 C 
                 13 
                 180.898 
                 1 
               
               
                 941 
                 609 
                 K 
                 H 
                 H 
                 1 
                 8.114 
                 1 
               
               
                 942 
                 609 
                 K 
                 N 
                 N 
                 15 
                 117.546 
                 1 
               
               
                 943 
                 610 
                 Y 
                 CA 
                 C 
                 13 
                 58.081 
                 1 
               
               
                 944 
                 610 
                 Y 
                 CB 
                 C 
                 13 
                 36.268 
                 1 
               
               
                 945 
                 610 
                 Y 
                 CO 
                 C 
                 13 
                 177.942 
                 1 
               
               
                 946 
                 610 
                 Y 
                 H 
                 H 
                 1 
                 9.584 
                 1 
               
               
                 947 
                 610 
                 Y 
                 N 
                 N 
                 15 
                 121.342 
                 1 
               
               
                 948 
                 611 
                 A 
                 CA 
                 C 
                 13 
                 55.284 
                 1 
               
               
                 949 
                 611 
                 A 
                 CB 
                 C 
                 13 
                 17.36 
                 1 
               
               
                 950 
                 611 
                 A 
                 CO 
                 C 
                 13 
                 179.296 
                 1 
               
               
                 951 
                 611 
                 A 
                 H 
                 H 
                 1 
                 7.3 
                 1 
               
               
                 952 
                 611 
                 A 
                 N 
                 N 
                 15 
                 118.235 
                 1 
               
               
                 953 
                 612 
                 D 
                 CA 
                 C 
                 13 
                 57.496 
                 1 
               
               
                 954 
                 612 
                 D 
                 CB 
                 C 
                 13 
                 40.809 
                 1 
               
               
                 955 
                 612 
                 D 
                 CO 
                 C 
                 13 
                 177.083 
                 1 
               
               
                 956 
                 612 
                 D 
                 H 
                 H 
                 1 
                 8.285 
                 1 
               
               
                 957 
                 612 
                 D 
                 N 
                 N 
                 15 
                 119.051 
                 1 
               
               
                 958 
                 613 
                 C 
                 CA 
                 C 
                 13 
                 64.249 
                 1 
               
               
                 959 
                 613 
                 C 
                 CB 
                 C 
                 13 
                 26.401 
                 1 
               
               
                 960 
                 613 
                 C 
                 CO 
                 C 
                 13 
                 177.033 
                 1 
               
               
                 961 
                 613 
                 C 
                 H 
                 H 
                 1 
                 7.283 
                 1 
               
               
                 962 
                 613 
                 C 
                 N 
                 N 
                 15 
                 114.15 
                 1 
               
               
                 963 
                 614 
                 I 
                 CA 
                 C 
                 13 
                 64.188 
                 1 
               
               
                 964 
                 614 
                 I 
                 CB 
                 C 
                 13 
                 38.287 
                 1 
               
               
                 965 
                 614 
                 I 
                 CO 
                 C 
                 13 
                 180.531 
                 1 
               
               
                 966 
                 614 
                 I 
                 H 
                 H 
                 1 
                 8.523 
                 1 
               
               
                 967 
                 614 
                 I 
                 N 
                 N 
                 15 
                 119.103 
                 1 
               
               
                 968 
                 615 
                 T 
                 CB 
                 C 
                 13 
                 67.658 
                 1 
               
               
                 969 
                 615 
                 T 
                 CO 
                 C 
                 13 
                 174.525 
                 1 
               
               
                 970 
                 615 
                 T 
                 H 
                 H 
                 1 
                 8.251 
                 1 
               
               
                 971 
                 615 
                 T 
                 N 
                 N 
                 15 
                 108.325 
                 1 
               
               
                 972 
                 616 
                 K 
                 CA 
                 C 
                 13 
                 55.419 
                 1 
               
               
                 973 
                 616 
                 K 
                 CB 
                 C 
                 13 
                 31.971 
                 1 
               
               
                 974 
                 616 
                 K 
                 CO 
                 C 
                 13 
                 175.509 
                 1 
               
               
                 975 
                 616 
                 K 
                 H 
                 H 
                 1 
                 7.204 
                 1 
               
               
                 976 
                 616 
                 K 
                 N 
                 N 
                 15 
                 118.784 
                 1 
               
               
                 977 
                 617 
                 D 
                 CA 
                 C 
                 13 
                 55.028 
                 1 
               
               
                 978 
                 617 
                 D 
                 CB 
                 C 
                 13 
                 38.871 
                 1 
               
               
                 979 
                 617 
                 D 
                 CO 
                 C 
                 13 
                 174.882 
                 1 
               
               
                 980 
                 617 
                 D 
                 H 
                 H 
                 1 
                 7.982 
                 1 
               
               
                 981 
                 617 
                 D 
                 N 
                 N 
                 15 
                 117.696 
                 1 
               
               
                 982 
                 618 
                 R 
                 CA 
                 C 
                 13 
                 51.906 
                 1 
               
               
                 983 
                 618 
                 R 
                 CB 
                 C 
                 13 
                 30.614 
                 1 
               
               
                 984 
                 618 
                 R 
                 CO 
                 C 
                 13 
                 173.638 
                 1 
               
               
                 985 
                 618 
                 R 
                 H 
                 H 
                 1 
                 7.893 
                 1 
               
               
                 986 
                 618 
                 R 
                 N 
                 N 
                 15 
                 116.707 
                 1 
               
               
                 987 
                 620 
                 I 
                 CA 
                 C 
                 13 
                 62.112 
                 1 
               
               
                 988 
                 620 
                 I 
                 CB 
                 C 
                 13 
                 35.731 
                 1 
               
               
                 989 
                 620 
                 I 
                 CO 
                 C 
                 13 
                 177.018 
                 1 
               
               
                 990 
                 620 
                 I 
                 H 
                 H 
                 1 
                 8.465 
                 1 
               
               
                 991 
                 620 
                 I 
                 N 
                 N 
                 15 
                 121.915 
                 1 
               
               
                 992 
                 621 
                 N 
                 CA 
                 C 
                 13 
                 52.404 
                 1 
               
               
                 993 
                 621 
                 N 
                 CB 
                 C 
                 13 
                 38.108 
                 1 
               
               
                 994 
                 621 
                 N 
                 H 
                 H 
                 1 
                 7.952 
                 1 
               
               
                 995 
                 621 
                 N 
                 N 
                 N 
                 15 
                 126.058 
                 1 
               
               
                 996 
                 622 
                 F 
                 CA 
                 C 
                 13 
                 54.399 
                 1 
               
               
                 997 
                 622 
                 F 
                 CB 
                 C 
                 13 
                 41.066 
                 1 
               
               
                 998 
                 622 
                 F 
                 CO 
                 C 
                 13 
                 173.442 
                 1 
               
               
                 999 
                 622 
                 F 
                 H 
                 H 
                 1 
                 6.573 
                 1 
               
               
                 1000 
                 622 
                 F 
                 N 
                 N 
                 15 
                 114.01 
                 1 
               
               
                 1001 
                 623 
                 T 
                 CA 
                 C 
                 13 
                 59.922 
                 1 
               
               
                 1002 
                 623 
                 T 
                 CB 
                 C 
                 13 
                 73.255 
                 1 
               
               
                 1003 
                 623 
                 T 
                 H 
                 H 
                 1 
                 11.019 
                 1 
               
               
                 1004 
                 623 
                 T 
                 N 
                 N 
                 15 
                 112.666 
                 1 
               
               
                 1005 
                 624 
                 Q 
                 CA 
                 C 
                 13 
                 57.991 
                 1 
               
               
                 1006 
                 624 
                 Q 
                 CB 
                 C 
                 13 
                 28.115 
                 1 
               
               
                 1007 
                 624 
                 Q 
                 CO 
                 C 
                 13 
                 177.817 
                 1 
               
               
                 1008 
                 624 
                 Q 
                 H 
                 H 
                 1 
                 9.841 
                 1 
               
               
                 1009 
                 624 
                 Q 
                 N 
                 N 
                 15 
                 118.693 
                 1 
               
               
                 1010 
                 625 
                 Q 
                 CA 
                 C 
                 13 
                 57.772 
                 1 
               
               
                 1011 
                 625 
                 Q 
                 CB 
                 C 
                 13 
                 27.232 
                 1 
               
               
                 1012 
                 625 
                 Q 
                 CO 
                 C 
                 13 
                 177.118 
                 1 
               
               
                 1013 
                 625 
                 Q 
                 H 
                 H 
                 1 
                 8.35 
                 1 
               
               
                 1014 
                 625 
                 Q 
                 N 
                 N 
                 15 
                 118.528 
                 1 
               
               
                 1015 
                 626 
                 H 
                 CA 
                 C 
                 13 
                 59.023 
                 1 
               
               
                 1016 
                 626 
                 H 
                 CB 
                 C 
                 13 
                 32.018 
                 1 
               
               
                 1017 
                 626 
                 H 
                 CO 
                 C 
                 13 
                 175.195 
                 1 
               
               
                 1018 
                 626 
                 H 
                 H 
                 H 
                 1 
                 7.69 
                 1 
               
               
                 1019 
                 626 
                 H 
                 N 
                 N 
                 15 
                 116.12 
                 1 
               
               
                 1020 
                 627 
                 M 
                 CA 
                 C 
                 13 
                 58.703 
                 1 
               
               
                 1021 
                 627 
                 M 
                 CB 
                 C 
                 13 
                 29.282 
                 1 
               
               
                 1022 
                 627 
                 M 
                 CO 
                 C 
                 13 
                 175.481 
                 1 
               
               
                 1023 
                 627 
                 M 
                 H 
                 H 
                 1 
                 7.581 
                 1 
               
               
                 1024 
                 627 
                 M 
                 N 
                 N 
                 15 
                 117.619 
                 1 
               
               
                 1025 
                 629 
                 Y 
                 CA 
                 C 
                 13 
                 59.898 
                 1 
               
               
                 1026 
                 629 
                 Y 
                 CB 
                 C 
                 13 
                 36.935 
                 1 
               
               
                 1027 
                 629 
                 Y 
                 CO 
                 C 
                 13 
                 176.303 
                 1 
               
               
                 1028 
                 629 
                 Y 
                 H 
                 H 
                 1 
                 7.455 
                 1 
               
               
                 1029 
                 629 
                 Y 
                 N 
                 N 
                 15 
                 119.231 
                 1 
               
               
                 1030 
                 630 
                 F 
                 CA 
                 C 
                 13 
                 57.548 
                 1 
               
               
                 1031 
                 630 
                 F 
                 CO 
                 C 
                 13 
                 179.707 
                 1 
               
               
                 1032 
                 630 
                 F 
                 H 
                 H 
                 1 
                 8.72 
                 1 
               
               
                 1033 
                 630 
                 F 
                 N 
                 N 
                 15 
                 118.661 
                 1 
               
               
                 1034 
                 631 
                 R 
                 CA 
                 C 
                 13 
                 59.879 
                 1 
               
               
                 1035 
                 631 
                 R 
                 CB 
                 C 
                 13 
                 29.774 
                 1 
               
               
                 1036 
                 631 
                 R 
                 CO 
                 C 
                 13 
                 177.119 
                 1 
               
               
                 1037 
                 631 
                 R 
                 H 
                 H 
                 1 
                 8.743 
                 1 
               
               
                 1038 
                 631 
                 R 
                 N 
                 N 
                 15 
                 121.276 
                 1 
               
               
                 1039 
                 632 
                 K 
                 CB 
                 C 
                 13 
                 32.019 
                 1 
               
               
                 1040 
                 632 
                 K 
                 CO 
                 C 
                 13 
                 178.005 
                 1 
               
               
                 1041 
                 632 
                 K 
                 H 
                 H 
                 1 
                 7.027 
                 1 
               
               
                 1042 
                 632 
                 K 
                 N 
                 N 
                 15 
                 115.472 
                 1 
               
               
                 1043 
                 633 
                 R 
                 CA 
                 C 
                 13 
                 59.11 
                 1 
               
               
                 1044 
                 633 
                 R 
                 CB 
                 C 
                 13 
                 30.377 
                 1 
               
               
                 1045 
                 633 
                 R 
                 H 
                 H 
                 1 
                 8.483 
                 1 
               
               
                 1046 
                 633 
                 R 
                 N 
                 N 
                 15 
                 116.56 
                 1 
               
               
                 1047 
                 634 
                 M 
                 CA 
                 C 
                 13 
                 57.95 
                 1 
               
               
                 1048 
                 634 
                 M 
                 CB 
                 C 
                 13 
                 31.937 
                 1 
               
               
                 1049 
                 634 
                 M 
                 H 
                 H 
                 1 
                 8.212 
                 1 
               
               
                 1050 
                 634 
                 M 
                 N 
                 N 
                 15 
                 116.933 
                 1 
               
               
                 1051 
                 635 
                 V 
                 CA 
                 C 
                 13 
                 66.729 
                 1 
               
               
                 1052 
                 635 
                 V 
                 CB 
                 C 
                 13 
                 30.848 
                 1 
               
               
                 1053 
                 635 
                 V 
                 CG1 
                 C 
                 13 
                 22.182 
                 1 
               
               
                 1054 
                 635 
                 V 
                 CG2 
                 C 
                 13 
                 24.307 
                 1 
               
               
                 1055 
                 635 
                 V 
                 CO 
                 C 
                 13 
                 176.781 
                 1 
               
               
                 1056 
                 635 
                 V 
                 H 
                 H 
                 1 
                 7.401 
                 1 
               
               
                 1057 
                 635 
                 V 
                 HG1 
                 H 
                 1 
                 0.511 
                 1 
               
               
                 1058 
                 635 
                 V 
                 HG2 
                 H 
                 1 
                 1.078 
                 1 
               
               
                 1059 
                 635 
                 V 
                 N 
                 N 
                 15 
                 117.807 
                 1 
               
               
                 1060 
                 636 
                 W 
                 CA 
                 C 
                 13 
                 63.021 
                 1 
               
               
                 1061 
                 636 
                 W 
                 CB 
                 C 
                 13 
                 28.855 
                 1 
               
               
                 1062 
                 636 
                 W 
                 CO 
                 C 
                 13 
                 177.991 
                 1 
               
               
                 1063 
                 636 
                 W 
                 H 
                 H 
                 1 
                 6.945 
                 1 
               
               
                 1064 
                 636 
                 W 
                 HE1 
                 H 
                 1 
                 10.208 
                 1 
               
               
                 1065 
                 636 
                 W 
                 N 
                 N 
                 15 
                 117.761 
                 1 
               
               
                 1066 
                 636 
                 W 
                 NE1 
                 N 
                 15 
                 131.254 
                 1 
               
               
                 1067 
                 637 
                 E 
                 CA 
                 C 
                 13 
                 59.634 
                 1 
               
               
                 1068 
                 637 
                 E 
                 CB 
                 C 
                 13 
                 29.54 
                 1 
               
               
                 1069 
                 637 
                 E 
                 CO 
                 C 
                 13 
                 179.549 
                 1 
               
               
                 1070 
                 637 
                 E 
                 H 
                 H 
                 1 
                 8.942 
                 1 
               
               
                 1071 
                 637 
                 E 
                 N 
                 N 
                 15 
                 118.312 
                 1 
               
               
                 1072 
                 638 
                 I 
                 CA 
                 C 
                 13 
                 65.061 
                 1 
               
               
                 1073 
                 638 
                 I 
                 CB 
                 C 
                 13 
                 36.564 
                 1 
               
               
                 1074 
                 638 
                 I 
                 CO 
                 C 
                 13 
                 178.793 
                 1 
               
               
                 1075 
                 638 
                 I 
                 H 
                 H 
                 1 
                 8.516 
                 1 
               
               
                 1076 
                 638 
                 I 
                 N 
                 N 
                 15 
                 118.151 
                 1 
               
               
                 1077 
                 639 
                 L 
                 CA 
                 C 
                 13 
                 57.489 
                 1 
               
               
                 1078 
                 639 
                 L 
                 CB 
                 C 
                 13 
                 40.751 
                 1 
               
               
                 1079 
                 639 
                 L 
                 CD1 
                 C 
                 13 
                 25.065 
                 1 
               
               
                 1080 
                 639 
                 L 
                 CD2 
                 C 
                 13 
                 22.821 
                 1 
               
               
                 1081 
                 639 
                 L 
                 H 
                 H 
                 1 
                 8.021 
                 1 
               
               
                 1082 
                 639 
                 L 
                 HD1 
                 H 
                 1 
                 0.577 
                 1 
               
               
                 1083 
                 639 
                 L 
                 HD2 
                 H 
                 1 
                 0.498 
                 1 
               
               
                 1084 
                 639 
                 L 
                 N 
                 N 
                 15 
                 119.857 
                 1 
               
               
                 1085 
                 640 
                 H 
                 CA 
                 C 
                 13 
                 55.633 
                 1 
               
               
                 1086 
                 640 
                 H 
                 CB 
                 C 
                 13 
                 26.845 
                 1 
               
               
                 1087 
                 640 
                 H 
                 H 
                 H 
                 1 
                 7.758 
                 1 
               
               
                 1088 
                 640 
                 H 
                 N 
                 N 
                 15 
                 112.218 
                 1 
               
               
                 1089 
                 641 
                 R 
                 CA 
                 C 
                 13 
                 56.955 
                 1 
               
               
                 1090 
                 641 
                 R 
                 CB 
                 C 
                 13 
                 25.944 
                 1 
               
               
                 1091 
                 641 
                 R 
                 CO 
                 C 
                 13 
                 174.773 
                 1 
               
               
                 1092 
                 641 
                 R 
                 H 
                 H 
                 1 
                 7.879 
                 1 
               
               
                 1093 
                 641 
                 R 
                 N 
                 N 
                 15 
                 122.564 
                 1 
               
               
                 1094 
                 642 
                 K 
                 CA 
                 C 
                 13 
                 54.648 
                 1 
               
               
                 1095 
                 642 
                 K 
                 CB 
                 C 
                 13 
                 34.915 
                 1 
               
               
                 1096 
                 642 
                 K 
                 CO 
                 C 
                 13 
                 172.886 
                 1 
               
               
                 1097 
                 642 
                 K 
                 H 
                 H 
                 1 
                 8.22 
                 1 
               
               
                 1098 
                 642 
                 K 
                 N 
                 N 
                 15 
                 121.148 
                 1 
               
               
                 1099 
                 643 
                 L 
                 CA 
                 C 
                 13 
                 53.678 
                 1 
               
               
                 1100 
                 643 
                 L 
                 CB 
                 C 
                 13 
                 41.237 
                 1 
               
               
                 1101 
                 643 
                 L 
                 CD1 
                 C 
                 13 
                 27.306 
                 1 
               
               
                 1102 
                 643 
                 L 
                 CD2 
                 C 
                 13 
                 24.45 
                 1 
               
               
                 1103 
                 643 
                 L 
                 CO 
                 C 
                 13 
                 177.594 
                 1 
               
               
                 1104 
                 643 
                 L 
                 H 
                 H 
                 1 
                 8.136 
                 1 
               
               
                 1105 
                 643 
                 L 
                 HD1 
                 H 
                 1 
                 0.395 
                 1 
               
               
                 1106 
                 643 
                 L 
                 HD2 
                 H 
                 1 
                 0.572 
                 1 
               
               
                 1107 
                 643 
                 L 
                 N 
                 N 
                 15 
                 122.205 
                 1 
               
               
                 1108 
                 644 
                 L 
                 CA 
                 C 
                 13 
                 55.222 
                 1 
               
               
                 1109 
                 644 
                 L 
                 CB 
                 C 
                 13 
                 41.615 
                 1 
               
               
                 1110 
                 644 
                 L 
                 CO 
                 C 
                 13 
                 182.082 
                 1 
               
               
                 1111 
                 644 
                 L 
                 H 
                 H 
                 1 
                 8.863 
                 1 
               
               
                 1112 
                 644 
                 L 
                 N 
                 N 
                 15 
                 130.114 
                 1 
               
               
                   
               
               
                 *referenced using DSS (4,4-dimethyl-4-silapentane-1-sulfonic acid) as the H-1 standard with IUPAC-IUB recommended chemical shift referencing ratios. See, Wishart, et al., “1H, 13C and 15N Chemical Shift Referencing in Biomolecular NMR,” J. Biomol. NMR 6: 135-140 (1995); and Markley et al., “Recommendations for the Presentation of NMR Structures of Proteins and Nucleic Acids,”. Pure &amp; Appl. Chem. 70: 117-142 (1998). 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
               
                   
               
               
                 SENP1 C603S-SUMO 1-92  NMR Chemical Shift Values. 
               
               
                 Chemical Shift Ambiguity Index Value Definitions 
               
               
                 The values other than 1 are used for those atoms with 
               
               
                 different chemical shifts that cannot be assigned to 
               
               
                 stereospecific atoms or to specific residues or chains. 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Index 
                   
               
               
                 Value 
                 Definition 
               
               
                   
               
               
                 1 
                 Unique (including isolated methyl protons germinal atoms, 
               
               
                   
                 and geminal methyl groups with identical chemical shifts 
               
               
                   
                 (e.g. ILE HD11, HD12, HD13 protons) 
               
               
                 2 
                 Ambiguity of geminal atoms or geminal methyl proton groups 
               
               
                   
                 (e.g. ASP HB2 and HB3 protons, LEU CD1 and CD2 carbons, 
               
               
                   
                 or LEU HD11, HD12, HD13 and HD21, HD22, HD23 methyl 
               
               
                   
                 protons) 
               
               
                 3 
                 Aromatic atoms on opposite sides of symmetrical rings 
               
               
                   
                 (e.g. TYR HE1 and HE2 protons) 
               
               
                 4 
                 Intraresidue ambiguities (e.g. LYS HG and HD protons or 
               
               
                   
                 TRP HZ2 and HZ3 protons) 
               
               
                 5 
                 Interresidue ambiguities (LYS 12 vs. LYS 27) 
               
               
                 6 
                 Intermolecular ambiguities (e.g. ASP 31 CA in monomer 1 
               
               
                   
                 and ASP 31 CA in monomer 2 of an asymmetrical homodimer, 
               
               
                   
                 duplex DNA assignments, or other assignments that may apply 
               
               
                   
                 to atoms in one or more molecule in the molecular assembly) 
               
               
                 9 
                 Ambiguous, specific ambiguity not defined 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 Chemical 
                   
               
               
                 Atom 
                 Residue 
                 Amino 
                 Atom 
                 Atom 
                 Iso- 
                 shift 
                 Unique- 
               
               
                 number 
                 number 
                 acid 
                 context 
                 type 
                 type 
                 (ppm)* 
                 ness 
               
               
                   
               
               
                 1 
                 419 
                 E 
                 H 
                 H 
                 1 
                 7.974 
                 1 
               
               
                 2 
                 419 
                 E 
                 N 
                 N 
                 15 
                 121.157 
                 1 
               
               
                 3 
                 420 
                 F 
                 H 
                 H 
                 1 
                 7.947 
                 1 
               
               
                 4 
                 420 
                 F 
                 N 
                 N 
                 15 
                 119.83 
                 1 
               
               
                 5 
                 422 
                 E 
                 H 
                 H 
                 1 
                 8.562 
                 1 
               
               
                 6 
                 422 
                 E 
                 N 
                 N 
                 15 
                 125.045 
                 1 
               
               
                 7 
                 423 
                 I 
                 H 
                 H 
                 1 
                 8.443 
                 1 
               
               
                 8 
                 423 
                 I 
                 N 
                 N 
                 15 
                 123.042 
                 1 
               
               
                 9 
                 424 
                 T 
                 H 
                 H 
                 1 
                 7.558 
                 1 
               
               
                 10 
                 424 
                 T 
                 N 
                 N 
                 15 
                 122.22 
                 1 
               
               
                 11 
                 425 
                 E 
                 H 
                 H 
                 1 
                 8.835 
                 1 
               
               
                 12 
                 425 
                 E 
                 N 
                 N 
                 15 
                 122.015 
                 1 
               
               
                 13 
                 426 
                 E 
                 H 
                 H 
                 1 
                 8.343 
                 1 
               
               
                 14 
                 426 
                 E 
                 N 
                 N 
                 15 
                 119.067 
                 1 
               
               
                 15 
                 427 
                 M 
                 H 
                 H 
                 1 
                 7.295 
                 1 
               
               
                 16 
                 427 
                 M 
                 N 
                 N 
                 15 
                 120.177 
                 1 
               
               
                 17 
                 428 
                 E 
                 H 
                 H 
                 1 
                 8.525 
                 1 
               
               
                 18 
                 428 
                 E 
                 N 
                 N 
                 15 
                 119.639 
                 1 
               
               
                 19 
                 429 
                 K 
                 H 
                 H 
                 1 
                 7.793 
                 1 
               
               
                 20 
                 429 
                 K 
                 N 
                 N 
                 15 
                 119.161 
                 1 
               
               
                 21 
                 430 
                 E 
                 H 
                 H 
                 1 
                 7.247 
                 1 
               
               
                 22 
                 430 
                 E 
                 N 
                 N 
                 15 
                 120.017 
                 1 
               
               
                 23 
                 432 
                 K 
                 H 
                 H 
                 1 
                 8.269 
                 1 
               
               
                 24 
                 432 
                 K 
                 N 
                 N 
                 15 
                 117.252 
                 1 
               
               
                 25 
                 433 
                 D 
                 H 
                 H 
                 1 
                 7.542 
                 1 
               
               
                 26 
                 433 
                 D 
                 N 
                 N 
                 15 
                 116.02 
                 1 
               
               
                 27 
                 434 
                 V 
                 CG1 
                 C 
                 13 
                 22.744 
                 1 
               
               
                 28 
                 434 
                 V 
                 H 
                 H 
                 1 
                 7.456 
                 1 
               
               
                 29 
                 434 
                 V 
                 N 
                 N 
                 15 
                 115.391 
                 1 
               
               
                 32 
                 434 
                 V 
                 HG1 
                 H 
                 1 
                 0.768 
                 1 
               
               
                 33 
                 435 
                 F 
                 H 
                 H 
                 1 
                 7.229 
                 1 
               
               
                 34 
                 435 
                 F 
                 N 
                 N 
                 15 
                 118.53 
                 1 
               
               
                 35 
                 436 
                 R 
                 H 
                 H 
                 1 
                 7.082 
                 1 
               
               
                 36 
                 436 
                 R 
                 N 
                 N 
                 15 
                 119.966 
                 1 
               
               
                 37 
                 437 
                 D 
                 H 
                 H 
                 1 
                 8.266 
                 1 
               
               
                 38 
                 437 
                 D 
                 N 
                 N 
                 15 
                 120.742 
                 1 
               
               
                 39 
                 438 
                 G 
                 H 
                 H 
                 1 
                 7.994 
                 1 
               
               
                 40 
                 438 
                 G 
                 N 
                 N 
                 15 
                 110.561 
                 1 
               
               
                 41 
                 439 
                 D 
                 H 
                 H 
                 1 
                 8.68 
                 1 
               
               
                 42 
                 439 
                 D 
                 N 
                 N 
                 15 
                 121.505 
                 1 
               
               
                 43 
                 440 
                 Q 
                 H 
                 H 
                 1 
                 8.954 
                 1 
               
               
                 44 
                 440 
                 Q 
                 N 
                 N 
                 15 
                 126.9 
                 1 
               
               
                 45 
                 441 
                 D 
                 H 
                 H 
                 1 
                 7.858 
                 1 
               
               
                 46 
                 441 
                 D 
                 N 
                 N 
                 15 
                 115.853 
                 1 
               
               
                 47 
                 442 
                 E 
                 H 
                 H 
                 1 
                 7.08 
                 1 
               
               
                 48 
                 442 
                 E 
                 N 
                 N 
                 15 
                 122.689 
                 1 
               
               
                 49 
                 443 
                 V 
                 CG1 
                 C 
                 13 
                 21.595 
                 1 
               
               
                 50 
                 443 
                 V 
                 CG2 
                 C 
                 13 
                 22.122 
                 1 
               
               
                 51 
                 443 
                 V 
                 H 
                 H 
                 1 
                 8.563 
                 1 
               
               
                 52 
                 443 
                 V 
                 N 
                 N 
                 15 
                 128.078 
                 1 
               
               
                 55 
                 443 
                 V 
                 HG1 
                 H 
                 1 
                 0.731 
                 1 
               
               
                 58 
                 443 
                 V 
                 HG2 
                 H 
                 1 
                 0.896 
                 1 
               
               
                 59 
                 444 
                 L 
                 CD1 
                 C 
                 13 
                 27.192 
                 1 
               
               
                 60 
                 444 
                 L 
                 H 
                 H 
                 1 
                 8.928 
                 1 
               
               
                 61 
                 444 
                 L 
                 N 
                 N 
                 15 
                 128.342 
                 1 
               
               
                 64 
                 444 
                 L 
                 HD1 
                 H 
                 1 
                 0.609 
                 1 
               
               
                 65 
                 445 
                 S 
                 H 
                 H 
                 1 
                 7.327 
                 1 
               
               
                 66 
                 445 
                 S 
                 N 
                 N 
                 15 
                 112.548 
                 1 
               
               
                 67 
                 446 
                 E 
                 H 
                 H 
                 1 
                 7.889 
                 1 
               
               
                 68 
                 446 
                 E 
                 N 
                 N 
                 15 
                 125.959 
                 1 
               
               
                 69 
                 447 
                 A 
                 H 
                 H 
                 1 
                 8.267 
                 1 
               
               
                 70 
                 447 
                 A 
                 N 
                 N 
                 15 
                 125.511 
                 1 
               
               
                 71 
                 448 
                 F 
                 H 
                 H 
                 1 
                 8.549 
                 1 
               
               
                 72 
                 448 
                 F 
                 N 
                 N 
                 15 
                 117.045 
                 1 
               
               
                 73 
                 449 
                 R 
                 H 
                 H 
                 1 
                 8.43 
                 1 
               
               
                 74 
                 449 
                 R 
                 N 
                 N 
                 15 
                 112.963 
                 1 
               
               
                 75 
                 450 
                 L 
                 CD1 
                 C 
                 13 
                 26.152 
                 1 
               
               
                 76 
                 450 
                 L 
                 CD2 
                 C 
                 13 
                 23.171 
                 1 
               
               
                 77 
                 450 
                 L 
                 H 
                 H 
                 1 
                 8.288 
                 1 
               
               
                 78 
                 450 
                 L 
                 N 
                 N 
                 15 
                 121.64 
                 1 
               
               
                 81 
                 450 
                 L 
                 HD1 
                 H 
                 1 
                 0.918 
                 1 
               
               
                 84 
                 450 
                 L 
                 HD2 
                 H 
                 1 
                 1.032 
                 1 
               
               
                 85 
                 451 
                 T 
                 H 
                 H 
                 1 
                 8.297 
                 1 
               
               
                 86 
                 451 
                 T 
                 N 
                 N 
                 15 
                 113.505 
                 1 
               
               
                 87 
                 452 
                 I 
                 H 
                 H 
                 1 
                 8.385 
                 1 
               
               
                 88 
                 452 
                 I 
                 N 
                 N 
                 15 
                 124.62 
                 1 
               
               
                 89 
                 453 
                 T 
                 H 
                 H 
                 1 
                 9.666 
                 1 
               
               
                 90 
                 453 
                 T 
                 N 
                 N 
                 15 
                 120.795 
                 1 
               
               
                 91 
                 454 
                 R 
                 H 
                 H 
                 1 
                 8.168 
                 1 
               
               
                 92 
                 454 
                 R 
                 N 
                 N 
                 15 
                 123.055 
                 1 
               
               
                 93 
                 455 
                 K 
                 H 
                 H 
                 1 
                 8.41 
                 1 
               
               
                 94 
                 455 
                 K 
                 N 
                 N 
                 15 
                 120.473 
                 1 
               
               
                 95 
                 456 
                 D 
                 H 
                 H 
                 1 
                 7.227 
                 1 
               
               
                 96 
                 456 
                 D 
                 N 
                 N 
                 15 
                 118.114 
                 1 
               
               
                 97 
                 457 
                 I 
                 H 
                 H 
                 1 
                 8.102 
                 1 
               
               
                 98 
                 457 
                 I 
                 N 
                 N 
                 15 
                 122.652 
                 1 
               
               
                 99 
                 458 
                 Q 
                 H 
                 H 
                 1 
                 7.821 
                 1 
               
               
                 100 
                 458 
                 Q 
                 N 
                 N 
                 15 
                 119.174 
                 1 
               
               
                 101 
                 459 
                 T 
                 H 
                 H 
                 1 
                 7.826 
                 1 
               
               
                 102 
                 459 
                 T 
                 N 
                 N 
                 15 
                 114.259 
                 1 
               
               
                 103 
                 460 
                 L 
                 CD1 
                 C 
                 13 
                 26.138 
                 1 
               
               
                 104 
                 460 
                 L 
                 CD2 
                 C 
                 13 
                 26.003 
                 1 
               
               
                 105 
                 460 
                 L 
                 H 
                 H 
                 1 
                 7.18 
                 1 
               
               
                 106 
                 460 
                 L 
                 N 
                 N 
                 15 
                 116.293 
                 1 
               
               
                 109 
                 460 
                 L 
                 HD1 
                 H 
                 1 
                 0.845 
                 1 
               
               
                 112 
                 460 
                 L 
                 HD2 
                 H 
                 1 
                 0.954 
                 1 
               
               
                 113 
                 461 
                 D 
                 H 
                 H 
                 1 
                 7.356 
                 1 
               
               
                 114 
                 461 
                 D 
                 N 
                 N 
                 15 
                 121.211 
                 1 
               
               
                 115 
                 462 
                 H 
                 H 
                 H 
                 1 
                 7.659 
                 1 
               
               
                 116 
                 462 
                 H 
                 N 
                 N 
                 15 
                 120.742 
                 1 
               
               
                 117 
                 465 
                 W 
                 H 
                 H 
                 1 
                 8.258 
                 1 
               
               
                 118 
                 465 
                 W 
                 N 
                 N 
                 15 
                 121.504 
                 1 
               
               
                 119 
                 465 
                 W 
                 HE1 
                 H 
                 1 
                 9.997 
                 1 
               
               
                 120 
                 465 
                 W 
                 NE1 
                 H 
                 1 
                 130.62 
                 1 
               
               
                 121 
                 466 
                 L 
                 CD1 
                 C 
                 13 
                 25.625 
                 1 
               
               
                 122 
                 466 
                 L 
                 CD2 
                 C 
                 13 
                 23.625 
                 1 
               
               
                 123 
                 466 
                 L 
                 H 
                 H 
                 1 
                 7.529 
                 1 
               
               
                 124 
                 466 
                 L 
                 N 
                 N 
                 15 
                 126.826 
                 1 
               
               
                 127 
                 466 
                 L 
                 HD1 
                 H 
                 1 
                 0.684 
                 1 
               
               
                 130 
                 466 
                 L 
                 HD2 
                 H 
                 1 
                 0.704 
                 1 
               
               
                 131 
                 467 
                 D 
                 H 
                 H 
                 1 
                 6.937 
                 1 
               
               
                 132 
                 467 
                 D 
                 N 
                 N 
                 15 
                 117.87 
                 1 
               
               
                 133 
                 468 
                 D 
                 H 
                 H 
                 1 
                 8.19 
                 1 
               
               
                 134 
                 468 
                 D 
                 N 
                 N 
                 15 
                 115.279 
                 1 
               
               
                 135 
                 470 
                 I 
                 H 
                 H 
                 1 
                 7.581 
                 1 
               
               
                 136 
                 470 
                 I 
                 N 
                 N 
                 15 
                 118.739 
                 1 
               
               
                 137 
                 471 
                 I 
                 H 
                 H 
                 1 
                 6.823 
                 1 
               
               
                 138 
                 471 
                 I 
                 N 
                 N 
                 15 
                 118.333 
                 1 
               
               
                 139 
                 472 
                 D 
                 H 
                 H 
                 1 
                 8.781 
                 1 
               
               
                 140 
                 472 
                 D 
                 N 
                 N 
                 15 
                 116.126 
                 1 
               
               
                 141 
                 473 
                 F 
                 H 
                 H 
                 1 
                 8.248 
                 1 
               
               
                 142 
                 473 
                 F 
                 N 
                 N 
                 15 
                 124.484 
                 1 
               
               
                 143 
                 475 
                 M 
                 H 
                 H 
                 1 
                 8.642 
                 1 
               
               
                 144 
                 475 
                 M 
                 N 
                 N 
                 15 
                 116.267 
                 1 
               
               
                 145 
                 476 
                 D 
                 H 
                 H 
                 1 
                 7.328 
                 1 
               
               
                 146 
                 476 
                 D 
                 N 
                 N 
                 15 
                 118.167 
                 1 
               
               
                 147 
                 477 
                 M 
                 H 
                 H 
                 1 
                 7.588 
                 1 
               
               
                 148 
                 477 
                 M 
                 N 
                 N 
                 15 
                 122.218 
                 1 
               
               
                 149 
                 478 
                 L 
                 CD1 
                 C 
                 13 
                 27.574 
                 1 
               
               
                 150 
                 478 
                 L 
                 CD2 
                 C 
                 13 
                 22.365 
                 1 
               
               
                 151 
                 478 
                 L 
                 H 
                 H 
                 1 
                 7.689 
                 1 
               
               
                 152 
                 478 
                 L 
                 N 
                 N 
                 15 
                 121.041 
                 1 
               
               
                 155 
                 478 
                 L 
                 HD1 
                 H 
                 1 
                 0.707 
                 1 
               
               
                 158 
                 478 
                 L 
                 HD2 
                 H 
                 1 
                 0.458 
                 1 
               
               
                 159 
                 479 
                 M 
                 H 
                 H 
                 1 
                 7.581 
                 1 
               
               
                 160 
                 479 
                 M 
                 N 
                 N 
                 15 
                 120.182 
                 1 
               
               
                 161 
                 480 
                 E 
                 H 
                 H 
                 1 
                 8.04 
                 1 
               
               
                 162 
                 480 
                 E 
                 N 
                 N 
                 15 
                 123.808 
                 1 
               
               
                 163 
                 481 
                 R 
                 H 
                 H 
                 1 
                 7.872 
                 1 
               
               
                 164 
                 481 
                 R 
                 N 
                 N 
                 15 
                 121.587 
                 1 
               
               
                 165 
                 482 
                 S 
                 H 
                 H 
                 1 
                 7.133 
                 1 
               
               
                 166 
                 482 
                 S 
                 N 
                 N 
                 15 
                 114.199 
                 1 
               
               
                 167 
                 483 
                 K 
                 H 
                 H 
                 1 
                 6.896 
                 1 
               
               
                 168 
                 483 
                 K 
                 N 
                 N 
                 15 
                 119.755 
                 1 
               
               
                 169 
                 484 
                 E 
                 H 
                 H 
                 1 
                 8.035 
                 1 
               
               
                 170 
                 484 
                 E 
                 N 
                 N 
                 15 
                 122.017 
                 1 
               
               
                 171 
                 485 
                 K 
                 H 
                 H 
                 1 
                 8.183 
                 1 
               
               
                 172 
                 485 
                 K 
                 N 
                 N 
                 15 
                 122.621 
                 1 
               
               
                 173 
                 486 
                 G 
                 H 
                 H 
                 1 
                 8.674 
                 1 
               
               
                 174 
                 486 
                 G 
                 N 
                 N 
                 15 
                 112.424 
                 1 
               
               
                 175 
                 487 
                 L 
                 CD1 
                 C 
                 13 
                 25.976 
                 1 
               
               
                 176 
                 487 
                 L 
                 CD2 
                 C 
                 13 
                 23.426 
                 1 
               
               
                 177 
                 487 
                 L 
                 H 
                 H 
                 1 
                 7.277 
                 1 
               
               
                 178 
                 487 
                 L 
                 N 
                 N 
                 15 
                 122.648 
                 1 
               
               
                 181 
                 487 
                 L 
                 HD1 
                 H 
                 1 
                 0.802 
                 1 
               
               
                 184 
                 487 
                 L 
                 HD2 
                 H 
                 1 
                 0.853 
                 1 
               
               
                 185 
                 489 
                 S 
                 H 
                 H 
                 1 
                 9.049 
                 1 
               
               
                 186 
                 489 
                 S 
                 N 
                 N 
                 15 
                 119.012 
                 1 
               
               
                 187 
                 490 
                 V 
                 CG1 
                 C 
                 13 
                 21.236 
                 1 
               
               
                 188 
                 490 
                 V 
                 CG2 
                 C 
                 13 
                 23.244 
                 1 
               
               
                 189 
                 490 
                 V 
                 H 
                 H 
                 1 
                 7.325 
                 1 
               
               
                 190 
                 490 
                 V 
                 N 
                 N 
                 15 
                 119.713 
                 1 
               
               
                 191 
                 490 
                 V 
                 HG1 
                 H 
                 1 
                 0.583 
                 1 
               
               
                 196 
                 490 
                 V 
                 HG2 
                 H 
                 1 
                 0.912 
                 1 
               
               
                 197 
                 491 
                 H 
                 H 
                 H 
                 1 
                 8.716 
                 1 
               
               
                 198 
                 491 
                 H 
                 N 
                 N 
                 15 
                 125.135 
                 1 
               
               
                 199 
                 492 
                 A 
                 H 
                 H 
                 1 
                 7.396 
                 1 
               
               
                 200 
                 492 
                 A 
                 N 
                 N 
                 15 
                 130.645 
                 1 
               
               
                 201 
                 494 
                 D 
                 H 
                 H 
                 1 
                 8.676 
                 1 
               
               
                 202 
                 494 
                 D 
                 N 
                 N 
                 15 
                 117.371 
                 1 
               
               
                 203 
                 495 
                 T 
                 H 
                 H 
                 1 
                 8.641 
                 1 
               
               
                 204 
                 495 
                 T 
                 N 
                 N 
                 15 
                 112.625 
                 1 
               
               
                 205 
                 497 
                 F 
                 H 
                 H 
                 1 
                 7.868 
                 1 
               
               
                 206 
                 497 
                 F 
                 N 
                 N 
                 15 
                 122.062 
                 1 
               
               
                 207 
                 498 
                 F 
                 H 
                 H 
                 1 
                 9.932 
                 1 
               
               
                 208 
                 498 
                 F 
                 N 
                 N 
                 15 
                 121.373 
                 1 
               
               
                 209 
                 499 
                 T 
                 H 
                 H 
                 1 
                 6.901 
                 1 
               
               
                 210 
                 499 
                 T 
                 N 
                 N 
                 15 
                 113.079 
                 1 
               
               
                 211 
                 500 
                 K 
                 H 
                 H 
                 1 
                 7.689 
                 1 
               
               
                 212 
                 500 
                 K 
                 N 
                 N 
                 15 
                 123.985 
                 1 
               
               
                 213 
                 501 
                 L 
                 CD1 
                 C 
                 13 
                 21.431 
                 1 
               
               
                 214 
                 501 
                 L 
                 CD2 
                 C 
                 13 
                 26.226 
                 1 
               
               
                 217 
                 501 
                 L 
                 HD1 
                 H 
                 1 
                 0.589 
                 1 
               
               
                 220 
                 501 
                 L 
                 HD2 
                 H 
                 1 
                 0.244 
                 1 
               
               
                 221 
                 502 
                 K 
                 H 
                 H 
                 1 
                 8.034 
                 1 
               
               
                 222 
                 502 
                 K 
                 N 
                 N 
                 15 
                 118.063 
                 1 
               
               
                 223 
                 503 
                 T 
                 H 
                 H 
                 1 
                 7.409 
                 1 
               
               
                 224 
                 503 
                 T 
                 N 
                 N 
                 15 
                 109.905 
                 1 
               
               
                 225 
                 504 
                 A 
                 H 
                 H 
                 1 
                 8.332 
                 1 
               
               
                 226 
                 504 
                 A 
                 N 
                 N 
                 15 
                 125.057 
                 1 
               
               
                 227 
                 505 
                 G 
                 H 
                 H 
                 1 
                 7.268 
                 1 
               
               
                 228 
                 505 
                 G 
                 N 
                 N 
                 15 
                 109.015 
                 1 
               
               
                 229 
                 506 
                 Y 
                 H 
                 H 
                 1 
                 8.399 
                 1 
               
               
                 230 
                 506 
                 Y 
                 N 
                 N 
                 15 
                 118.799 
                 1 
               
               
                 231 
                 507 
                 Q 
                 H 
                 H 
                 1 
                 8.555 
                 1 
               
               
                 232 
                 507 
                 Q 
                 N 
                 N 
                 15 
                 114.738 
                 1 
               
               
                 233 
                 508 
                 A 
                 H 
                 H 
                 1 
                 7.049 
                 1 
               
               
                 234 
                 508 
                 A 
                 N 
                 N 
                 15 
                 118.763 
                 1 
               
               
                 235 
                 509 
                 V 
                 CG1 
                 C 
                 13 
                 19.211 
                 1 
               
               
                 236 
                 509 
                 V 
                 CG2 
                 C 
                 13 
                 20.045 
                 1 
               
               
                 237 
                 509 
                 V 
                 H 
                 H 
                 1 
                 6.759 
                 1 
               
               
                 238 
                 509 
                 V 
                 N 
                 N 
                 15 
                 105.237 
                 1 
               
               
                 241 
                 509 
                 V 
                 HG1 
                 H 
                 1 
                 0.198 
                 1 
               
               
                 244 
                 509 
                 V 
                 HG2 
                 H 
                 1 
                 0.47 
                 1 
               
               
                 245 
                 510 
                 K 
                 H 
                 H 
                 1 
                 7.119 
                 1 
               
               
                 246 
                 510 
                 K 
                 N 
                 N 
                 15 
                 128.018 
                 1 
               
               
                 247 
                 511 
                 R 
                 H 
                 H 
                 1 
                 8.684 
                 1 
               
               
                 248 
                 511 
                 R 
                 N 
                 N 
                 15 
                 117.231 
                 1 
               
               
                 249 
                 512 
                 W 
                 H 
                 H 
                 1 
                 8.542 
                 1 
               
               
                 250 
                 512 
                 W 
                 N 
                 N 
                 15 
                 120.625 
                 1 
               
               
                 251 
                 512 
                 W 
                 HE1 
                 H 
                 1 
                 9.942 
                 1 
               
               
                 252 
                 512 
                 W 
                 NE1 
                 H 
                 1 
                 130.341 
                 1 
               
               
                 253 
                 513 
                 T 
                 H 
                 H 
                 1 
                 7.069 
                 1 
               
               
                 254 
                 513 
                 T 
                 N 
                 N 
                 15 
                 106.003 
                 1 
               
               
                 255 
                 514 
                 K 
                 H 
                 H 
                 1 
                 7.238 
                 1 
               
               
                 256 
                 514 
                 K 
                 N 
                 N 
                 15 
                 121.358 
                 1 
               
               
                 257 
                 515 
                 K 
                 H 
                 H 
                 1 
                 8.487 
                 1 
               
               
                 258 
                 515 
                 K 
                 N 
                 N 
                 15 
                 116.476 
                 1 
               
               
                 259 
                 516 
                 V 
                 CG1 
                 C 
                 13 
                 22.32 
                 1 
               
               
                 260 
                 516 
                 V 
                 CG2 
                 C 
                 13 
                 19.555 
                 1 
               
               
                 261 
                 516 
                 V 
                 H 
                 H 
                 1 
                 7.299 
                 1 
               
               
                 262 
                 516 
                 V 
                 N 
                 N 
                 15 
                 119.473 
                 1 
               
               
                 265 
                 516 
                 V 
                 HG1 
                 H 
                 1 
                 1.018 
                 1 
               
               
                 268 
                 516 
                 V 
                 HG2 
                 H 
                 1 
                 0.836 
                 1 
               
               
                 269 
                 517 
                 D 
                 H 
                 H 
                 1 
                 8.389 
                 1 
               
               
                 270 
                 517 
                 D 
                 N 
                 N 
                 15 
                 124.991 
                 1 
               
               
                 271 
                 518 
                 V 
                 CG1 
                 C 
                 13 
                 21.972 
                 1 
               
               
                 272 
                 518 
                 V 
                 CG2 
                 C 
                 13 
                 17.937 
                 1 
               
               
                 273 
                 518 
                 V 
                 H 
                 H 
                 1 
                 8.864 
                 1 
               
               
                 274 
                 518 
                 V 
                 N 
                 N 
                 15 
                 122.483 
                 1 
               
               
                 277 
                 518 
                 V 
                 HG1 
                 H 
                 1 
                 0.73 
                 1 
               
               
                 280 
                 518 
                 V 
                 HG2 
                 H 
                 1 
                 0.268 
                 1 
               
               
                 281 
                 519 
                 F 
                 H 
                 H 
                 1 
                 7.156 
                 1 
               
               
                 282 
                 519 
                 F 
                 N 
                 N 
                 15 
                 111.705 
                 1 
               
               
                 283 
                 520 
                 S 
                 H 
                 H 
                 1 
                 7.418 
                 1 
               
               
                 284 
                 520 
                 S 
                 N 
                 N 
                 15 
                 114.604 
                 1 
               
               
                 285 
                 521 
                 V 
                 CG1 
                 C 
                 13 
                 21.606 
                 1 
               
               
                 286 
                 521 
                 V 
                 CG2 
                 C 
                 13 
                 19.292 
                 1 
               
               
                 287 
                 521 
                 V 
                 H 
                 H 
                 1 
                 6.57 
                 1 
               
               
                 288 
                 521 
                 V 
                 N 
                 N 
                 15 
                 114.783 
                 1 
               
               
                 291 
                 521 
                 V 
                 HG1 
                 H 
                 1 
                 0.698 
                 1 
               
               
                 294 
                 521 
                 V 
                 HG2 
                 H 
                 1 
                 0.757 
                 1 
               
               
                 295 
                 522 
                 D 
                 H 
                 H 
                 1 
                 8.102 
                 1 
               
               
                 296 
                 522 
                 D 
                 N 
                 N 
                 15 
                 121.096 
                 1 
               
               
                 297 
                 523 
                 I 
                 H 
                 H 
                 1 
                 8.117 
                 1 
               
               
                 298 
                 523 
                 I 
                 N 
                 N 
                 15 
                 118.339 
                 1 
               
               
                 299 
                 524 
                 L 
                 CD1 
                 C 
                 13 
                 24.558 
                 2 
               
               
                 300 
                 524 
                 L 
                 CD2 
                 C 
                 13 
                 24.558 
                 2 
               
               
                 301 
                 524 
                 L 
                 H 
                 H 
                 1 
                 9.253 
                 1 
               
               
                 302 
                 524 
                 L 
                 N 
                 N 
                 15 
                 122.892 
                 1 
               
               
                 305 
                 524 
                 L 
                 HG1 
                 H 
                 1 
                 0.841 
                 2 
               
               
                 308 
                 524 
                 L 
                 HG2 
                 H 
                 1 
                 0.841 
                 2 
               
               
                 309 
                 525 
                 L 
                 CD1 
                 C 
                 13 
                 27.708 
                 2 
               
               
                 310 
                 525 
                 L 
                 CD2 
                 C 
                 13 
                 23.849 
                 1 
               
               
                 311 
                 525 
                 L 
                 H 
                 H 
                 1 
                 8.636 
                 1 
               
               
                 312 
                 525 
                 L 
                 N 
                 N 
                 15 
                 121.574 
                 1 
               
               
                 315 
                 525 
                 L 
                 HD1 
                 H 
                 1 
                 0.775 
                 1 
               
               
                 318 
                 525 
                 L 
                 HD2 
                 H 
                 1 
                 0.735 
                 1 
               
               
                 319 
                 526 
                 V 
                 CG1 
                 C 
                 13 
                 20.514 
                 1 
               
               
                 320 
                 526 
                 V 
                 CG2 
                 C 
                 13 
                 19.367 
                 1 
               
               
                 323 
                 526 
                 V 
                 HG1 
                 H 
                 1 
                 −0.557 
                 1 
               
               
                 326 
                 526 
                 V 
                 HG2 
                 H 
                 1 
                 0.332 
                 1 
               
               
                 327 
                 528 
                 I 
                 H 
                 H 
                 1 
                 8.599 
                 1 
               
               
                 328 
                 528 
                 I 
                 N 
                 N 
                 15 
                 125.838 
                 1 
               
               
                 329 
                 529 
                 H 
                 H 
                 H 
                 1 
                 9.049 
                 1 
               
               
                 330 
                 529 
                 H 
                 N 
                 N 
                 15 
                 130.138 
                 1 
               
               
                 331 
                 530 
                 L 
                 CD1 
                 C 
                 13 
                 25.956 
                 1 
               
               
                 332 
                 530 
                 L 
                 CD2 
                 C 
                 13 
                 23.945 
                 1 
               
               
                 333 
                 530 
                 L 
                 H 
                 H 
                 1 
                 8.536 
                 1 
               
               
                 334 
                 530 
                 L 
                 N 
                 N 
                 15 
                 131.927 
                 1 
               
               
                 337 
                 530 
                 L 
                 HD1 
                 H 
                 1 
                 0.891 
                 1 
               
               
                 340 
                 530 
                 L 
                 HD2 
                 H 
                 1 
                 0.759 
                 1 
               
               
                 341 
                 531 
                 G 
                 H 
                 H 
                 1 
                 8 
                 1 
               
               
                 342 
                 531 
                 G 
                 N 
                 N 
                 15 
                 116.007 
                 1 
               
               
                 343 
                 532 
                 V 
                 CG1 
                 C 
                 13 
                 20.988 
                 1 
               
               
                 344 
                 532 
                 V 
                 CG2 
                 C 
                 13 
                 17.895 
                 1 
               
               
                 347 
                 532 
                 V 
                 HG1 
                 H 
                 1 
                 0.507 
                 1 
               
               
                 350 
                 532 
                 V 
                 HG2 
                 H 
                 1 
                 0.396 
                 1 
               
               
                 351 
                 533 
                 H 
                 H 
                 H 
                 1 
                 7.652 
                 1 
               
               
                 352 
                 533 
                 H 
                 N 
                 N 
                 15 
                 123.973 
                 1 
               
               
                 353 
                 534 
                 W 
                 H 
                 H 
                 1 
                 7.787 
                 1 
               
               
                 354 
                 534 
                 W 
                 N 
                 N 
                 15 
                 125.281 
                 1 
               
               
                 355 
                 534 
                 W 
                 HE1 
                 H 
                 1 
                 9.36 
                 1 
               
               
                 356 
                 534 
                 W 
                 NE1 
                 H 
                 1 
                 128.566 
                 1 
               
               
                 357 
                 535 
                 C 
                 H 
                 H 
                 1 
                 9.374 
                 1 
               
               
                 358 
                 535 
                 C 
                 N 
                 N 
                 15 
                 118.493 
                 1 
               
               
                 359 
                 536 
                 L 
                 CD1 
                 C 
                 13 
                 22.488 
                 1 
               
               
                 360 
                 536 
                 L 
                 CD2 
                 C 
                 13 
                 26.383 
                 1 
               
               
                 363 
                 536 
                 L 
                 HD1 
                 H 
                 1 
                 0.708 
                 1 
               
               
                 366 
                 536 
                 L 
                 HD2 
                 H 
                 1 
                 0.622 
                 1 
               
               
                 367 
                 537 
                 A 
                 H 
                 H 
                 1 
                 8.735 
                 1 
               
               
                 368 
                 537 
                 A 
                 N 
                 N 
                 15 
                 127.969 
                 1 
               
               
                 369 
                 538 
                 V 
                 CG1 
                 C 
                 13 
                 21.782 
                 1 
               
               
                 370 
                 538 
                 V 
                 CG2 
                 C 
                 13 
                 22.071 
                 1 
               
               
                 371 
                 538 
                 V 
                 H 
                 H 
                 1 
                 8.971 
                 1 
               
               
                 372 
                 538 
                 V 
                 N 
                 N 
                 15 
                 120.496 
                 1 
               
               
                 375 
                 538 
                 V 
                 HG1 
                 H 
                 1 
                 0.885 
                 1 
               
               
                 378 
                 538 
                 V 
                 HG2 
                 H 
                 1 
                 0.831 
                 1 
               
               
                 379 
                 539 
                 V 
                 CG1 
                 C 
                 13 
                 20.583 
                 1 
               
               
                 380 
                 539 
                 V 
                 CG2 
                 C 
                 13 
                 19.613 
                 1 
               
               
                 381 
                 539 
                 V 
                 H 
                 H 
                 1 
                 9.299 
                 1 
               
               
                 382 
                 539 
                 V 
                 N 
                 N 
                 15 
                 131.537 
                 1 
               
               
                 385 
                 539 
                 V 
                 HG1 
                 H 
                 1 
                 0.452 
                 1 
               
               
                 388 
                 539 
                 V 
                 HG2 
                 H 
                 1 
                 0.894 
                 1 
               
               
                 389 
                 540 
                 D 
                 H 
                 H 
                 1 
                 8.849 
                 1 
               
               
                 390 
                 540 
                 D 
                 N 
                 N 
                 15 
                 127.571 
                 1 
               
               
                 391 
                 541 
                 F 
                 H 
                 H 
                 1 
                 9.394 
                 1 
               
               
                 392 
                 541 
                 F 
                 N 
                 N 
                 15 
                 125.014 
                 1 
               
               
                 393 
                 542 
                 R 
                 H 
                 H 
                 1 
                 8.636 
                 1 
               
               
                 394 
                 542 
                 R 
                 N 
                 N 
                 15 
                 118.378 
                 1 
               
               
                 395 
                 543 
                 K 
                 H 
                 H 
                 1 
                 6.667 
                 1 
               
               
                 396 
                 543 
                 K 
                 N 
                 N 
                 15 
                 115.058 
                 1 
               
               
                 397 
                 544 
                 K 
                 H 
                 H 
                 1 
                 7.337 
                 1 
               
               
                 398 
                 544 
                 K 
                 N 
                 N 
                 15 
                 116.66 
                 1 
               
               
                 399 
                 545 
                 D 
                 H 
                 H 
                 1 
                 7.143 
                 1 
               
               
                 400 
                 545 
                 D 
                 N 
                 N 
                 15 
                 114.477 
                 1 
               
               
                 401 
                 546 
                 I 
                 H 
                 H 
                 1 
                 8.348 
                 1 
               
               
                 402 
                 546 
                 I 
                 N 
                 N 
                 15 
                 121.213 
                 1 
               
               
                 403 
                 547 
                 T 
                 H 
                 H 
                 1 
                 8.68 
                 1 
               
               
                 404 
                 547 
                 T 
                 N 
                 N 
                 15 
                 122.503 
                 1 
               
               
                 405 
                 548 
                 Y 
                 H 
                 H 
                 1 
                 8.599 
                 1 
               
               
                 406 
                 548 
                 Y 
                 N 
                 N 
                 15 
                 129.81 
                 1 
               
               
                 407 
                 549 
                 Y 
                 H 
                 H 
                 1 
                 8.988 
                 1 
               
               
                 408 
                 549 
                 Y 
                 N 
                 N 
                 15 
                 126.841 
                 1 
               
               
                 409 
                 550 
                 D 
                 H 
                 H 
                 1 
                 7.986 
                 1 
               
               
                 410 
                 550 
                 D 
                 N 
                 N 
                 15 
                 124.111 
                 1 
               
               
                 411 
                 551 
                 S 
                 H 
                 H 
                 1 
                 9.257 
                 1 
               
               
                 412 
                 551 
                 S 
                 N 
                 N 
                 15 
                 123.506 
                 1 
               
               
                 413 
                 552 
                 M 
                 H 
                 H 
                 1 
                 9.118 
                 1 
               
               
                 414 
                 552 
                 M 
                 N 
                 N 
                 15 
                 122.883 
                 1 
               
               
                 415 
                 553 
                 G 
                 H 
                 H 
                 1 
                 7.765 
                 1 
               
               
                 416 
                 553 
                 G 
                 N 
                 N 
                 15 
                 110.571 
                 1 
               
               
                 417 
                 554 
                 G 
                 H 
                 H 
                 1 
                 7.593 
                 1 
               
               
                 418 
                 554 
                 G 
                 N 
                 N 
                 15 
                 108.922 
                 1 
               
               
                 419 
                 555 
                 I 
                 H 
                 H 
                 1 
                 7.986 
                 1 
               
               
                 420 
                 555 
                 I 
                 N 
                 N 
                 15 
                 119.104 
                 1 
               
               
                 421 
                 556 
                 D 
                 H 
                 H 
                 1 
                 7.676 
                 1 
               
               
                 422 
                 556 
                 D 
                 N 
                 N 
                 15 
                 125.208 
                 1 
               
               
                 423 
                 557 
                 D 
                 H 
                 H 
                 1 
                 8.221 
                 1 
               
               
                 424 
                 557 
                 D 
                 N 
                 N 
                 15 
                 122.087 
                 1 
               
               
                 425 
                 558 
                 E 
                 H 
                 H 
                 1 
                 8.444 
                 1 
               
               
                 426 
                 558 
                 E 
                 N 
                 N 
                 15 
                 121.771 
                 1 
               
               
                 427 
                 559 
                 A 
                 H 
                 H 
                 1 
                 7.431 
                 1 
               
               
                 428 
                 559 
                 A 
                 N 
                 N 
                 15 
                 121.623 
                 1 
               
               
                 429 
                 560 
                 C 
                 H 
                 H 
                 1 
                 6.749 
                 1 
               
               
                 430 
                 560 
                 C 
                 N 
                 N 
                 15 
                 112.908 
                 1 
               
               
                 431 
                 561 
                 R 
                 H 
                 H 
                 1 
                 7.935 
                 1 
               
               
                 432 
                 561 
                 R 
                 N 
                 N 
                 15 
                 121.153 
                 1 
               
               
                 433 
                 562 
                 I 
                 H 
                 H 
                 1 
                 8.494 
                 1 
               
               
                 434 
                 562 
                 I 
                 N 
                 N 
                 15 
                 121.654 
                 1 
               
               
                 435 
                 563 
                 L 
                 CD1 
                 C 
                 13 
                 26.251 
                 1 
               
               
                 436 
                 563 
                 L 
                 H 
                 H 
                 1 
                 7.51 
                 1 
               
               
                 437 
                 563 
                 L 
                 N 
                 N 
                 15 
                 121.675 
                 1 
               
               
                 440 
                 563 
                 L 
                 HD1 
                 H 
                 1 
                 0.705 
                 1 
               
               
                 441 
                 564 
                 L 
                 CD1 
                 C 
                 13 
                 23.21 
                 1 
               
               
                 442 
                 564 
                 L 
                 CD2 
                 C 
                 13 
                 25.851 
                 1 
               
               
                 443 
                 564 
                 L 
                 H 
                 H 
                 1 
                 7.927 
                 1 
               
               
                 444 
                 564 
                 L 
                 N 
                 N 
                 15 
                 123.395 
                 1 
               
               
                 447 
                 564 
                 L 
                 HD1 
                 H 
                 1 
                 0.527 
                 1 
               
               
                 450 
                 564 
                 L 
                 HD2 
                 H 
                 1 
                 0.857 
                 1 
               
               
                 451 
                 565 
                 Q 
                 H 
                 H 
                 1 
                 7.814 
                 1 
               
               
                 452 
                 565 
                 Q 
                 N 
                 N 
                 15 
                 117.094 
                 1 
               
               
                 453 
                 566 
                 Y 
                 H 
                 H 
                 1 
                 8.072 
                 1 
               
               
                 454 
                 566 
                 Y 
                 N 
                 N 
                 15 
                 122.424 
                 1 
               
               
                 455 
                 567 
                 L 
                 CD1 
                 C 
                 13 
                 26.248 
                 1 
               
               
                 456 
                 567 
                 L 
                 H 
                 H 
                 1 
                 7.659 
                 1 
               
               
                 457 
                 567 
                 L 
                 N 
                 N 
                 15 
                 119.901 
                 1 
               
               
                 460 
                 567 
                 L 
                 HD1 
                 H 
                 1 
                 0.295 
                 1 
               
               
                 461 
                 568 
                 K 
                 H 
                 H 
                 1 
                 7.303 
                 1 
               
               
                 462 
                 568 
                 K 
                 N 
                 N 
                 15 
                 117.193 
                 1 
               
               
                 463 
                 569 
                 Q 
                 H 
                 H 
                 1 
                 7.605 
                 1 
               
               
                 464 
                 569 
                 Q 
                 N 
                 N 
                 15 
                 120.146 
                 1 
               
               
                 465 
                 570 
                 E 
                 H 
                 H 
                 1 
                 8.815 
                 1 
               
               
                 466 
                 570 
                 E 
                 N 
                 N 
                 15 
                 125.031 
                 1 
               
               
                 467 
                 571 
                 S 
                 H 
                 H 
                 1 
                 7.999 
                 1 
               
               
                 468 
                 571 
                 S 
                 N 
                 N 
                 15 
                 113.963 
                 1 
               
               
                 469 
                 572 
                 I 
                 H 
                 H 
                 1 
                 6.963 
                 1 
               
               
                 470 
                 572 
                 I 
                 N 
                 N 
                 15 
                 120.839 
                 1 
               
               
                 471 
                 573 
                 D 
                 H 
                 H 
                 1 
                 8.221 
                 1 
               
               
                 472 
                 573 
                 D 
                 N 
                 N 
                 15 
                 120.607 
                 1 
               
               
                 473 
                 574 
                 K 
                 H 
                 H 
                 1 
                 8.471 
                 1 
               
               
                 474 
                 574 
                 K 
                 N 
                 N 
                 15 
                 110.577 
                 1 
               
               
                 475 
                 575 
                 K 
                 H 
                 H 
                 1 
                 7.695 
                 1 
               
               
                 476 
                 575 
                 K 
                 N 
                 N 
                 15 
                 115.597 
                 1 
               
               
                 477 
                 580 
                 D 
                 H 
                 H 
                 1 
                 7.94 
                 1 
               
               
                 478 
                 580 
                 D 
                 N 
                 N 
                 15 
                 129.176 
                 1 
               
               
                 479 
                 581 
                 T 
                 H 
                 H 
                 1 
                 7.92 
                 1 
               
               
                 480 
                 581 
                 T 
                 N 
                 N 
                 15 
                 115.295 
                 1 
               
               
                 481 
                 582 
                 D 
                 H 
                 H 
                 1 
                 8.477 
                 1 
               
               
                 482 
                 582 
                 D 
                 N 
                 N 
                 15 
                 125.759 
                 1 
               
               
                 483 
                 584 
                 W 
                 HE1 
                 H 
                 1 
                 10.14 
                 1 
               
               
                 484 
                 584 
                 W 
                 NE1 
                 H 
                 1 
                 131.131 
                 1 
               
               
                 485 
                 585 
                 Q 
                 H 
                 H 
                 1 
                 8.228 
                 1 
               
               
                 486 
                 585 
                 Q 
                 N 
                 N 
                 15 
                 121.5 
                 1 
               
               
                 487 
                 586 
                 L 
                 CD1 
                 C 
                 13 
                 24.774 
                 1 
               
               
                 488 
                 586 
                 L 
                 H 
                 H 
                 1 
                 8.179 
                 1 
               
               
                 489 
                 586 
                 L 
                 N 
                 N 
                 15 
                 123.493 
                 1 
               
               
                 492 
                 586 
                 L 
                 HD1 
                 H 
                 1 
                 0.902 
                 1 
               
               
                 493 
                 587 
                 F 
                 H 
                 H 
                 1 
                 8.927 
                 1 
               
               
                 494 
                 587 
                 F 
                 N 
                 N 
                 15 
                 120.564 
                 1 
               
               
                 495 
                 588 
                 S 
                 H 
                 H 
                 1 
                 8.491 
                 1 
               
               
                 496 
                 588 
                 S 
                 N 
                 N 
                 15 
                 116.853 
                 1 
               
               
                 497 
                 589 
                 K 
                 H 
                 H 
                 1 
                 8.272 
                 1 
               
               
                 498 
                 589 
                 K 
                 N 
                 N 
                 15 
                 125.148 
                 1 
               
               
                 499 
                 590 
                 K 
                 H 
                 H 
                 1 
                 9.035 
                 1 
               
               
                 500 
                 590 
                 K 
                 N 
                 N 
                 15 
                 125.714 
                 1 
               
               
                 501 
                 591 
                 S 
                 H 
                 H 
                 1 
                 8.628 
                 1 
               
               
                 502 
                 591 
                 S 
                 N 
                 N 
                 15 
                 117.949 
                 1 
               
               
                 503 
                 592 
                 Q 
                 H 
                 H 
                 1 
                 7.72 
                 1 
               
               
                 504 
                 592 
                 Q 
                 N 
                 N 
                 15 
                 115.49 
                 1 
               
               
                 505 
                 593 
                 E 
                 H 
                 H 
                 1 
                 8.054 
                 1 
               
               
                 506 
                 593 
                 E 
                 N 
                 N 
                 15 
                 117.488 
                 1 
               
               
                 507 
                 594 
                 I 
                 H 
                 H 
                 1 
                 7.053 
                 1 
               
               
                 508 
                 594 
                 I 
                 N 
                 N 
                 15 
                 112.806 
                 1 
               
               
                 509 
                 596 
                 Q 
                 H 
                 H 
                 1 
                 8.456 
                 1 
               
               
                 510 
                 596 
                 Q 
                 N 
                 N 
                 15 
                 120.73 
                 1 
               
               
                 511 
                 597 
                 Q 
                 H 
                 H 
                 1 
                 8.576 
                 1 
               
               
                 512 
                 597 
                 Q 
                 N 
                 N 
                 15 
                 119.759 
                 1 
               
               
                 513 
                 598 
                 M 
                 H 
                 H 
                 1 
                 9.401 
                 1 
               
               
                 514 
                 598 
                 M 
                 N 
                 N 
                 15 
                 120.151 
                 1 
               
               
                 515 
                 599 
                 D 
                 H 
                 H 
                 1 
                 7.357 
                 1 
               
               
                 516 
                 599 
                 D 
                 N 
                 N 
                 15 
                 116.972 
                 1 
               
               
                 517 
                 602 
                 D 
                 H 
                 H 
                 1 
                 7.383 
                 1 
               
               
                 518 
                 602 
                 D 
                 N 
                 N 
                 15 
                 119.804 
                 1 
               
               
                 519 
                 603 
                 S 
                 H 
                 H 
                 1 
                 8.061 
                 1 
               
               
                 520 
                 603 
                 S 
                 N 
                 N 
                 15 
                 121.228 
                 1 
               
               
                 521 
                 604 
                 G 
                 H 
                 H 
                 1 
                 8.814 
                 1 
               
               
                 522 
                 604 
                 G 
                 N 
                 N 
                 15 
                 109.019 
                 1 
               
               
                 523 
                 605 
                 M 
                 H 
                 H 
                 1 
                 6.87 
                 1 
               
               
                 524 
                 605 
                 M 
                 N 
                 N 
                 15 
                 119.181 
                 1 
               
               
                 525 
                 606 
                 F 
                 H 
                 H 
                 1 
                 8.087 
                 1 
               
               
                 526 
                 606 
                 F 
                 N 
                 N 
                 15 
                 120.065 
                 1 
               
               
                 527 
                 607 
                 A 
                 H 
                 H 
                 1 
                 7.948 
                 1 
               
               
                 528 
                 607 
                 A 
                 N 
                 N 
                 15 
                 119.608 
                 1 
               
               
                 529 
                 608 
                 C 
                 H 
                 H 
                 1 
                 7.095 
                 1 
               
               
                 530 
                 608 
                 C 
                 N 
                 N 
                 15 
                 112.346 
                 1 
               
               
                 531 
                 609 
                 K 
                 H 
                 H 
                 1 
                 7.948 
                 1 
               
               
                 532 
                 609 
                 K 
                 N 
                 N 
                 15 
                 118.448 
                 1 
               
               
                 533 
                 610 
                 Y 
                 H 
                 H 
                 1 
                 9.542 
                 1 
               
               
                 534 
                 610 
                 Y 
                 N 
                 N 
                 15 
                 122.405 
                 1 
               
               
                 535 
                 611 
                 A 
                 H 
                 H 
                 1 
                 7.333 
                 1 
               
               
                 536 
                 611 
                 A 
                 N 
                 N 
                 15 
                 119.249 
                 1 
               
               
                 537 
                 612 
                 D 
                 H 
                 H 
                 1 
                 8.263 
                 1 
               
               
                 538 
                 612 
                 D 
                 N 
                 N 
                 15 
                 120.131 
                 1 
               
               
                 539 
                 613 
                 C 
                 H 
                 H 
                 1 
                 7.203 
                 1 
               
               
                 540 
                 613 
                 C 
                 N 
                 N 
                 15 
                 115.162 
                 1 
               
               
                 541 
                 614 
                 I 
                 H 
                 H 
                 1 
                 8.484 
                 1 
               
               
                 542 
                 614 
                 I 
                 N 
                 N 
                 15 
                 120.137 
                 1 
               
               
                 543 
                 615 
                 T 
                 H 
                 H 
                 1 
                 8.165 
                 1 
               
               
                 544 
                 615 
                 T 
                 N 
                 N 
                 15 
                 109.158 
                 1 
               
               
                 545 
                 616 
                 K 
                 H 
                 H 
                 1 
                 7.126 
                 1 
               
               
                 546 
                 616 
                 K 
                 N 
                 N 
                 15 
                 119.661 
                 1 
               
               
                 547 
                 617 
                 D 
                 H 
                 H 
                 1 
                 7.896 
                 1 
               
               
                 548 
                 617 
                 D 
                 N 
                 N 
                 15 
                 118.551 
                 1 
               
               
                 549 
                 618 
                 R 
                 H 
                 H 
                 1 
                 7.855 
                 1 
               
               
                 550 
                 618 
                 R 
                 N 
                 N 
                 15 
                 117.684 
                 1 
               
               
                 551 
                 620 
                 I 
                 H 
                 H 
                 1 
                 8.365 
                 1 
               
               
                 552 
                 620 
                 I 
                 N 
                 N 
                 15 
                 122.909 
                 1 
               
               
                 553 
                 621 
                 D 
                 H 
                 H 
                 1 
                 7.872 
                 1 
               
               
                 554 
                 621 
                 D 
                 N 
                 N 
                 15 
                 127.17 
                 1 
               
               
                 555 
                 622 
                 F 
                 H 
                 H 
                 1 
                 6.479 
                 1 
               
               
                 556 
                 622 
                 F 
                 N 
                 N 
                 15 
                 114.836 
                 1 
               
               
                 557 
                 623 
                 T 
                 H 
                 H 
                 1 
                 10.893 
                 1 
               
               
                 558 
                 623 
                 T 
                 N 
                 N 
                 15 
                 113.615 
                 1 
               
               
                 559 
                 624 
                 Q 
                 H 
                 H 
                 1 
                 9.761 
                 1 
               
               
                 560 
                 624 
                 Q 
                 N 
                 N 
                 15 
                 119.808 
                 1 
               
               
                 561 
                 625 
                 Q 
                 H 
                 H 
                 1 
                 8.292 
                 1 
               
               
                 562 
                 625 
                 Q 
                 N 
                 N 
                 15 
                 119.007 
                 1 
               
               
                 563 
                 626 
                 H 
                 H 
                 H 
                 1 
                 7.627 
                 1 
               
               
                 564 
                 626 
                 H 
                 N 
                 N 
                 15 
                 117.04 
                 1 
               
               
                 565 
                 627 
                 M 
                 H 
                 H 
                 1 
                 7.554 
                 1 
               
               
                 566 
                 627 
                 M 
                 N 
                 N 
                 15 
                 118.727 
                 1 
               
               
                 567 
                 629 
                 Y 
                 H 
                 H 
                 1 
                 7.389 
                 1 
               
               
                 568 
                 629 
                 Y 
                 N 
                 N 
                 15 
                 120.089 
                 1 
               
               
                 569 
                 630 
                 F 
                 H 
                 H 
                 1 
                 8.629 
                 1 
               
               
                 570 
                 630 
                 F 
                 N 
                 N 
                 15 
                 119.732 
                 1 
               
               
                 571 
                 631 
                 R 
                 H 
                 H 
                 1 
                 8.753 
                 1 
               
               
                 572 
                 631 
                 R 
                 N 
                 N 
                 15 
                 122.645 
                 1 
               
               
                 573 
                 632 
                 K 
                 H 
                 H 
                 1 
                 6.955 
                 1 
               
               
                 574 
                 632 
                 K 
                 N 
                 N 
                 15 
                 116.472 
                 1 
               
               
                 575 
                 633 
                 R 
                 H 
                 H 
                 1 
                 8.412 
                 1 
               
               
                 576 
                 633 
                 R 
                 N 
                 N 
                 15 
                 117.619 
                 1 
               
               
                 577 
                 634 
                 M 
                 H 
                 H 
                 1 
                 8.154 
                 1 
               
               
                 578 
                 634 
                 M 
                 N 
                 N 
                 15 
                 117.932 
                 1 
               
               
                 579 
                 635 
                 V 
                 CG1 
                 C 
                 13 
                 22.402 
                 1 
               
               
                 580 
                 635 
                 V 
                 CG2 
                 C 
                 13 
                 24.472 
                 1 
               
               
                 581 
                 635 
                 V 
                 H 
                 H 
                 1 
                 7.322 
                 1 
               
               
                 582 
                 635 
                 V 
                 N 
                 N 
                 15 
                 118.68 
                 1 
               
               
                 585 
                 635 
                 V 
                 HG1 
                 H 
                 1 
                 0.533 
                 1 
               
               
                 588 
                 635 
                 V 
                 HG2 
                 H 
                 1 
                 1.092 
                 1 
               
               
                 589 
                 636 
                 W 
                 H 
                 H 
                 1 
                 6.859 
                 1 
               
               
                 590 
                 636 
                 W 
                 N 
                 N 
                 15 
                 118.812 
                 1 
               
               
                 591 
                 636 
                 W 
                 HE1 
                 H 
                 1 
                 10.124 
                 1 
               
               
                 592 
                 636 
                 W 
                 NE1 
                 H 
                 1 
                 132.344 
                 1 
               
               
                 593 
                 637 
                 E 
                 H 
                 H 
                 1 
                 8.839 
                 1 
               
               
                 594 
                 637 
                 E 
                 N 
                 N 
                 15 
                 119.355 
                 1 
               
               
                 595 
                 638 
                 I 
                 H 
                 H 
                 1 
                 8.41 
                 1 
               
               
                 596 
                 638 
                 I 
                 N 
                 N 
                 15 
                 119.139 
                 1 
               
               
                 597 
                 639 
                 L 
                 CD1 
                 C 
                 13 
                 25.313 
                 1 
               
               
                 598 
                 639 
                 L 
                 CD2 
                 C 
                 13 
                 22.916 
                 1 
               
               
                 599 
                 639 
                 L 
                 H 
                 H 
                 1 
                 7.977 
                 1 
               
               
                 600 
                 639 
                 L 
                 N 
                 N 
                 15 
                 120.642 
                 1 
               
               
                 603 
                 639 
                 L 
                 HD1 
                 H 
                 1 
                 0.596 
                 1 
               
               
                 606 
                 639 
                 L 
                 HD2 
                 H 
                 1 
                 0.514 
                 1 
               
               
                 607 
                 640 
                 H 
                 H 
                 H 
                 1 
                 7.669 
                 1 
               
               
                 608 
                 640 
                 H 
                 N 
                 N 
                 15 
                 113.238 
                 1 
               
               
                 609 
                 641 
                 R 
                 H 
                 H 
                 1 
                 7.794 
                 1 
               
               
                 610 
                 641 
                 R 
                 N 
                 N 
                 15 
                 123.547 
                 1 
               
               
                 611 
                 642 
                 K 
                 H 
                 H 
                 1 
                 8.152 
                 1 
               
               
                 612 
                 642 
                 K 
                 N 
                 N 
                 15 
                 122.071 
                 1 
               
               
                 613 
                 643 
                 L 
                 CD1 
                 C 
                 13 
                 27.478 
                 1 
               
               
                 614 
                 643 
                 L 
                 CD2 
                 C 
                 13 
                 24.632 
                 1 
               
               
                 615 
                 643 
                 L 
                 H 
                 H 
                 1 
                 8.058 
                 1 
               
               
                 616 
                 643 
                 L 
                 N 
                 N 
                 15 
                 123.331 
                 1 
               
               
                 619 
                 643 
                 L 
                 HD1 
                 H 
                 1 
                 0.412 
                 1 
               
               
                 622 
                 643 
                 L 
                 HD2 
                 H 
                 1 
                 0.573 
                 1 
               
               
                 623 
                 644 
                 L 
                 H 
                 H 
                 1 
                 8.748 
                 1 
               
               
                 624 
                 644 
                 L 
                 N 
                 N 
                 15 
                 131.146 
                 1 
               
               
                   
               
               
                 *referenced using DSS (4,4-dimethyl-4-silapentane-1-sulfonic acid) as the H-1 standard with IUPAC-IUB recommended chemical shift referencing ratios. See, Wishart, et al., “1H, 13C and 15N Chemical Shift Referencing in Biomolecular NMR,” J. Biomol. NMR 6: 135-140 (1995); and Markley et al., “Recommendations for the Presentation of NMR Structures of Proteins and Nucleic Acids,”. Pure &amp; Appl. Chem. 70: 117-142 (1998). 
               
            
           
         
       
     
     
       
         
           
               
             
               
                   
               
               
                 Sequence Listing 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 SEQ ID NO: 1 Isoform 1 SENP1  
               
               
                 MDDIADRMRM DAGEVTLVNH NSVFKTHLLP QTGFPEDQLS  
               
               
                 LSDQQILSSR QGHLDRSFTC STRSAAYNPS YYSDNPSSDS FLGSGDLRTF  
               
               
                 GQSANGQWRN STPSSSSSLQ KSRNSRSLYL ETRKTSSGLS NSFAGKSNHH  
               
               
                 CHVSAYEKSF PIKPVPSPSW SGSCRRSLLS PKKTQRRHVS TAEETVQEEE  
               
               
                 REIYRQLLQM VTGKQFTIAK PTTHFPLHLS RCLSSSKNTL KDSLFKNGNS  
               
               
                 CASQIIGSDT SSSGSASILT NQEQLSHSVY SLSSYTPDVA FGSKDSGTLH  
               
               
                 HPHHHHSVPH QPDNLAASNT QSEGSDSVIL LKVKDSQTPT PSSTFFQAEL  
               
               
                 WIKELTSVYD SRARERLRQI EEQKALALQL QNQRLQEREH SVHDSVELHL  
               
               
                 RVPLEKEIPV TVVQETQKKG HKLTDSEDEF PEITEEMEKE IKNVFRNGNQ  
               
               
                 DEVLSEAFRL TITRKDIQTL NHLNWLNDEI INFYMNMLME RSKEKGLPSV  
               
               
                 HAFNTFFFTK LKTAGYQAVK RWTKKVDVFS VDILLVPIHL GVHWCLAVVD  
               
               
                 FRKKNITYYD SMGGINNEAC RILLQYLKQE SIDKKRKEFD TNGWQLFSKK  
               
               
                 SQEIPQQMNG SDCGMFACKY ADCITKDRPI NFTQQHMPYF RKRMVWEILH  
               
               
                 RKLL  
               
               
                   
               
               
                 SEQ ID NO: 2 Isoform 2 SENP1  
               
               
                 MDDIADRMRM DAGEVTLVNH NSVFKTHLLP QTGFPEDQLS  
               
               
                 LSDQQILSSR QGHLDRSFTC STRSAAYNPS YYSDNPSSDS FLGSGDLRTF  
               
               
                 GQSANGQWRN STPSSSSSLQ KSRNSRSLYL ETRKTSSGLS NSFAGKSNHH  
               
               
                 CHVSAYEKSF PIKPVPSPSW SGSCRRSLLS PKKTQRRHVS TAEETVQEEE  
               
               
                 REIYRQLLQM VTGKQFTIAK PTTHFPLHLS RCLSSSKNTL KDSLFKNGNS  
               
               
                 CASQIIGSDT SSSGSASILT NQEQLSHSVY SLSSYTPDVA FGSKDSGTLH  
               
               
                 HPHHHHSVPH QPDNLAASNT QSEGSDSVIL LKVKDSQTPT PSSTFFQAEL  
               
               
                 WIKELTSVYD SRARERLRQI EEQKALALQL QNQRLQEREH SVHDSVELHL  
               
               
                 RVPLEKEIPV TVVQETQKKG HKLTDSEDEF PEITEEMEKE IKNVFRNGNQ  
               
               
                 DEVLSEAFRL TITRKDIQTL NHLNWLNDEI INFYMNMLME RSKEKGLPSV  
               
               
                 HAFNTFFFTK LKTAGYQAVK RWTKKVDVFS VDILLVPIHL GVHWCLAVVD  
               
               
                 FRKKNITYYD SMGGINNEAC RILLQYLKQE SIDKKRKEFD TNGWQLFSKK  
               
               
                 SQIPQQMNGS DCGMFACKYA DCITKDRPIN FTQQHMPYFR KRMVWEILHR  
               
               
                 KLL  
               
               
                   
               
               
                 SEQ ID NO: 3 (Isoform 1) C-Terminal Region SENP1  
               
               
                 EFPEITEEMEKEIKNVFRNGNQDEVLSEAFRLTITRKDIQTLNHLNWLNDEI  
               
               
                 INFYMNMLMERSKEKGLPSVHAFNTFFFTKLKTAGYQAVKRWTKKVDVFSVDI  
               
               
                 LLVPIHLGVHWCLAVVDFRKKNITYYDSMGGINNEACRILLQYLKQESIDKKRKE  
               
               
                 FDTNGWQLFSKKSQEIPQQMNGSDCGMFACKYADCITKDRPINFTQQHMPYFRK  
               
               
                 RMVWEILHRKLL  
               
               
                   
               
               
                 SEQ ID NO: 4 (Isoform 1) C-Terminal Region SENP1 C6035  
               
               
                 EFPEITEEMEKEIKNVFRNGNQDEVLSEAFRLTITRKDIQTLNHLNWLNDEI  
               
               
                 INFYMNMLMERSKEKGLPSVHAFNTFFFTKLKTAGYQAVKRWTKKVDVFSVDI 
               
               
                 LLVPIHLGVHWCLAVVDFRKKNITYYDSMGGINNEACRILLQYLKQESIDKKRKE  
               
               
                 FDTNGWQLFSKKSQEIPQQMNGSDSGMFACKYADCITKDRPINFTQQHMPYFRK  
               
               
                 RMVWEILHRKLL  
               
               
                   
               
               
                 SEQ ID NO: 5 (Isoform 2) C-Terminal Region SENP1  
               
               
                 EFPEITEEMEKEIKNVFRNGNQDEVLSEAFRLTITRKDIQTLNHLNWLNDEI  
               
               
                 INFYMNMLMERSKEKGLPSVHAFNTFFFTKLKTAGYQAVKRWTKKVDVFSVDI 
               
               
                 LLVPIHLGVHWCLAVVDFRKKNITYYDSMGGINNEACRILLQYLKQESIDKKRKE  
               
               
                 FDTNGWQLFSKKSQIPQQMNGSDCGMFACKYADCITKDRPINFTQQHMPYFRKR  
               
               
                 MVWEILHRKLL  
               
               
                   
               
               
                 SEQ ID NO: 6 (Isoform 1) Protease Region 450-613 SENP1  
               
               
                 LTITRKDIQTLNHLNWLNDEIINFYMNMLMERSKEKGLPSVHAFNTFFFTK  
               
               
                 LKTAGYQAVKRWTKKVDVFSVDILLVPIHLGVHWCLAVVDFRKKNITYYDSMG  
               
               
                 GINNEACRILLQYLKQESIDKKRKEFDTNGWQLFSKKSQEIPQQMNGSDCGMFA  
               
               
                 CKYADC  
               
               
                   
               
               
                 SEQ ID NO: 7 (Isoform 1) Protease Region 450-613 SENP1 C603S  
               
               
                 LTITRKDIQTLNHLNWLNDEIINFYMNMLMERSKEKGLPSVHAFNTFFFTK  
               
               
                 LKTAGYQAVKRWTKKVDVFSVDILLVPIHLGVHWCLAVVDFRKKNITYYDSMG  
               
               
                 GINNEACRILLQYLKQESIDKKRKEFDTNGWQLFSKKSQEIPQQMNGSDSGMFA  
               
               
                 CKYADC  
               
               
                   
               
               
                 SEQ ID NO: 8 SUMO1  
               
               
                 MSDQEAKPSTEDLGDKKEGEYIKLKVIGQDSSEIHFKVKMTTHLKKLKES  
               
               
                 YCQRQGVPMNSLRFLFEGQRIADNHTPKELGMEEEDVIEVYQEQTGGHSTV  
               
               
                   
               
               
                 SEQ ID NO: 9 SUMO1 (1-92)  
               
               
                 MSDQEAKPSTEDLGDKKEGEYIKLKVIGQDSSEIHFKVKMTTHLKKLKESYCQR  
               
               
                 QGVPMNSLRFLFEGQRIADNHTPKELGMEEEDVIEVYQ  
               
               
                   
               
            
           
         
       
     
     EMBODIMENTS 
     Embodiment 1 
     A method of detecting binding of an SENP1 polypeptide to a compound, the method comprising: 
     (i) contacting an SENP1 polypeptide with a compound; 
     (ii) allowing the compound to bind to the SENP1 polypeptide, thereby forming a SENP1-compound complex; 
     (iii) detecting the SENP1-compound complex using nuclear magnetic resonance, thereby detecting binding of the SENP1 polypeptide to the compound. 
     Embodiment 2 
     The method of embodiment 1, wherein the detecting comprises determining a chemical shift for an amino acid in an active site of the SENP1 polypeptide. 
     Embodiment 3 
     The method of embodiment 2, wherein the chemical shift in the presence of the compound is changed relative to the corresponding chemical shift in the absence of the compound. 
     Embodiment 4 
     The method of embodiment 2 or 3, wherein the amino acid is an amino acid of SEQ ID NOs:3, 4, 5, 6 or 7. 
     Embodiment 5 
     The method of embodiment 2 or 3, wherein the amino acid is selected from the group consisting of D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596. 
     Embodiment 6 
     The method of embodiment 2 or 3, wherein the amino acid is S603. 
     Embodiment 7 
     The method of embodiment 2 or 3, wherein the amino acid is amino acid residue 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. 
     Embodiment 8 
     The method of embodiment 1, wherein the SENP1 polypeptide comprises SEQ ID NOs:1, 2, 3, 4, 5, 6, or 7. 
     Embodiment 9 
     The method of embodiment 1, wherein the SENP1 polypeptide comprises amino acid residue 603 of SEQ ID NO:1. 
     Embodiment 10 
     The method of embodiment 9, wherein the SENP1 polypeptide comprises a mutation at amino acid residue 603 of SEQ ID NO:1. 
     Embodiment 11 
     The method of embodiment 10, wherein the mutation is C603S. 
     Embodiment 12 
     The method of embodiment 1, wherein the SENP1 polypeptide comprises amino acid residues 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. 
     Embodiment 13 
     The method of any one of embodiments 1-12, wherein the SENP1 or SENP1-compound complex is bound to a SUMO protein thereby forming a SENP1-SUMO complex or SENP1-SUMO-compound complex. 
     Embodiment 14 
     The method of embodiment 13, wherein the SUMO protein is a truncated SUMO protein. 
     Embodiment 15 
     The method of embodiment 2, wherein the active site is a catalytically active site. 
     Embodiment 16 
     The method of embodiment 2, wherein the active site is a site that binds to the SUMO protein. 
     Embodiment 17 
     The method of any one of embodiments 1-16, wherein the compound is a small molecule. 
     Embodiment 18 
     The method of any one of embodiments 1 or 8-17, wherein the detecting comprises producing an NMR spectra of the SENP1-compound complex and identifying a change in the NMR spectra relative to the absence of the compound. 
     Embodiment 19 
     The method of embodiment 18, wherein the change is a change in the chemical shift of an amino acid of SEQ ID NOs:3, 4, 5, 6 or 7. 
     Embodiment 20 
     The method of embodiment 18, wherein the change is a change in the chemical shift of an amino acid selected from the group consisting of D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596. 
     Embodiment 21 
     The method of embodiment 18, wherein the change is a change in the chemical shift of the amino acid S603. 
     Embodiment 22 
     The method of embodiment 18, wherein the change is a change in the chemical shift of an amino acid residue 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. 
     Embodiment 23 
     An aqueous composition comprising an SENP1 polypeptide at a pH from about 6.0 to about 7.5. 
     Embodiment 24 
     The aqueous composition of embodiment 23, wherein the pH is about 6.8. 
     Embodiment 25 
     The aqueous composition of embodiment 23 or 24, further comprising a buffering agent, reducing agent, solvent, a base, or combinations thereof. 
     Embodiment 26 
     The aqueous composition of any one of embodiments 23-25, further comprising sodium phosphate, dimethyl sulfoxide, D2O, sodium azide, dithiothreitol or combinations thereof. 
     Embodiment 27 
     The aqueous composition of embodiment 26, wherein the sodium phosphate is present at about 20 mM. 
     Embodiment 28 
     The aqueous composition of any one of embodiments 23-27, wherein the SENP1 polypeptide comprises SEQ ID NO:1, 2, 3, 4, 5, 6, or 7. 
     Embodiment 29 
     The aqueous composition of any one of embodiments 23-27, wherein the SENP1 polypeptide comprises amino acid residues 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 numbered relative to SEQ ID NO:1. 
     Embodiment 30 
     The aqueous composition of any one of embodiments 23-29, wherein the SENP1 polypeptide is bound to a SUMO protein thereby forming a SENP1-SUMO complex. 
     Embodiment 31 
     The aqueous composition of any one of embodiments 23-29, wherein the SENP1 polypeptide is bound to a compound thereby forming a SENP1-compound complex. 
     Embodiment 32 
     The aqueous composition of embodiment 31, wherein the SENP1 polypeptide is bound to a SUMO protein thereby forming a SENP1-SUMO-compound complex. 
     Embodiment 33 
     The aqueous composition of embodiment 30 or 32, wherein the SUMO protein is a truncated SUMO protein. 
     Embodiment 34 
     An NMR apparatus comprising an NMR sample container for NMR analysis, the NMR sample container comprising the aqueous composition of any one of embodiments 23-33. 
     Embodiment 35 
     A method of screening for an inhibitor of SENP1 comprising contacting a composition comprising an SENP1 polypeptide with a test compound and detecting whether the test compound binds the SENP1 polypeptide or fragment thereof by nuclear magnetic resonance. 
     Embodiment 36 
     The method of embodiment 35, wherein the detecting comprises determining a chemical shift for an amino acid in an active site of the SENP1 polypeptide. 
     Embodiment 37 
     The method of embodiment 36, wherein the amino acid is an amino acid of SEQ ID NOs:3, 4, 5, 6 OR 7. 
     Embodiment 38 
     The method of embodiment 36, wherein the amino acid is selected from the group consisting of D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596. 
     Embodiment 39 
     The method of embodiment 36, wherein the amino acid is S603. 
     Embodiment 40 
     The method of embodiment 36, wherein the amino acid is amino acid residue 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. 
     Embodiment 41 
     The method of embodiment 35, wherein the SENP1 polypeptide comprises SEQ ID NOs:1, 2, 3, 4, 5, 6, or 7. 
     Embodiment 42 
     The method of embodiment 35, wherein the SENP1 polypeptide comprises amino acid residue 603 of SEQ ID NO:1. 
     Embodiment 43 
     The method of embodiment 42, wherein the SENP1 polypeptide comprises a mutation at amino acid residue 603 of SEQ ID NO:1. 
     Embodiment 44 
     The method of embodiment 43, wherein the mutation is C603S. 
     Embodiment 45 
     The method of embodiment 35, wherein the SENP1 polypeptide comprises amino acid residues 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. 
     Embodiment 46 
     The method of any one of embodiments 35-45, wherein the SENP1 polypeptide is bound to a SUMO protein thereby forming a SENP1-SUMO complex. 
     Embodiment 47 
     The method of embodiment 46, wherein the SUMO protein is a truncated SUMO protein. 
     Embodiment 48 
     The method of any one of embodiments 35-47, wherein the chemical shift in the presence of the test compound is changed relative to the corresponding chemical shift in the absence of the test compound. 
     Embodiment 49 
     The method of any one of embodiments 35-47, wherein the SENP1 binds the compound forming an SENP1-compound complex and the detecting comprises producing an NMR spectra of the SENP1-compound complex and identifying a change in the NMR spectra relative to the absence of the compound. 
     Embodiment 50 
     The method of embodiment 49, wherein the change is a change in the chemical shift of an amino acid of SEQ ID NOs:3, 4, 5, 6 or 7. 
     Embodiment 51 
     The method of embodiment 49, wherein the change is a change in the chemical shift of an amino acid selected from the group consisting of D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596. 
     Embodiment 52 
     The method of embodiment 49, wherein the change is a change in the chemical shift of the amino acid S603. 
     Embodiment 53 
     The method of embodiment 49, wherein the change is a change in the chemical shift of an amino acid residue 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. 
     Embodiment 54 
     The method of embodiment 49, wherein the change is a change in the chemical shift of an amino acid in the active site of SENP1. 
     Embodiment 55 
     The method of embodiment 54, wherein the active site is a catalytically active site. 
     Embodiment 56 
     The method of embodiment 54, wherein the active site is a site that binds to the SUMO protein. 
     Embodiment 57 
     The method of any one of embodiments 35-56, wherein the test compound is a small molecule. 
     Embodiment 58 
     The method of any one of embodiments 35-57, wherein the composition is an aqueous solution. 
     Embodiment 59 
     The method of any one of embodiments 35-58, wherein the composition is at a pH from about 6.0 to about 7.5. 
     Embodiment 60 
     The method of embodiment 59, wherein the pH is about 6.8. 
     Embodiment 61 
     The method of any one of embodiments 35-60, wherein the composition further comprises a buffering agent, solvent, reducing agent, a base, or combinations thereof. 
     Embodiment 62 
     The method of any one of embodiments 35-60, further comprising sodium phosphate, D2O, sodium azide, dimethyl sulfoxide, dithiothreitol or combinations thereof. 
     Embodiment 63 
     The method of embodiment 62, wherein the sodium phosphate is present at about 20 mM. 
     Embodiment 64 
     A method of identifying an SENP1 inhibitor, the method comprising: 
     combining an SENP1 polypeptide, a SUMO protein, and a test compound in a reaction vessel; 
     allowing the SENP1 polypeptide, SUMO protein and test compound to form a SENP1-SUMO-compound complex; and 
     detecting the SENP1-SUMO-compound complex thereby identifying the compound as a SENP1 inhibitor. 
     Embodiment 65 
     The method of embodiment 64, wherein one or more of the SENP1 polypeptide, SUMO protein or test compound is labeled. 
     Embodiment 66 
     The method of embodiment 65, wherein the label is a fluorescent label. 
     Embodiment 67 
     The method of any one of embodiments 64-66, wherein the test compound comprises a fluorescent label. 
     Embodiment 68 
     The method of any one of embodiments 64-67, wherein binding is detected by fluorescent polarization. 
     Embodiment 69 
     The method of embodiment 64, wherein binding is detected by detecting a change in the thermal properties of SENP1. 
     Embodiment 70 
     The method of embodiment 69, wherein the thermal property is the melting temperature of SENP1. 
     Embodiment 71 
     The method of any one of embodiments 64-70, wherein the SUMO is a truncated SUMO protein. 
     Embodiment 72 
     The method of any one of embodiments 64-70, wherein the SUMO comprises amino acid residues 1-92 of the SUMO protein. 
     Embodiment 73 
     The method of any one of embodiments 64-70, wherein the SUMO protein comprises SEQ ID NO:8. 
     Embodiment 74 
     The method of any one of embodiments 64-70, wherein the SUMO protein comprises SEQ ID NO:9. 
     Embodiment 75 
     The method of any one of embodiments 64-74, wherein the SENP1 polypeptide comprises SEQ ID NOs:1, 2, 3, 4, 5, 6, or 7. 
     Embodiment 76 
     The method of any one of embodiments 64-74, wherein the SENP1 polypeptide comprises amino acid residue 603 of SEQ ID NO:1. 
     Embodiment 77 
     The method of any one of embodiments 64-74, wherein the SENP1 polypeptide comprises a mutation at amino acid residue 603 of SEQ ID NO:1. 
     Embodiment 78 
     The method of embodiment 77, wherein the mutation is C603S. 
     Embodiment 79 
     The method of any one of embodiments 64-74, wherein the SENP1 polypeptide comprises amino acid residues 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. 
     Embodiment 80 
     The method of any one of embodiments 64 or 71-79, wherein the detecting is performed using nuclear magnetic resonance. 
     Embodiment 81 
     The method of embodiment 80, wherein the detecting comprises producing an NMR spectra of the SENP1-SUMO-compound complex and identifying a change in the NMR spectra relative to the absence of the test compound. 
     Embodiment 82 
     The method of embodiment 81, wherein the change is a change in the chemical shift of an amino acid in an active site of the SENP1 polypeptide. 
     Embodiment 83 
     The method of embodiment 82, wherein the active site is a catalytically active site. 
     Embodiment 84 
     The method of embodiment 82, wherein the active site is a site that binds to the SUMO protein. 
     Embodiment 85 
     The method of embodiment 82, wherein the amino acid is an amino acid of SEQ ID NOs:3, 4, 5, 6 OR 7. 
     Embodiment 86 
     The method of embodiment 82, wherein the amino acid is selected from the group consisting of D550, H533, C603, W465, W534, L466, G531, C535, M552, G554, E469 and Q596. 
     Embodiment 87 
     The method of embodiment 82, wherein the amino acid is S603. 
     Embodiment 88 
     The method of embodiment 82, wherein the amino acid is amino acid residue 440-455, 463-473, 493-515, 529-535, 550-554, or 596-603 of SEQ ID NO:1. 
     Embodiment 89 
     The method of any one of embodiments 64-88, wherein the test compound is a small molecule.