# Patent

## Title
Crystalline TNF-α-converting enzyme and uses thereof

## Abstract

A tumor necrosis factor-α converting enzyme (TACE) is produced, purified, and crystallized. The three-dimensional coordinates of the crystal are obtained by X-ray diffraction. The coordinates can be recorded on a computer readable medium, or are part of a video memory, where they can be used as part of a system for studying for studying TACE. The coordinates are also used in designing, screening, and developing compounds that associate with TACE.

## Background
INFORMATION ON RELATED APPLICATIONS
This application claims the priority benefit of U.S. provisional patent application serial No. 60/073,7,09, filed Feb. 4, 1998, U.S. provisional patent application No. 60/135,499, filed Mar. 30, 1998, and U.S. provisional patent application No. 60/117,476, filed Jan. 27, 1999.


BACKGROUND OF THE INVENTION
The cytokine tumor necrosis factor-α (TNFα) plays a role in the induction of inflammatory reactions and is known to be cytotoxic towards tumor cells. TNFα, however, also may cause severe damage to the human body when produced in excess by eventually leading to multiple organ failure and death. See Bemelmans et al., “Tumor Necrosis Factor: Function, Release and Clearance,” Crit. Rev. Immun. 16: 1-11 (1996).
Tumor necrosis factor-α is produced by activated cells, such as mononuclear phagocytes, T-Cells, B-Cells, mast cells and NK cells. TNFα exists in two forms: a type II membrane protein having a relative molecular mass of 26 kD and a soluble 17 kD form generated from the membrane form by proteolytic cleavage. The TNFα membrane protein is synthesized as a 223 amino acid membrane-anchored precursor. The soluble TNFα is released from the membrane-bound precursor by a membrane-anchored proteinase. This proteinase was recently identified as a multidomain metalloproteinase called TNFα-converting enzyme (TACE). See, Black et al., “A metalloproteinase disintigrin that releases tumor-necrosis factor-α from cells,” Nature 385. 729-733 (1997), Moss et al., “Cloning of a disintigrin metalloproteinase that processes precursor tumor-necrosis factor-α,” Nature 385: 733-736 (1997). TACE has recently been identified as a zinc endopeptidase consisting of an extracellular region comprising an N-terminal signal peptide, a pro-domain, a 263 residue catalytic domain (TCD) that is preceded by a furin cleavage site (residues 211-214), a disintegrin domain, an EFF-like domain, and a crambin-like domain, an apparent transmembrane helix and the intracellular C-terminal tail. Tumor necrosis factors converting enzyme (TACE), including a polynucleotide sequence, is described in detail in the published PCT application No. WO 96/41624, herein incorporated in the entirety by reference.
As noted above, the over-production or unregulated production of TNF-α presents serious physiological dangers. It has been implicated in various deleterious physiological diseases such as rheumatoid arthritis, cachexia and endotoxic shock. It also may eventually lead to organ failure and death. Thus, a way to control or block release of TNFα into the circulation is needed. Because of TACE's role in the conversion of TNFα, inhibition, modulation, or regulation of TACE would affect the release of TNFα into circulation. Inhibitors of metalloproteinases and structure based design thereof are described in Zask et al., “Inhibition of Matrix Metalloproteinases: Structure Based Design” Current Pharmaceutical Design, 2:624-661 (1996). Thus, compounds that associate with TACE, such as inhibitors, receptors or modulators will be useful to protect patients from adverse effects associated with the over-production or unregulated production of tumor necrosis factor-α.
SUMMARY OF THE INVENTION
According to one aspect of the invention, there is provided a composition comprising a polypeptide in crystalline form, wherein the polypeptide is a TNF-α-converting enzyme polypeptide. In one embodiment, the TNF-α-converting enzyme polypeptide comprises the TNF-α-converting enzyme catalytic domain. In another embodiment, the TNF-α-converting enzyme polypeptide is the expression product of a polynucleotide encoding the pro and catalytic domains of TNF-α-converting enzyme. In a further embodiment, the TNF-α-converting enzyme polypeptide is the expression product of a polynucleotide encoding the amino acid residues 1-477 of TNF-α-converting enzyme. In yet another embodiment, the polynucleotide is substituted such that amino acid residue Ser266 is changed to Ala and amino acid residue Asn542 is changed to Gln, and wherein a second polynucleotide encoding the sequence Gly-Ser-(His)6 (SEQ ID NO: 2) is fused to the C-terminus.
According to another aspect of the invention, the compositions above further comprising a binding partner suitable for co-crystallization with the TNF-α-converting enzyme polypeptide. In one embodiment, the binding partner is a hydroxamate-based binding partner. In another embodiment, the binding partner is N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-amino-2-dimethylbutanoyl-L-alanine,2-(amino)ethyl amide.
According to further embodiments, the compositions above have a crystal structure diffracting to 2.0 Å, are monoclinic, have a unit cell comprising four crystallographically independent TNF-α-converting enzyme catalytic domain (TCD) molecules, have the TCD molecules are in an asymmetric unit, and/or have monoclinic space group P21 and the cell has the constants a=61.38 A, b=126.27 A, c=81.27 A, and β=107.41°.
In still another embodiment of the invention, the polypeptides above are characterized by the structure coordinates according to Table 1, or a substantial part thereof.
According to a further aspect of the invention, there is provided a method for crystallizing a TNF-α-converting enzyme polypeptide, comprising (A) mixing a solution comprising a TACE polypeptide and a binding partner with a crystallization buffer, and (B) crystallizing the mixture of step (A) by drop vapor diffusion to form a crystalline precipitate. In one embodiment, the method further comprises (C) transferring seeds from the crystalline precipitate formed by the drop vapor diffusion and a crystallization promotor into a mixture of a concentrated solution comprising a TACE polypeptide and binding partner substrate, and a crystallization buffer, and (D) crystallizing the mixture of step (C) by drop vapor diffusion to form a crystal. In another embodiment, the crystallization buffer is 0.1M Na Citrate pH 5.4, 20% w/v PEG 4000, and 20% v/v Isopropanol. In still another embodiment, the binding partner is N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-amino-2-dimethylbutanoyl-L-alanine, 2-(amino)ethyl amide. In yet another embodiment, crystallization is at a temperature ranging from 4 to 20 degrees Celsius. In another embodiment, the solution comprising the TACE polypeptide and the inhibitor is at a concentration of about 5 mg/mL to about 12 mg/mL in a buffer. In a further embodiment, the solution comprising a TACE polypeptide and the binding partner is mixed with the crystallization buffer in a 1:1 ratio.
According to still another aspect of the invention, there is provided a tumor necrosis factor-α (TNF-α)-converting enzyme crystal made by co-crystallizing a TNF-α-converting enzyme polypeptide with a co-crystallization substrate.
According to yet another aspect of the invention, there is provided a computer-readable medium having recorded thereon x-ray crystallographic coordinate data for the catalytic domain of TNF-α converting enzyme, or a portion thereof. In one embodiment, the computer-readable medium has recorded thereon the x-ray crystallographic coordinate data set forth in Table 1, or a portion thereof. In another embodiment, the medium is selected from the group consisting of a floppy disc, a hard disc, computer tape, RAM, ROM, CD, DVD, a magnetic disk, and an optical disk. In still another embodiment, the computer-readable medium has recorded thereon machine-readable data, wherein the computer-readable medium, when used in conjunction with a machine programmed with instructions for using the data, is capable of generating image signals for depicting a graphical, three-dimensional representation of a TNF-α converting enzyme polypeptide, or portion thereof.
According to a further aspect of the invention, there is provided a system for studying a TNF-α converting enzyme polypeptide, said system comprising (a) a memory capable of storing information representing at least a portion of a TNF-α converting enzyme polypeptide, wherein said memory comprises at least one first-type storage region, including a set of spatial coordinates specifying a location in a three dimensional space, and at least one second-type storage region comprising information representing a characteristic of one of a plurality of amino acids, said second-type storage regions being logically associated with said first-type storage regions in said memory to represent a geometric arrangement of at least one characteristic of said at least a portion of said TNF-α converting enzyme peptide in said three dimensional space; (b) a processor coupled to said memory to access said first-type storage regions and said second-type storage regions, wherein the processor generates image signals for depicting a visual image representing three dimensional image of said at least one characteristic of said at least a portion of said TNF-α converting enzyme polypeptide in said three dimensional space based on data from said memory; and (c) a display coupled to said processor to receive said image signals, wherein the display depicts a visual three dimensional image of said at least one characteristic of said at least a portion of said TNF-α converting enzyme polypeptide in said three dimensional space based on said image signals. In one embodiment of the invention, the image signals include signals for depicting a visual three dimensional image of a ribbon structure of said at least a portion of said TNF-α converting enzyme polypeptide in said three dimensional space. In another embodiment of the invention, the image signals include signals for depicting a visual image of a solid model representation of said at least a portion of said TNF-α converting enzyme polypeptide in said three dimensional space. In still another embodiment of the invention, the image signals include signals for depicting a visual three dimensional image of electrostatic surface potential of said at least a portion of said TNF-α converting enzyme polypeptide in said three dimensional space. In yet another embodiment of the invention, the image signals include signals for depicting a visual three dimensional stereo image of said at least a portion of said TNF-α converting enzyme polypeptide in said three dimensional space. In a further embodiment of the invention, the system further comprises a storage device capable of storing data representing a geometric arrangement of a characteristic of a composition other than said TNF-α converting enzyme polypeptide; and an operator interface for receiving instructions from a operator; and wherein said processor is coupled to said storage device and to said operator interface and generates additional image signals for depicting said geometric arrangement of said characteristic of said composition relative to said visual three dimensional image of said at least one characteristic of said at least a portion of said TNF-α converting enzyme polypeptide on said display based on instructions from the operator interface. In one embodiment, the storage device is part of said memory. In another embodiment, the system comprises a plurality of first-type and second-type storage regions.
According to another aspect of the invention, there is provided a video memory capable of storing information for generating a visual display of at least a portion of a TNF-α converting enzyme polypeptide, said video memory comprising (a) at least one first-type storage region, each of said first-type storage regions including a set of spatial coordinates specifying a location in a three dimensional space; and (b) at least one second-type storage region, each of said second-type storage regions containing information for visually depicting a characteristic of one of a plurality of amino acids; wherein said second-type storage regions are logically associated with said first-type storage regions in said video memory to represent a geometric arrangement of at least one characteristic of said at least a portion of said TNF-α converting enzyme polypeptide in said three dimensional space. In one embodiment, the second-type storage regions are logically associated with said first-type storage regions in said video memory to represent a geometric arrangement of at least one characteristic of a catalytic domain portion of said TNF-α converting enzyme polypeptide in said three dimensional space. In another embodiment, the first-type storage regions and said second-type storage regions are regions of a semiconductor memory. In yet another embodiment, the first-type storage regions and said second-type storage regions are regions of an optical disk. In still another embodiment, the first-type storage regions and said second-type storage regions are regions of a magnetic memory. In a further embodiment, the video memory comprises a plurality of first-type and second-type storage regions.
In a still further aspect of the invention, there is provided a method of identifying a compound that associates with TNF-α-convening enzyme, comprising (A) designing an associating compound for said polypeptide that forms a bond with the TNF-α-converting enzyme catalytic domain based on x-ray diffraction coordinates of a TNF-α-converting enzyme polypeptide crystal; (B) synthesizing said compound; and (C) determining the associate capability of said compound with said TNF-α-converting enzyme. In one embodiment, the associating compound is an inhibitor, mediator, or other compound that regulates TNF-α-converting enzyme activity. In another embodiment, the associating compound is a competitive inhibitor, un-competitive inhibitor, or non-competitive inhibitor. In still another embodiment, the coordinates are the coordinates of Table 1, or a substantial part thereof. In a further embodiment, the TNF-α-converting enzyme polypeptide crystal comprises the TNF-α-converting enzyme catalytic domain. In still another embodiment, the TNF-α-converting enzyme polypeptide is the expression product of a polynucleotide encoding the pro and catalytic domains of TNF-α-converting enzyme. In yet another embodiment, the TNF-α-converting enzyme polypeptide is the expression product of a polynucleotide encoding the amino acid residues 1-477 of TNF-α-converting enzyme. In another embodiment, the polynucleotide is substituted such that amino acid residue Ser266 is changed to Ala and amino acid residue Asn542 is changed to Gln, and wherein a second polynucleotide encoding the sequence Gly-Ser-(His)6 (SEQ ID NO: 2) is fused to the C-terminus. In a further embodiment, the TNF-α-converting enzyme polypeptide crystal is co-crystallized with a binding partner. In still another embodiment, the binding partner is a hydroxamate-based binding partner or N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-amino-2-dimethylbutanoyl-L-alanine,2-(amino)ethyl amide. In yet other embodiments, the TNF-α-converting enzyme polypeptide crystal has a crystal structure diffracting to 2.0 Å, is monoclinic, has a unit cell comprising four crystallographically independent TNF-α-converting enzyme catalytic domain (TCD) molecules, has the TCD molecules are in an asymmetric, unit, and/or is of monoclinic space group P21 and the cell has the constants a=61.38 Å, b=126.27 Å, c=81.27 Å, and β=107.41°. In still another embodiment, the invention the associating compound is designed to associate with the S1′ region of TNF-α-converting enzyme. In yet another embodiment, the associating compound is designed to associate with the S1′S3′ pocket of TNF-α-converting enzyme. In still other embodiments of the invention, the associating compound is designed to (i) incorporate a moiety that chelates zinc, (ii) form a hydrogen bond with Leu348 or Gly349 of TNF-α-converting enzyme, (iii) introduce a non-polar group which occupies the S1′ pocket of TNF-α-converting enzyme, (iv) introduce a group which lies within the channel joining S1′-S3′ pockets of TNF-α-converting enzyme and which makes appropriate van der Waal contact with the channel, and/or (v) form a hydrogen bond with Leu348 or Gly349 on the backbone amide groups of TNF-α-converting enzyme.
These and other aspects of the invention will become apparent to the skilled artisan in view of the teachings contained herein.



BRIEF DESCRIPTION OF THE FIGURES
The file of this patent contains at least one drawing executed in color. Copies of this patent with color drawings are provided to the Patent and Trademark Office with payment of the necessary fee.
FIG. 1: FIG. 1 is a ribbon diagram of the TACE catalytic domain (TCD). The chain starts on the lower left back side, runs through the structural elements sI, hAI, hA, sII, hB, hB2, sIII, IV, IVa, sIVb, sV, hC, Met-turn and hD, and ends in the upper left back. The three disulfides are shown as connections, with the sulphurs given as small spheres. The catalytic zinc (central sphere) is liganded by the three imidazoles of His4O5, His4O9 and His415, and by the hydroxyl and the carbonyl oxygen atoms of the inhibitor hydroxamic acid group. The inhibitor mimicking interaction of primed-site residues of a peptide substrate is shown in full. FIG. 1 was made using SETOR. See Evans, S. “SETOR: Hardware Lighted Three-Dimensional Solid Model Representations of Macromolecules” J. Mol. Graph. 11:134-138 (1993).
FIGS. 2a and 2b: FIGS. 2a and 2b are solid surface representations of the catalytic domains of TACE (TCD) (FIG. 2a) and MMP-3 (FIG. 2b). The electrostatic surface potential is contoured from −15 (intense red) to 15 (intense blue) k8T/e. Both active-site clefts run from left to right, with the catalytic zinc atoms (spheres) in the centers. In TACE, the bound inhibitor is shown in full structure, binding with its isobutyl (P1′) and its Ala (P3′) sidechains into the deep S1′ and the novel S3′ pockets. The orientation is similar to FIG. 1. FIGS. 2a and 2b were made using GRASP. Nicolls, A., Bharadwaj, R. and Houig, B., “Grasp—Graphical representation and analysis of surface properties,” Biophys. 64, A166 (1993).
FIG. 3: FIG. 3 aligns the catalytic domain sequences of adamalysin II (ADAM_CROAD) (SEQ ID NO: 4), TACE (SEQ ID NO: 5) and human ADAM 10 (hADAM1O) (SEQ ID NO: 6), according to their topological equivalence and sequence similarity, respectively. The residue numbers are due to the generic TACE numbering. Arrows and braces represent β-strands and α-helices in TACE.
FIG. 4: FIG. 4 is a stereo section of the final 2.0 Å electron density around the catalytic zinc (large, central sphere) superimposed with the final TACE model. Visible are the three zinc liganding imidazole rings of His4O5 (top), His4O9 (left) and His415 (bottom), the “catalytic” Glu406, and the hydroxamic acid moiety of the inhibitor. The orientation is similar to FIG. 1. FIG. 4 was made using TURBO-FRODO. See Roussel, A. & Cambilleau, C., “Turbo-Frodo in Silicon Graphics Geometry,” Partners Directory, Silicon Graphics, Mountain View, Calif. (1989).
FIG. 5: FIG. 5 is a superposition of the ribbon plots of the catalytic domain of TACE (light) and adamalysin (dark). Also shown is the catalytic zinc of TACE (sphere) and the three (TACE) and two (adamalysin) disulfide bridges. The orientation is similar to FIG. 1. FIG. 5 was made using GRASP.
FIG. 6: FIG. 6 illustrates a system for studying a TNF-α converting enzyme, including a video memory storing information for generating a visual display of at least a portion of a TNF-α converting enzyme.



DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a highly purified tumor necrosis factor-α converting enzyme (TACE) polypeptide, a method of producing and purifying a TACE polypeptide, a method of crystallizing a TACE polypeptide, and a TACE polypeptide crystal. The invention further relates to a X-ray diffraction method using a TACE polypeptide crystal, and to a method of obtaining the X-ray crystallographic structural coordinates of a TACE polypeptide as well as the structural coordinates themselves. Still further, the present invention relates using the structural coordinates of a TACE polypeptide to elucidate the three-dimensional structure of a TACE polypeptide and designing and developing compounds that associate with TACE. Knowledge of the three-dimensional structure and structure coordinates provided according to the invention permit the skilled person to make compounds that will interact with TACE. Such interacting compounds can be made by a variety of techniques and design criteria, including those disclosed in Protein Engineering (Oxender and Fox, eds.) (Alan R. Liss, Inc. 1987).
As used herein, TACE refers to a group of polypeptides that are capable of converting the 26 kD cell membrane-bound form of TNF-α into the soluble 17 kD form that comprises the C-terminal 156 residues of the TNFα protein. TACE encompasses proteins having the amino acid sequence described in PCT application No. WO 96/41624, herein incorporated in its entirety by reference, as well as any of those proteins having homology, preferably no less than 50%, more preferably at least 80% homology, still more preferably 90% homology to such sequence, at the amino acid level. Additionally, TACE further refers to the expression products of nucleotide sequences disclosed in PCT application No. WO 96/41624. TACE further encompasses the membrane-bound protein and soluble or truncated proteins comprising the extracellular portion of the protein and which retain biological activity and are capable of being secreted. Examples of such proteins are described in PCT application No. WO 96/41624.
The TACE amino acid sequence, or any part or residue thereof, can be found in Black et al., “A Metalloproteinase disintigrin that releases tumour-necrosis factor-α from cells,” Nature 385: 729-733 (February 1997), herein incorporated in the entirety by reference. Variations in the amino acid sequence of TACE are within the present invention as well. All references to the TACE amino acid sequence contained herein refer to the sequence in Black et al., supra.
As used herein, the TACE catalytic domain (TCD) refers to the portion of a TACE polypeptide between residues 215 and 477 and including the preceding furin cleavage site (residues 211-214), or any part thereof that is capable of cleaving the peptide PLAQAVRSSS (SEQ ID NO: 1).
Expression, Isolation and Purification of TACE Polypeptides
Tumor necrosis factor-α converting enzyme (TACE) is described in the published PCT application No. WO 96/41624. The application describes isolated nucleic acids encoding TACE or portions of TACE, expression vectors comprising a cDNA encoding TACE or portions thereof, and host cells transformed or transfected with the expression vectors comprising a cDNA encoding TACE or portions of TACE. The application further describes processes for producing TACE and portions thereof, for example by culturing transfected cells engineered to express TACE, followed by purification of the recombinantly produced TACE or portion thereof. Methods of isolating, expressing, and purifying a TACE polypeptide are described in detail in published PCT application No. WO 96/41624. The entirety of PCT 96/41624 is incorporated herein by reference.
According to the invention, cDNA encoding the signal peptide, pro and catalytic domains of TACE, i.e., amino acid residues 1-477 is inserted into a suitable expression vector and expressed in a suitable cell line. The cDNA also may include other regions that facilitate expression or achieve other objects that otherwise that do not depart from the essence of the invention, such as flanking regions.
The cDNAs encoding the TACE polypeptide, or functional portions thereof, such as the TCD, may be altered by addition, substitution, deletion, or insertion. Such alterations may be made, for example, to prevent glycosolation, prevent formation of incorrect or undesired disulfide bridges, and/or enhance expression. Examples of such alterations are described in WO 96/41624 and can be carried out by the methods described therein and other conventional methods. TACE may also be conjugated. Such conjugates may comprise peptides added to facilitate purification and/or identification. Such peptides include, for example, poly-His peptides. Conjugation is described in U.S. Pat. No. 5,011,912 and Hopp et al., Bio/Technology 6:1204 (1988).
In one embodiment of the invention, the cDNA encodes a TNF-α converting enzyme polypeptide comprising the signal peptide, pro and catalytic domains of TACE (TCD), residues 1-477, with Ser266 changed to Ala and Asn452 changed to Gln. These substitutions are useful in preventing N-linked glycosolation. Additionally, the sequence Gly-Ser(His)6 (SEQ ID NO: 2) may be added to the C-terminus. The addition of the sequence Gly-Ser(His)6 (SEQ ID NO: 2) facilitates purification of the polypeptide using metal-chelate affinity resins, such as Ni-NTA resins.
Recombinant expression vectors containing the nucleotide sequence encoding TACE, or a portion thereof, may be prepared using well known methods. Suitable host cells for expression of TACE polypeptides include prokaryotic, yeast, and higher eukaryotic cells. Vectors and host cells suitable for use in the present invention are described in WO 96/41624. Further examples of suitable expression systems that can be employed to express recombinant TACE according to the present invention include mammalian or insect host cell culture expression systems, including baculovirus systems in insect cells (Sec Luckow and Summers, Bio/Technology 6:47 (1988))and mammalian cell lines such as COS-7 cells (Gluzman et al., Cell 23:175 (1981)). Additional examples are known in the art and include those described in WO 96/41624. In one embodiment of the invention, the TACE polypeptide is expressed in CHO cells. In this embodiment, the cells secrete a mixture of TACE polypeptide beginning with Val212 and Arg215.
In one embodiment, stable expressing cells may be selected by culturing the cells in a drug that kills those cells that do not incorporate the vector. Examples of suitable selection methods are described in, for example, Kaufman, R. J., “Selection and coamplification of heterologous genes in mammalian cells,” Methods in Enzymology, 185:537-566 (1990).
Purification of the expressed TACE polypeptide may be carried out by any suitable means, such as those described in WO 96/41624. According to one aspect of the invention, it is preferable to obtain a TACE polypeptide that is suitable for crystallization. In obtaining a TACE polypeptide suitable for crystallization, it is important that the process for purifying the TACE polypeptide is sufficient to yield a polypeptide pure enough to properly crystallize.
A preferred method of purification starts with a suitable amount of medium from the culture of TACE-secreting cells. This medium is generally a supernate of the culture. The medium contains the TACE polypeptide to be purified. Preferably, the TACE polypeptide is recombinantly produced using DNA coding for the TACE polypeptide with the sequence altered to encode a conjugate or conjugates that facilitate purification. For example, the sequence encoding Gly-Ser-(His)6 (SEQ ID NO: 2) may be added to the C-terminus to facilitate purification using metal-chelate resins.
The medium is concentrated, for example, by diafiltration. Suitable diafiltration units include a Millipore 10K cut-off, 1 ft2 TFF diafiltration unit. A suitable buffer solution is then added to the concentrated medium. Any suitable buffer may be used. One such suitable buffer contains 20 mM Tris (pH 7.5) and 300 mM NaCl.
The sample is reconcentrated and diluted numerous times. For example, the sample may be reconcentrated and diluted a second time with the buffer, reconcentrated again, diluted a third time with the buffer, and reconcentrated a final time. The sample retained in the diafiltration unit is recovered by a suitable method, such as by a back-flush method. The recovered material may then be filtered through a suitable membrane. Suitable membranes include, for example, 0.45 or 0.22 micron pore-size membranes. Azide is then added. The filtered sample may then be stored overnight at a low temperature, such as about 2-9° C. After overnight storage, imidazole from a stock solution in water and ZnCl2 from a stock solution in water are added to the filtered sample. The sample then is pumped over a suitable column. One suitable column, particularly when the TACE polypeptide is conjugated with the sequence Gly-Ser-(His)6, is a metal-chelate resin, such as a Ni-NTA resin.
The column is washed with a buffer, such as a buffer of 20 mM Tris pH 7.5, 300 mM NaCl, 5 mM imidazole, and 5 uM ZnCl2. The TACE polypeptide is then eluted with an increasing gradient of imidazole. Fractions are collected in tubes containing glycerol in water Tris pH 8. Preferably, the glycerol solution is prepared the day of the column run.
An aliquot from each fraction is spotted on a membrane which is stained with amido black to determine which fractions contain a significant amount of protein. Alternatively, a small amount, for example 5 μl, from each fraction may be used for gel analysis using Coomassie staining. The fractions with a significant amount of protein are pooled, and the pool is then concentrated with, for example, a diafiltration unit.
In some cases, aggregation of polypeptide may occur. In order to eliminate aggregates and further facilitate purification, an inhibitor of TACE, such as a hydroxamate-based inhibitor, may be added to the concentrated sample from a stock solution in water, and octylglucoside (commercially available from Boehringer Mannheim) is added from a stock solution in water. The sample is then incubated at room temperature for 15-24 hours.
Following incubation, the sample is applied to a size exclusion column. The column is first equilibrated with a suitable buffer, such as a buffer of 10 mM Tris pH 7.5, 100 mM NaCl, 10% glycerol. Suitable size exclusion columns include, for example, LKB 2135-365, packed with TSK-G3000 SWG or the like such as Superdex-200. The buffer is then pumped through the column. The highly purified TACE polypeptide can be detected by absorption at 280 nm.
A gel analysis of all fractions with significant protein is carried out to determine which fractions should be pooled. The size exclusion chromatography pool is concentrated using, for example, a diafiltration unit.
A binding partner, such as an inhibitor, may then be added to the purified sample. The binding partner is particularly useful in stabilizing the TACE polypeptide. The binding partner may be any suitable compound. Suitable binding partners include, for example, hydroxamate-based inhibitors. One suitable inhibitor is N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-amino-2-dimethylbutanoyl-L-alanine, 2-(amino)ethyl amide. This inhibitor, as well as other inhibitors, are described in U.S. Pat. No. 5,594,106 (Black et al.), herein incorporated in its entirety by reference.
The protein complex can be stored at low temperature, for example, at about 4° C.
TACE Crystal and Methods of Crystallization of TACE Polypeptides
One aspect of the invention relates to a method of crystallizing a TACE polypeptide. A preferred method comprises co-crystallizing a TACE polypeptide with a binding partner described above. Exemplary means for obtaining the TACE polypeptide, as well as purification of the polypeptide are described above.
Crystals may be grown or formed by any suitable method, including drop vapor diffusion, batch, liquid bridge, and dialysis, and under any suitable conditions. Crystallization by drop vapor diffusion is often preferable. In addition, those of skill in the art will appreciate that the crystallization conditions may be varied. Various methods of crystallizing polypeptides are generally known in the art. See, for example, WO 95/35367, WO 97/15588, EP 646 599 A2, GB 2 306 961 A, and WO 97/08300.
In one embodiment of the invention, a DNA construct comprising TACE residues 1-477, with Ser266 changed to Ala, Asn452 changed to Gln, and the sequence Gly-Ser-(His)6 (SEQ ID NO: 2) added to the C-terminus, may be expressed in CHO cells. These cells primarily secrete a processed mixture of TACE, about half beginning with Val212 and about half with Arg215. The mixture is purified as described above. The purified TACE polypeptide, with the added binding partner, is stored in a buffer as described above.
The TACE polypeptide and binding partner are co-crystallized. The TACE/binding partner solution, at a polypeptide concentration of about 5 mg/mL to about 12 mg/mL in a TACE buffer described above, is mixed with a suitable crystallization buffer and crystallized using a suitable crystallization technique, for example drop vapor diffusion. Suitable crystallization buffers, for example, include: 0.1 M Na Acetate pH 5.3, 0.2 M CaCl2, 30% v/v Ethanol; 0.1 M Na Citrate pH 5.0, 40% v/v Ethanol; 0.1 M Na Citrate pH 8.7, 20% w/v PEG 4000, 20% v/v Isopropanol; and 0.1 M Na Citrate pH 5.4, 20% w/v PEG 4000, 20% v/v Isopropanol. The sample is incubated at a temperature ranging from about 4 to 20 degrees Celsius. A crystalline precipitate is formed.
Seeds from the crystalline precipitate obtained, as whole crystals or crushed crystal suspensions, are transferred, along with a suitable crystallization promoter, such as hair of rabbit, to a solution of concentrated TACE/substrate in a crystallization buffer. Crystals suitable for X-ray data collection are formed.
Another aspect of the invention relates to a TACE polypeptide crystal. One such crystal comprises a TNF-α converting enzyme catalytic domain (TCD) polypeptide co-crystallized with an inhibitor. The crystal diffracts to about 2 A and belongs to the monoclinic space group P21. The crystal's unit cell comprises four crystallographically independent TCD molecules. The TCD molecules are in an asymmetric unit and are not clustered into separate tetrameres, but are integrated into the infinite periodic structure. The crystal has the cell constants: a=61.38 Å (angstrom), b=126.27 Å, C=81.27 Å and β=107.41°.
X-Ray Diffraction
Another aspect of the invention relates to the structure of TACE, particularly the structure of the TACE catalytic domain (TCD). The structure of TACE can be determined utilizing a crystal comprising a TACE polypeptide as described above. According to the present invention, the structure of TACE, and particularly the TCD, is determined using X-ray crystallography. Any suitable X-ray diffraction method for obtaining three-dimensional structural coordinates of a polypeptide may be used. The three-dimensional structure coordinates, or any part thereof that characterizes the part of the TACE polypeptide of interest, such as the TACE catalytic domain or part thereof that is capable of cleaving the peptide PLAQAVRSSS (SEQ ID NO: 1), can be used as described herein.
Methods of Using TACE X-Ray Diffraction Coordinates
The invention also relates to use of the structure coordinates obtained from the above described X-ray diffraction studies of the TACE catalytic domain. The coordinates may be utilized, by direct analysis, with the aide of computers, or combinations thereof, to determine the structure, including secondary and tertiary structure, of the TACE catalytic domain. The TACE catalytic domain structure coordinates also may be used to develop, design, and/or screen compounds that associate with TACE. As used herein, “associate” means that the compound may bind to or interact with TACE ionically, covalently, by hydrogen bond, van der Waals interaction, salt bridges, steric interaction, hydophilic interactions and hydrophobic interaction. Moreover, the term “associate” encompasses associations with any portion of the TACE catalytic domain. For example, compounds that associate with TACE may be compounds that act as competitive inhibitors, un-competitive inhibitors, and non-competitive inhibitors. Compounds that associate with TACE also may be compounds that act as mediators or other regulatory compounds. Compounds that associate with TACE also may be compounds that isomerize to short-lived reaction intermediates in the chemical reaction of substrate with TACE. In particular, compounds designed to associate with TACE may be used therapeutically as inhibitors, mediators and other regulatory compounds.
The use of X-ray coordinates for structure determination, molecular design and selection and synthesis of compounds that associate with other polypeptides is known in the art. Published PCT application WO 95/35367 describes the use of X-ray structure coordinates to design, evaluate, synthesize and use compounds that associate with the active site of an enzyme. UK Patent Application 2306961A describes the use of X-ray coordinates in rational drug design. Published PCT application, WO 97/15588 describes the structural determination of a polypeptide using x-ray diffraction patterns as well as use of the coordinates and three-dimensional structure in finding compounds that associate with the polypeptide of interest. This invention, however, for the first time allows the use of X-ray coordinates for a TACE polypeptide for structural determination, molecular design, and selection and synthesis of compounds that associate with TACE.
In one aspect of the invention, the structure coordinates obtained by the foregoing methods may be displayed as, or converted to, a graphical representation, including three-dimensional shape representations. This may be accomplished using commercially available computer programs capable of generating graphical representations of molecules, or parts thereof, from a set of structural coordinates. Examples of computer programs capable of generating graphical representations of molecules, or parts thereof, from a set of structural coordinates are described in published PCT application WO 97/08300, incorporated in the entirety by reference.
In another aspect of the invention, the structure coordinates and structure may be compared to, or superimposed over, other similar molecules, such as other metalloproteinases. For example, the TACE structure coordinates and structure may be compared to or superimposed over the structure coordinates or structure of snake venom metalloproteinases, such as, for example, adamalysin II. The TACE structure coordinates and structure also may be compared to or superimposed over the structure coordinates or structure of matrix metalloproteinases, such as ADAM 10, including human ADAM 10. Comparison of TACE and other molecules for which a graphical structure or three-dimensional structural coordinates are available may be carried out with the aide of available software applications, such as the Molecular Similarity application of QUANTA (Molecular Simulations, Inc., Waltham, Mass.).
Compounds that associate with TACE also may be computationally evaluated and designed by screening and selecting chemical entities or fragments for their ability to associate with TACE, and specifically the TACE catalytic domain. Several methods may be used to accomplish this aspect of the invention. In one embodiment, one may visually inspect a computer-generated model of TACE, and specifically the catalytic domain, based on the structure coordinates described herein. Computer generated models of chemical entities or specific chemical moieties can then be positioned in or around the catalytic domain and evaluated based on energy minimization and molecular dynamics, using, for example, available programs such as CHARMM or AMBER. Positioning of the chemical entity or fragment can be accomplished, for example with docking software such as Quanta and Sybyl. Additionally, known and commercially available computer programs may be used in selecting chemical entities or fragments. Once suitable chemical entities or fragments are selected, they may be assembled into a single compound, such as an inhibitor, mediator, or other regulatory compound. Known and commercially available model building software may assist in assembly.
In one aspect of the invention, compounds that associate with TACE and specifically the TACE catalytic domain may be designed as a whole, rather than by assembly of specific chemical moieties or chemical entities. This embodiment may be carried out using computer programs such as LUDI (Biosym Technologies, San Diego, Calif.), LEGEND (Molecular Simulations, Burlington, Mass.), and Leap Frog (Tripos Associates, St. Louis, Mo.).
In one embodiment, a candidate compound is chosen based upon the desired sites of interaction with TACE and the candidate compound in light of the sites of interaction identified previously. Once the specific candidate compound-TACE interactions are determined, docking studies, using commercially available docking software, are performed to provide preliminary “modeled” complexes of selected candidate compound with TACE.
Constrained conformational analysis is performed using, for example, molecular dynamics (MD) to check the integrity of the modeled TACE-inhibitor complex. Once the complex reaches its most favorable conformational state, the structure as proposed by the MD study is analyzed visually to ensure that the modeled complex complies with known experimental SAR/QSAR (structure-activity relationship/quantitative structure-activity relationship) based on measured binding affinities.
Other modeling techniques also may be used in accordance with the invention. Examples of these techniques are disclosed in Cohen et al., “Molecular Modeling Software and Methods for Medicinal Chemistry,” J. Med. Chem., 33:883-894 (1990) and Navia et al., “The Use of Structural Information in Drug Design,” Current Opinions in Structural Biology, 2:202-210 (1992), herein incorporated by reference in the entirety.
Compounds developed or designed to associate with TACE may be optimized or the efficiency of association can be tested using a number of methods known in the art. For example, the deformation energy and electrostatic interactions may be determined and optimized. Known and commercially available software and hardware systems may be used. Examples of such software are disclosed in WO 95/07619. Structure-based analoging for optimization of the inhibitor potency, selectivity and physical drug-like properties in an iterative manner also may be performed by one skilled in the art of drug design.
Substitutions also may be made to selected or designed compounds. These substitutions can be made to improve or modify the association properties of the compound. Such substitutions may be made, for example, in side groups or particular atoms of the compounds. Generally, one should begin with conservative substitutions that have approximately the same size, shape, charge and other characteristics of the original group or atom. Substituted compounds may be further analyzed and optimized as described above.
In a further aspect of the invention, the potential inhibitory, mediatory, regulatory, or other binding effect of a compound may be analyzed and evaluated, using, for example, commercially available computer software, prior to actual synthesis and testing of such compound. In this way, one can evaluate the probability of synthesizing and testing of inoperative compounds.
Procedures for measuring inhibition generally are known in the art and are disclosed, for example, in PCT 96/41624. Such methods include assays based on reaction with a peptide substrate.
TACE Catalytic Domain Structure
The physical features of the TCD, determined based on the X-ray diffraction data obtained using the methods described and its use in creating molecular models of the TCD, are further described, with reference to the Figures.
The domain depicted in FIG. 1 has the shape of an oblate ellipsoid, notched at its flat side to give a relatively small active-site cleft separating the small “lower” subdomain from the “upper” main molecular body (FIG. 2a). The TCD polypeptide chain starts on the molecular surface (in the lower back, FIG. 1), with the chain becoming well defined between Asp217 and Met221 (see FIG. 3). Central to the molecule is the five-stranded β-pleated sheet, with the β-strands arranged in the order (from back to front, see FIG. 1) sII, sI, sII, sV and sIV (see FIG. 3), with sIV, the “edge” strand, running antiparallel to the others. This β-sheet is highly twisted flanked by two α-helices (hB and hB2) on its convex and two helices (hA and hC) on its concave side. The β-strands sI and sII are connected by the short α-helix hA1 and the long, α-helix hA (the obliquely running helix on the backside, FIG. 1). The β-strands sII and sIII are linked by the large “multiple-turn loop”, the long “intermediate” α-helix hB and the adjacent short α-helix hB2, all of them arranged on “top” of the β-sheet thus fully shielding its central part from bulk water (FIG. 1). The multiple-turn loop is bulged out at two sites giving rise to a “spur-like” and a quite acidic protuberance, respectively (visible in FIG. 2a on top of the molecule). The sIII-sIV linker terminates in a short “bulge”, before it enters the edge strand sIV. The sIV-sV connecting segment is dissected into two large “ear-like” surface-located loops, a first one nestling to the main molecular body (giving rise to the “blue” surface, center left, in FIG. 2a), and a long β-hairpin loop (sIIa-sIIb) projecting from the molecular surface (top left in FIGS. 1 and 2). A bulged-out loop links sV with the “active-site helix” hC, which is located in the center of the molecule and stops abruptly at the strictly conserved Gly412, where the chain kinks down to build the lower subdomain.
The C-terminal chain comprising the last 61 TCD residues (FIG. 3) first forms three short straight almost perpendicularly arranged segments linked by two “narrow” supertwisted loops, returns via the tight “Met-turn” Tyr433-Val434-Met435-Tyr436 back to the surface where it kinks at Pro437 to form the Pro437-Ile438-Ala439 outer “wall” of the S1′ crevice, approaches in a wide loop the C-terminal α-helix hD and runs through it, and ends up on the molecular “back” surface close to the N-terminus, with the last defined residues Arg473-Ser474 fixed via hydrogen bonds to the main molecular body. Via Cys423-Cys453, the first of the two “narrow” loops is disulfide-linked with the N-terminus of helix hD, whose C-terminal end in turn is clamped to the “ear-like” sIV-sV linker peptide through Cys365-Cys469. Spatially adjacent, the third disulfide bridge of TCD, Cys225-Cys333, connects the N-terminal parts of β-strands sI and sIII. In the intact TACE molecule, four residues downstream of Ser474 would reside Cys478, which is already integral part of the compact elongated disintegrin domain (Saudek et al., “Three-dimensional structure of echistatin, the smallest active RGD protein” Biochem. 30, 7369-7372 (1991)). Considering Ser474 and this Cys478 as pivot points of their respective domains, the three residue linker would allow relatively unconstrained docking of the disintegrin domain to the “left” surface side of the catalytic domain.
The active-site cleft of TACE (FIG. 2a) is relatively flat on the left hand (nonprimed) side, but becomes notched towards the right. The catalytic zinc residing in its center is penta-coordinated by the three imidazole Nε2 atoms of His4O5, His4O9 and His415 (provided by the active-site helix and the following “descending” chain comprising the conserved zinc binding consensus motif HEXXHXXGXXH) (SEQ ID NO: 3), and by the carbonyl and the hydroxyl oxygen of the hydroxamic acid moiety of the inhibiter (see FIGS. 1, 2a and 4). This zinc-imidazole ensemble is based on the distal ε-methyl-sulphur moiety of the strictly conserved Met435, harbored in the Met-turn characteristic for the metzincin clan (Bode et al., “Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc binding environments (HEXXHXXGXXH (SEQ ID NO: 3) and Met-turn) and topologies and should be grouped into a common family, the ‘metzincins’” FEBS Lett. 331, 134-140 (1993); Stöcker et al., “The metzincins: Topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases” Protein Sci. 4, 823-840 (1995)). Both carboxylate oxygens of the “catalytic” Glu4O6 (which acts as a general base during catalysis (Grams et al., “X-ray structures of human neutrophil collagenase complexed with peptide hydroxamate and peptide thiol inhibitors: Implications for substrate binding and rational drug design” Eur. J. Biochem. 228,. 830-841 (1995)) squeezed between the zinc-liganding imidazole of His4O5 and the edge strand, are hydrogen bonded to the hydroxyl and the N—H group of the hydroxamic acid (see FIG. 4). To the right of the catalytic zinc opens the deep S1′ pocket, which, besides the S1′ wall-forming segment (bottom, FIGS. 1 and 2a), is bordered by the side chains of His4O5 and Glu4O6 (left), the sIV main chain and the Leu345 side chain (top), and the side chains of Val44O (back) and Ala439 (right). To the right of Ala439 opens a second (S3′) pocket, which inside the molecule merges with the S1′ pocket, leaving a small bridge made of the opposing side chains of Ala439 and Leu348 (FIG. 2a).
The (pseudo)peptide part of the inhibitor binds in an extended geometry to the notched right-hand side of the active-site cleft, mimicking the interaction of the primed residues of a productively bound peptide substrate (FIG. 2a). It runs antiparallel to the upper short bulge Gly346-Thr347-Leu348 and parallel to the S1′ wall-forming segment Pro437-Ile438-Ala439, making two and two inter-main chain hydrogen bonds, respectively. The dominant intermolecular interactions are made by the P1′ isobutyl (pseudo-leucyl) side chain of the inhibitor and the essentially hydrophobic S1′ pocket, however, is large and accommodates three partially ordered solvent molecules in addition. The P2′ t-butyl side chain extends away from the enzyme, but nestles to the hydrophobic canopy above formed by the enzyme's bulge. The P3′ Ala side chain points into the large negatively charged S3′ pocket, but is too short to make favorable contacts. The C-terminal diaminoethyl group has different conformations in the four molecules.
The P1′ to P3′ segment Val77-Arg78-Ser79 of a bound pro-TNFα probably binds in a similar manner, possibly under better matching with the underlying cleft surface; the preceding P3 to P1 residues Ala74-Gln75-Ala76 certainly will align antiparallel to the edge strand, with their side chains extending into the (partially charged) S3 pocket and the (negatively charged) shallow S2 depression, and projecting out of the central cleft, respectively. The primed subsites and surrounding molecular surfaces of TACE are dominated by negative charges, while the non-primed subsites are essentially hydrophobic in nature (FIG. 2a). More distant interactions may be involved in the specificity of TACE for processing pro-TNFα. The 12 residue substrate comprising the pro-TNFα cleavage site can also be split by some of the MMPs, although with less specificity and efficacy (Black et al., “Relaxed specificity of matrix metalloproteinases (MMPs) and TIMP intensity of tumor necrosis factor-α (TNF-α) production suggest the major TNF-α converting enzyme is not an MMP” Biochem. Biophys. Res. Commun. 225, 400-405 (1996)). Thus, the preferential processing of the (probably trimeric) (Tang et al., “Human pro-tumor necrosis factor is a homotrimer” Biochem. 35, 8216-8225 (1996a); Tang et al., “Length of the linking domain of human pro-tumor necrosis factor determines the cleavage processing” Biochem. 35, 8226-8233 (1996b)) membrane-bound pro-TNFα in vivo might in part be due to correct assembling, i.e. suitable presentation of the pro-TNFα cleavage segment to the TACE active site in a distinct distance from the anchoring membrane. Some experimental evidence (Tang et al., Biochem. 35, 8216-8225 (1996a); Tang et al., Biochem. 35, 8226-8233 (1996b)) suggests that the cleavage site might not be determined by the cleavage sequence alone, but that also the distance to the base of the compact cone formed by the associated C-terminal segments of three TNFα molecules (Jones et al., “Structure of tumor necrosis factor” Nature 338, 225-228 (1989)) plays a role. In a productive TACE-proTNFα complex, the base of this TNFα-trimer cone (into which the disordered N-termini run up) may be recognized by the “right” side of the TACE catalytic domain (FIG. 2a), with the about 10 residues long spacer favoring the correct placement of the proTNFα Ala76-Val77 scissile peptide bond in the active site of TACE.
The polypeptide topology and in particular the surface presentation of the catalytic zinc prove the catalytic domain of TACE to be a typical metzincin. (Bode et al., “Astacins, scrralysins, snake venom and matrix metalloproteinases exhibitidentical zinc binding environments (HEXXHXXGXXH (SEQ ID NO: 3) and Met-turn) and topologies and should be grouped into a common family, the ‘metzincins’” FEBS lett. 331, 134-140 (1993); Stöcker et al., “The metzincins: Topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases” Protein Sci. 4, 823-840 (1995)) A superposition with the other metzincins shows, however, that its topology is most similar to that of the catalytic domain of snake venom metalloproteinases such as adamalysin II (FIG. 5). (Gomis-Rüth et al., “First structure of a snake venom metalloproteinase: prototype for matrix metalloproteinases/collagenases” EMBO J. 12, 4151-4157 (1993); Zhang et al., “Structural interaction of natural and synthetic inhibitors with the venom metalloproteinase, atrolysin C (form d)” Proc. Natl. Acad. Sci. USA 91, 8447-8451 (1994); Kumasaka et al., “Crystal structure of H2-proteinase from the venom of Trimeresurus flavoviridis” J. Biochem. 119, 49-57 (1996)) This close homology is reflected by the much better simultaneous superposition of the central sheet and the large helices, but in particularly also by a couple of structural features, which TACE shares exclusively with the adamalysins such as: the long helix hB and the preceding multiple-turn loop arranged on top of the β-sheet; the typically arranged and shaped C-terminal helix hC; and the extended C-terminus placed on the backside surface. About 175 of the 263 TACE and 201 adamalysin α-atoms are topologically equivalent (with an rms deviation of 1.3 Å, 39 of which have identical side chains (FIG. 3). These numbers are close to those obtained from a comparison of members within the different metzincin families. (Stöcker et al., supra) In addition, detailed structural features prove the close relationship of TACE to the adamalysins: a more conserved core structure; the loosely arranged N-terminus; the characteristic Asp416 (directly following the zinc binding consensus motif, FIG. 3) involved in identical intramolecular hydrogen bond interactions; the adjacent disulfide bridge Cys423-Cys453 linking the first narrow loop to the C-terminal helix hD (which TACE does not share with adamalysin II, but with the H2-proteinase from the snake venom of T. flavoviridis) (Kumasaka et al., supra); disulfide bridge Cys365-Cys469 connecting the sIV-sV linker with the C-terminal helix hD; a similarly shaped active-site cleft, with particularly strong similarities in the S1′ pocket and other primed subsites.
The catalytic domain of TACE (TCD) also differs from adamalysin II in several respects: with 263 residues, its chain is much longer; most of the additional residues of TACE are clustered giving rise to a more projecting hA-sII turn, to the two surface protuberances of the multiple-turn loop, to the two “ears” of the sIV-sV linker, and to a more bulged-out sV-hC connector (see FIGS. 3 and 5); lack of a calcium binding site but presence of a third disulfide bridge Cys225-Cys333 in TACE, both elements serving, however, for the same function namely to clamp the N-terminal chain to strand sIII; the quite deep S3′ pocket of TACE which merges with its S1′ pocket; an almost inverted charge pattern in and around the primed subsites, with an absolute predominance of positive charges in adamalysin.
According to its sequence, and probably with respect to its three-dimensional structure, the TACE catalytic domain is thus not a typical member of the mammalian ADAMs proper (a family of membrane-anchored cell-surface proteins, with the catalytic domain quite homologous to adamalysin (Wolfsberg et al., “ADAMs in Fertilization and Development” Developm. Biol. 180, 389-401 (1996))) TACE presumably shares this “outsider” role with (bovine) ADAM 10 (FIG. 3), which does also possess some TACE-like activity (Lunn et al., “Purification of ADAM 10 from bovine spleen as a TNFα convertase,” FEBS Lett. 400, 333-335 (1997)), and whose Drosophila version (kuz) has recently been shown to process the Notch receptor (Rooke et al., Science 273, 1227-1231 (1996)). Also ADAM 10 probably exhibits an elongated hA-sII loop and the two “ears” typical for TACE, but might have a multiple-turn intermediate insize between TACE and adamalysin (see FIG. 3). Ninety of the ADAM 10 catalytic domain residues are identical to TACE further underlining the close homology (see FIG. 3), whereas the other mammalian ADAMs probably resemble much more adamalysin II (Gomis-Ruth et al., “Refined 2.0 A crystal structure of snake venom zinc endopeptidase adamalysin II” J. Mol. Biol. 239, 513-544 (1994)).
The structural homology of TACE to the MMPs is significantly lower. The relative arrangement of the common secondary structural elements differs more (reflected by the significantly larger mnis deviation of 1.6 Å of the about 120 topologically equivalent Cα-atoms), and the MMPs lack characteristic TACE/adamalysin structural elements (such as the intermediate helix hB and the multiple-turn loop, the Asp residue behind the third zinc-binding histidine), or exhibit typical determinants (such as the structural zinc and the integrated calcium ions) not seen in TACE. Notwithstanding the differences in secondary structure, the active-site cleft of TACE bears some similarity with that of the MMPs, with the flat nonprimed (left-hand) side, and the narrow primed side centering in the deep S1′ pocket (FIG. 2b). This subsite similarity to the MMPs explains the observed partial sensitivity of TNFα-convertase activity towards synthetic hydroxamic acid inhibitors originally designed for inhibition of various MMPs (DiMartino et al., “Anti-arthritic activity of hydroxamic acid-based pseudopeptide inhibitors of matrix metalloproteinases and TNF-α processing” Inflamm. Res. 46, 211-215 (1997)). Model building experiments with TIMP-1 structure (Gomis-Rüth et al., “Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1” Nature 389, 77-81(1997)) show no obvious obstacles in the active-site region of TACE that would easily explain its resistance to blockage by the TIMPs.
This TCD crystal structure thus gives evidence for a topological similarity of the catalytic domain of TACE with that of the adamalysins/ADAMs, and for a share of its substrate binding site to that of the MMPs. TACE exhibits, however, several structural peculiarities regarding surface contour, charge and shape, which facilitates the design of potent selective synthetic inhibitors.
In designing and developing compounds, such as inhibitors, mediators and other compounds having activities with biological significance, that associate with TACE, it is desirable to select compounds with a view toward the particular surface contour, charge, shape, and other physical characteristics of the TACE catalytic domain. Generally, the compounds should be capable of physically and structurally associating with TACE, as well as be able to assume a conformation that allows it to associate with TACE. The features described above will direct the skilled artisan in this regard. In particular, compounds with a linear functionality should be particularly suitable. Such compounds will be particularly suitable in light of the deep pockets of the TACE catalytic domain.
The compounds that associate with TACE, for example, may be designed to associate with the S1′ region or the S1′S3′ pocket of TACE. Compounds that associate with TACE also may be designed to (i) incorporate a moiety that chelates zinc. Further exemplary compounds include compounds are designed to form a hydrogen bond with Leu348 or Gly349 of TACE, (ii) introduce a non-polar group which occupies the S1′ pocket of TACE, (iii) introduce a group which lies within the channel joining S1′-S3′ pockets of TACE and which makes appropriate van der Waal contact with the channel, and (iv) form a hydrogen bond with Leu348 or Gly349 on the backbone amide groups of TNF-α-converting enzyme, or (v) any combination of the above.
Computer-Readable Medium
The present invention also relates to a computer-readable medium having recorded thereon the x-ray diffraction structure coordinates of a crystalline TACE polypeptide. The computer-readable media of the invention are useful for storage, transfer, and use with software of the TACE structural coordinates. The computer readable medium may be any suitable data storage material, including, but not limited to, a floppy disc, a hard disc, computer-type Random Access Memory, Read-Only Memory flash memory, CD-ROM, recordable and rewritable CDs, recordable and rewritable DVDs, magnetic-optical disk, ZIP drive, JAZ drive, Syquist drive, digital tape drive, or the like. Other suitable media will be known to those of skill in the art.
In one embodiment, the computer readable medium comprises the coordinates of Table 1 or a substantial portion thereof. The computer-readable medium may be used in conjunction with a machine programmed with instructions for using the data recorded on the medium, such as a computer loaded with one or more programs identified throughout the specification, to display a graphical, three-dimensional representation of a TACE polypeptide, or any part thereof.
Computer Based System
FIG. 6 illustrates a system 1000 for studying a TACE polypeptide. The system includes a video memory 110 that stores information representing at least a portion of a TACE polypeptide. The memory has at least one first-type storage region 112, having recorded thereon a set of spatial coordinates specifying a location in a three dimensional space, and at least one second-type storage region 114, having recording thereon information representing a characteristic of one of a plurality of amino acids. The second-type storage regions are logically associated with the first-type storage regions in the video memory 110 to represent a geometric arrangement of at least one characteristic of at least a portion of the TACE polypeptide in the three dimensional space. Memory, 112 and 114 can comprise, for example, the data shown in Table 1. The system 1000 also includes a processor, coupled to the memory to access the first-type storage regions 112 and the second-type storage regions 114, to generate image signals for depicting a visual three dimensional image of at least one characteristic of at least a portion of the TACE polypeptide in the three dimensional space based on data from the memory 110. The processor can be any general purpose processor with a CPU, register, memory and the like. A display 130 coupled to the processor 120 via lines 125 to receive the image signals, for depicting a visual three dimensional image of at least one characteristic of at least a portion of the TACE polypeptide in the three dimensional space based on the image data on a screen 132.
In one embodiment of the invention, the image data includes data for depicting a visual three dimensional image of a ribbon structure of at least a portion of a TACE polypeptide in three dimensional space, such as shown in FIG. 1. In another embodiment, the image data includes data for depicting a visual three dimensional image of a solid model representation of at least a portion of said TACE polypeptide in three dimensional space, such as shown in FIG. 2. In still another embodiment, the image data includes data for depicting a visual three dimensional image of electrostatic surface potential of at least a portion of TACE polypeptide in three dimensional space, such as shown in FIG. 2. In yet another embodiment, the image data includes data for depicting a visual three dimensional stereo image of at least a portion of a TACE polypeptide in three dimensional space, such as shown in FIG. 4.
The system 1000 of the present invention may further comprise a storage device 145 that stores data representing a geometric arrangement of a characteristic of a composition other than the TACE polypeptide and an operator interface, such as a mouse 135, for receiving instructions from a operator. Storage device 145 can include, for example, the three-dimensional X-ray coordinate data for other chemical entities. The processor 120 is coupled to the storage device 145 and to said operator interface 135 and generates additional image data for depicting the geometric arrangement of the characteristic of the composition relative to said visual three dimensional image of said at least one characteristic of said at least a portion of TACE polypeptide on the screen 132 based on instructions from the operator interface. In the FIG. 6 embodiment, the storage device 145 is part of the memory 110.
The first-type storage regions 112 and said second-type storage regions 114 are regions of, for example, a semiconductor memory, regions of an optical disk, or regions of a magnetic memory.
In one embodiment, processor 120 and video memory 110 are in the form of a UNIX or VAX computer, such those available from Silicon Graphics, Sun Microsystems, and IBM. However, the invention is not limited to use of this particular hardware and software.
The invention is described in more detail in the following illustrative examples. Although the examples may represent only selected embodiments of the invention, it should be understood that the following examples are illustrative and not limiting.
EXAMPLE 1
TACE Polypeptide Expression, Isolation, and Purification
A cDNA encoding the signal peptide, pro and catalytic domains of TACE, amino acid residues 1-477, as disclosed in Black et al., “A Metalloproteinase disintigrin that releases tumour-necrosis factor-α from cells,” Nature 385: 729-733 (February 1997), with Ser266 changed to Ala, Asn452 changed to Gln and the sequence Gly-Ser-(His)6 added to the C-terminus, was inserted into an expression vector for CHO cells. The TACE polypeptide was expressed in CHO cells and a mixture of the TACE polypeptide beginning either with Val212 or Arg215 was secreted. The cells were cultured in the drug, methotrexate, which kills those cells that did not incorporate the vector.
The expressed TACE polypeptide was then purified. Purification started with 5 liters of the medium containing the expressed TACE polypeptide. The medium was concentrated to about 200 mL with a Millipore 10K cut-off, 1 ft2 TFF diafiltration unit. The pumping rate was 50-100 mL/min. Two liters of a buffer solution of 20 mM Tris (pH 7.5) and 300 mM NaCl (Buffer E) was then added to the sample.
The sample was reconcentrated as described above and diluted a second time with 2 liters of Buffer E, reconcentrated again, diluted a third time with 2 liters of Buffer E, and reconcentrated to about 100 mL. The sample retained in the diafiltration unit was recovered by a back-flush. This material was then filtered through a 0.45 μm and was azide added to 0.05%. The filtered sample was stored overnight at 4° C.
After overnight storage, imidazole was added to the filtered sample to 5 mM from a 200 mM stock in water and ZnCl2 was added to 5 uM from a 1 M stock in water. The sample then was pumped over 2.2 mL of Quiagen Ni-NTA Superflow resin (Cat. # 30430) at 3 mL/min (column size 7.5×50 mm).
The column was washed at 5 mL/min with 100 mL of a buffer of 20 mM Tris pH 7.5, 300 mM NaCl, 5 mM imidazole, and 5 uM ZnCl2 (Buffer A). The protein was then eluted with an increasing gradient of imidazole, going up to 200 mM in 1 minute (5 mL total volume), followed by 35 mL of 200 mM imidazole in Buffer A. Two mL fractions were collected, TACE generally coming off about 6 mL into the elution. The fractions were collected in tubes containing 500 ul of 50% glycerol in water and 200 ul of 1 M Tris pH 8. The glycerol in water was prepared the day of the column run.
A dot blot, with 3 μl from each fraction, was stained with amido black to determine which fractions contained a significant amount of protein. The fractions with a significant amount of protein were pooled. The pool was then concentrated to 1-2 mL with a 10 K cut-off Amicon Centriprep concentrator.
The inhibitor N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-amino-2-dimethylbutanoyl-L-alanine, 2amino)ethyl amide was added to the concentrated sample to 1 mM from a 50 mM stock in water, and octylglucoside was added to 1% from a 10% stock in water. The sample was then incubated at room temperature for 15-24 hours.
Following incubation, the sample was applied to a 21.5×600 mm size exclusion column, LKB 2135-365, packed with TSK-G3000 SWG, and equilibrated with 10 mM Tris pH 7.5, 100 mM NaCl, 10% glycerol. This buffer was then pumped through the column at 2.5 mL/min for 100 minutes. The TACE polypeptide in the effluent was detected by absorption at 280 nm. Excluded material generally eluted at about 38 minutes. The pure TACE generally eluted at about 78 minutes or longer.
A gel analysis, with 15 μl of all fractions with significant protein was then carried out to determine which fractions should be pooled. The size-exclusion chromatography pool was concentrated to about 1 mL with a 10 K cut-off Amicon Centriprep concentrator.
The inhibitor N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-amino-2-dimethylbutanoyl-L-alanine, 2-(amino)ethyl amide was then added to the purified sample to a concentration of 1 mM. The protein can be stored at 4° C.
EXAMPLE 2
Protein Crystallization
A DNA construct comprising the prodomain and the catalytic domain of human TACE (resides 1-477) was fused to the sequence Gly-Ser-(His)6 (SEQ ID NO: 2) to facilitate purification of the protein on a Ni-NTA affinity column. Chinese Hamster Ovary (CHO) were cells used for protein expression. The cells secreted a mixture of mature TACE beginning with either Val212 or Arg215. TACE-containing fractions from the Ni-NTA column were incubated in a buffer containing octylglucoside and the binding partner N-[D,L-[2-(hydroxyaminocarnbonyl)methyl]-4-methyl-pentanoyl)-L-3-(tert-butyl)-glycyl-L-alanine. The final purification step was performed on a gel filtration column. Purified TACE was stored in a buffer containing 10 mM Tris/HCL, pH 7.5, 100 mM NaCl, 10% glycerol and 1 mM of inhibitor (TACE buffer).
Crystallization experiments were set up at a TACE concentration of approximately 5 mg/mL by mixing TACE (in TACE buffer) in a 1:1 ratio with the crystallization buffers listed below and using the sitting drop vapor diffusion technique. The experiments were performed in duplicate and incubated either at about 4° C. or at 20° C. Crystalline precipitate was obtained at 20° C. in the following crystallization buffers:

    
    
        Buffer A) 0.1 M Na Acetate pH 5.3, 0.2 M CaCl2, 30% v/v Ethanol
        Buffer B) 0.1 M Na Citrate pH 5.0, 40% v/v Ethanol
        Buffer C) 0.1 M Na Citrate pH 8.7, 20% w/v PEG 4000, 20% v/v Isopropanol
    
    


Small crystals were obtained upon transferring seeds from the crystalline precipitate with a hair of a rabbit into a 1:1 mixture of a concentrated sample of TACE (12 mg/mL in TACE buffer) with either buffer B or C. Further refinement of buffer C resulted in buffer D, which allowed the production of crystals suitable for X-ray data collection.

    
    
        Buffer D) 0.1 M Na Citrate pH 5.4, 20% w/v PEG 4000, 20% v/v Isopropanol
    
    


The first data set was measured to a reduction of 2.5 Å on a MAR300 imaging plate scanner attached to a Rigaku-Denki totaling Cu-anode generator operated at 5.4 kW providing graphite-monochromatized CuKα radiation. The data were processed with MOSFLM v. 5.23 program and routines of the CCP4 suite. All attempts to solve the structure by molecular replacement methods using either adamalysin II, an all-alanine model of adamalysin II and models generated failed to produce useful starting points for phasing. Thus the locations of four independent zinc atoms were determined with the help of an anomalous difference Patterson synthesis. In order to measure MAD data, the crystals were deep-frozen in liquid nitrogen. Therefore, crystals were transferred into a cryo buffer (80% v/v buffer D containing 17% v/v glycerol) with the help of a silk loop of appropriate size, soaked for about 10 seconds and then immediately deep-frozen at 90 degrees K.
The crystals obtained belong to the monoclinic space group P21, have cell constants a=61.38 Å (angstrom), b=126.27 Å, c=81.27 Å, β=107.41°, and contain four molecules in the asymmetric unit.
EXAMPLE 3
X-ray Diffraction
Using the crystals described in Example 2, a first data set was measured to a resolution of 2.5 Å on a MAR300 imaging plate scanner attached to a Rigaku-Denki. rotating Cu-anode generator operated at 5.4 kW providing graphite-monochromatized CuKα radiation. The data were processed at with the MOSFLM v. 5.23 program and routines of the CCP4 suite.
All attempts to solve the structure by molecular replacement methods using either adamalysin II, an all-alanine model of adamalysin II, and other models failed to produce useful starting points for phasing.
Thus, the locations of the four independent zinc atoms were determined with the help of an anomalous difference Patterson synthesis. In order to measure MAD data, the crystals were deep-frozen in a nitrogen gas stream cooled down to the temperature of liquid nitrogen. The crystals were first transferred into a cryo-buffer of 80% v/v Buffer D (0.1 M Na Citrate pH 5.4, 20% w/v PEG 4000, 20% v/v Isopropanol) containing 17% v/v glycerol. Transfer to the cryo-buffer was performed with the help of a silk loop of appropriate size. The crystals were soaked in the cryo-buffer for about 10 seconds and then immediately deep-frozen at 90 K.
Anomalous diffraction data to 2.0 Å were collected with MAR345 imaging plate scanner at 90 K on the BW6 wiggler beamline of DORIS (DESY, Hamburg, Germany), using monochromatic X-ray radiation at the wavelengths of maximal f′′ (1.2769 Å) and minimal f′′ (1.2776 Å) at the K absorption edge of zinc and at a remote wavelength (1.060 Å). The data were scanned and evaluated using DENZO/SCALEPACK, yielding 77653 independent reflections from 1051836 measurements (96.9% completeness, R-merge 0.031 in intensities).
MAD phases were refined and calculated with MLPHARE including all measured data to 2.0 Å resolution. Their initial mean-figure-of-merit of 0.53 was increased to 0.76 by solvent flattening/histogram matching methods applying DM. This density allowed building of the complete chains of the four independent TACE catalytic domains and the bound hydroxamic acid substrates on an SGI system using TURBO-FRODO. This model was crystallographically refined with XPLOR and with CCP4 routines to a crystallographic R factor of 18.6% (Rfree 27.4%) using 79400 independent reflections from, 12.0 to 2 A. resolution.
Four independent TACE molecules form the periodic arrangement.
Molecules 1 and 2, and 3 and 4 are defined from Asp219 and Met221, respectively, to Ser474.
EXAMPLE 4
X-ray Diffraction
Anomalous dispersion diffraction data to 2.0 Å were collected with a MAR345 imaging plate scanner at 100 K on the wiggler beamline of DORIS (DESY, Hamburg, Germany), using monochromatic X-ray radiation of maximal f′ (1.2797 Å) and minimal f′ (1.2804 Å) at the K absorption edge of zinc and at a remote wavelength (1.060 Å). These data were evaluated and scanned using DENZO/SCALEPACK, yielding 77,653 independent reflections (96.9% completeness, R-merge 0.031).
The structure coordinates obtained are reproduced in Table 1.







TABLE 1







REMARK Created by MOLEMAN V. 961218/7.2.5 at Fri Sep 19 20:05:05 1997 for user


carlos


REMARK Moleman FDS file


CRYST1 61.387  126.278  81.273  90.00  107.42 90.00  P 21   4











CRIGX1
1.000000
0.000000
0.000000
0.00000


CRIGX2
0.000000
1.000000
0.000000
0.00000


CRIGX3
0.000000
0.000000
1.000000
0.00000


SCALE1
0.016290
0.000000
0.005111
0.00000


SCALE2
0.000000
0.007919
0.000000
0.00000


SCALE3
0.000000
0.000000
0.012896
0.00000

















Atom











Type
Residue
!
#
X
Y
Z
OCC
B




















ATOM
1
N
ASP
A
219
0.865
33.077
15.204
1.00
20.00


ATOM
2
OD2
ASP
A
219
5.154
33.868
14.335
1.00
20.00


ATOM
3
OD1
ASP
A
219
4.450
35.924
14.844
1.00
20.00


ATOM
4
CG
ASP
A
219
4.191
34.718
14.461
1.00
20.00


ATOM
5
CB
ASP
A
219
2.738
34.303
14.156
1.00
20.00


ATOM
6
CA
ASP
A
219
2.290
33.026
14.883
1.00
20.00


ATOM
7
C
ASP
A
219
3.166
32.889
16.123
1.00
20.00


ATOM
8
O
ASP
A
219
3.439
33.884
16.819
1.00
20.00


ATOM
9
N
PRO
A
220
3.629
31.679
16.386
1.00
20.00


ATOM
10
CG
PRO
A
220
4.073
29.436
16.118
1.00
20.00


ATOM
11
CD
PRO
A
220
3.224
30.531
15.588
1.00
20.00


ATOM
12
CB
PRO
A
220
4.893
29.974
17.303
1.00
20.00


ATOM
13
CA
PRO
A
220
4.523
31.452
17.495
1.00
20.00


ATOM
14
C
PRO
A
220
5.649
32.530
17.443
1.00
20.00


ATOM
15
O
PRO
A
220
6.513
32.741
18.173
1.00
20.00


ATOM
16
N
MET
A
221
5.766
33.341
16.625
1.00
48.83


ATOM
17
CE
MET
A
221
9.090
36.336
12.584
1.00
53.01


ATOM
18
SD
MET
A
221
9.248
36.147
14.337
1.00
54.21


ATOM
19
CG
MET
A
221
8.515
34.606
14.801
1.00
51.15


ATOM
20
CB
MET
A
221
7.101
34.778
15.298
1.00
48.69


ATOM
21
CA
MET
A
221
6.875
34.306
16.701
1.00
48.22


ATOM
22
C
MET
A
221
6.485
35.500
17.614
1.00
42.51


ATOM
23
O
MET
A
221
7.279
36.002
18.427
1.00
43.93


ATOM
24
N
LYS
A
222
5.215
35.817
17.508
1.00
36.53


ATOM
25
NZ
LYS
A
222
1.844
39.934
13.657
1.00
40.05


ATOM
26
CE
LYS
A
222
2.513
39.901
14.974
1.00
39.09


ATOM
27
CD
LYS
A
222
2.353
38.522
15.613
1.00
38.20


ATOM
28
CG
LYS
A
222
3.646
38.146
16.312
1.00
36.27


ATOM
29
CB
LYS
A
222
3.345
37.404
17.597
1.00
33.97


ATOM
30
CA
LYS
A
222
4.567
36.853
18.299
1.00
32.39


ATOM
31
C
LYS
A
222
4.144
36.220
19.633
1.00
29.13


ATOM
32
O
LYS
A
222
2.999
35.844
19.866
1.00
26.54


ATOM
33
N
ASN
A
223
5.157
36.011
20.462
1.00
23.62


ATOM
34
CA
ASN
A
223
4.951
35.296
21.704
1.00
22.97


ATOM
35
CB
ASN
A
223
5.756
33.987
21.611
1.00
25.44


ATOM
36
CG
ASN
A
223
7.229
34.245
21.372
1.00
26.32


ATOM
37
OD1
ASN
A
223
7.973
33.261
21.243
1.00
29.74


ATOM
38
ND2
ASN
A
223
7.688
35.482
21.319
1.00
25.96


ATOM
39
C
ASN
A
223
5.327
36.123
22.908
1.00
18.46


ATOM
40
O
ASN
A
223
5.365
35.556
23.983
1.00
18.08


ATOM
41
N
THR
A
224
5.611
37.408
22.709
1.00
17.03


ATOM
42
CA
THR
A
224
6.035
38.246
23.824
1.00
16.24


ATOM
43
CS
THR
A
224
7.507
38.721
23.599
1.00
17.52


ATOM
44
OG1
THR
A
224
8.317
37.590
23.318
1.00
16.14


ATOM
45
CG2
THR
A
224
8.002
39.440
24.849
1.00
17.72


ATOM
46
C
THR
A
224
5.152
39.464
24.033
1.00
16.13


ATOM
47
C
THR
A
224
4.863
40.275
23.152
1.00
15.14


ATOM
48
N
CYS
A
225
4.708
39.650
25.253
1.00
16.61


ATOM
49
CA
CYS
A
225
3.915
40.833
25.646
1.00
17.81


ATOM
50
CB
CYS
A
225
2.895
40.460
26.723
1.00
18.01


ATOM
51
SG
CYS
A
225
2.120
41.843
27.562
1.00
18.77


ATOM
52
C
CYS
A
225
4.899
41.914
26.101
1.00
17.46


ATOM
53
O
CYS
A
225
5.614
41.703
27.033
1.00
18.52


ATOM
54
N
LYS
A
226
5.070
42.945
25.285
1.00
17.94


ATOM
55
CA
LYS
A
226
6.011
44.033
25.573
1.00
18.62


ATOM
56
CB
LYS
A
226
6.373
44.816
24.311
1.00
21.04


ATOM
57
CG
LYS
A
226
6.985
43.974
23.202
1.00
22.16


ATOM
58
CD
LYS
A
226
8.395
43.451
23.514
1.00
24.95


ATOM
59
CE
LYS
A
226
8.867
42.585
23.365
1.00
28.75


ATOM
60
NZ
LYS
A
226
10.336
42.445
22.185
1.00
31.31


ATOM
61
C
LYS
A
226
5.461
44.940
26.658
1.00
17.48


ATOM
62
O
LYS
A
226
4.295
45.336
26.642
1.00
16.96


ATOM
63
N
LEU
A
227
6.281
45.274
27.641
1.00
15.78


ATOM
64
CA
LEU
A
227
5.848
46.025
28.777
1.00
15.23


ATOM
65
CB
LEU
A
227
6.182
45.347
30.117
1.00
15.96


ATOM
66
CG
LEU
A
227
5.848
43.884
30.334
1.00
15.88


ATOM
67
CD1
LEU
A
227
6.375
43.382
31.692
1.00
15.72


ATOM
68
CD2
LEU
A
227
4.356
43.646
30.314
1.00
13.61


ATOM
69
C
LEU
A
227
6.462
47.398
28.965
1.00
16.89


ATOM
70
O
LEU
A
227
7.639
47.635
28.725
1.00
17.35


ATOM
71
N
LEU
A
228
5.585
48.248
29.488
1.00
16.01


ATOM
72
CA
LEU
A
228
6.024
49.559
29.935
1.00
15.78


ATOM
73
CB
LEU
A
228
5.105
50.721
29.644
1.00
15.98


ATOM
74
CG
LEU
A
228
5.360
52.012
30.426
1.00
17.60


ATOM
75
CD1
LEU
A
228
6.596
52.712
29.853
1.00
15.81


ATOM
76
CD2
LEU
A
228
4.154
52.945
30.340
1.00
19.40


ATOM
77
C
LEU
A
228
6.144
49.360
31.455
1.00
16.70


ATOM
78
O
LEU
A
228
5.124
49.074
32.104
1.00
16.99


ATOM
79
N
VAL
A
229
7.356
49.488
33.983
1.00
13.83


ATOM
80
CA
VAL
A
229
7.484
49.343
33.450
1.00
12.75


ATOM
81
CB
VAL
A
229
8.600
48.320
33.747
1.00
15.41


ATOM
82
CG1
VAL
A
229
9.015
48.421
35.199
1.00
15.21


ATOM
83
CG2
VAL
A
229
8.062
46.910
33.451
1.00
16.11


ATOM
84
C
VAL
A
229
7.758
50.710
34.055
1.00
11.45


ATOM
85
O
VAL
A
229
8.592
51.462
33.529
1.00
10.78


ATOM
86
N
VAL
A
230
7.029
51.092
35.090
1.00
11.10


ATOM
87
CA
VAL
A
230
7.169
52.397
35.688
1.00
13.35


ATOM
88
CB
VAL
A
230
5.910
53.299
35.516
1.00
13.78


ATOM
89
CG1
VAL
A
230
6.096
54.643
36.192
1.0O
13.70


ATOM
90
CG2
VAL
A
230
5.577
53.586
34.050
1.00
12.14


ATOM
91
C
VAL
A
230
7.495
52.252
37.154
1.00
12.98


ATOM
92
O
VAL
A
230
6.791
51.546
37.877
1.00
14.51


ATOM
93
N
ALA
A
231
8.582
52.891
37.570
1.00
14.57


ATOM
94
CA
ALA
A
231
8.915
52.901
39.001
1.00
12.63


ATOM
95
CB
ALA
A
231
10.382
52.556
39.219
1.00
14.54


ATOM
96
C
ALA
A
231
8.616
54.305
39.505
1.00
13.54


ATOM
97
O
ALA
A
231
9.215
55.290
39.004
1.00
12.89


ATOM
98
N
ASP
A
232
7.739
54.412
40.500
1.00
13.89


ATOM
99
CA
ASP
A
232
7.440
55.781
40.947
1.00
15.63


ATOM
100
CB
ASP
A
232
6.061
55.875
41.560
1.00
16.03


ATOM
101
CG
ASP
A
232
5.856
55.198
42.876
1.00
17.24


ATOM
102
OD1
ASP
A
232
4.725
55.249
43.432
1.00
18.20


ATOM
103
CD2
ASP
A
232
6.804
54.565
43.403
1.00
15.69


ATOM
104
C
ASP
A
232
8.559
56.276
41.875
1.00
15.96


ATOM
105
O
ASP
A
232
9.395
55.459
42.253
1.00
13.21


ATOM
106
N
HIS
A
233
8.375
57.492
42.392
1.00
16.98


ATOM
107
CA
HIS
A
233
9.399
58.118
43.244
1.00
16.61


ATOM
108
CB
HIS
A
233
9.075
59.600
43.522
1.00
17.60


ATOM
109
CG
HIS
A
233
7.977
59.866
44.494
1.00
17.74


ATOM
110
CD2
HIS
A
233
8.012
60.040
45.836
1.00
18.92


ATOM
111
ND1
HIS
A
233
6.648
59.946
44.152
1.00
17.72


ATOM
112
CE1
HIS
A
233
5.910
60.144
45.222
1.00
18.19


ATOM
113
NE2
HIS
A
233
6.730
60.214
46.266
1.00
19.56


ATOM
114
C
HIS
A
233
9.562
57.364
44.535
1.00
16.98


ATOM
115
O
HIS
A
233
10.626
57.385
45.170
1.00
14.73


ATOM
116
N
ARG
A
234
8.457
56.762
45.005
1.00
16.26


ATOM
117
CA
ARG
A
234
8.476
55.997
46.231
1.00
16.71


ATOM
118
CB
ARG
A
234
7.083
55.600
46.688
1.00
19.19


ATOM
119
CG
ARG
A
234
6.078
56.729
46.814
1.00
18.94


ATOM
120
CD
ARG
A
234
4.726
56.181
47.250
1.00
21.89


ATOM
121
NE
ARG
A
234
3.696
57.214
47.125
1.00
23.72


ATOM
122
CZ
ARG
A
234
2.872
57.469
48.130
1.00
26.70


ATOM
123
NH1
ARG
A
234
2.923
56.798
49.270
1.00
27.34


ATOM
124
NH2
ARG
A
234
1.953
58.411
47.989
1.00
28.96


ATOM
125
C
ARG
A
234
9.319
54.728
46.062
1.00
17.39


ATOM
126
O
ARG
A
234
10.072
54.359
46.955
1.00
17.02


ATOM
127
N
PHE
A
235
9.149
54.039
44.954
1.00
15.45


ATOM
128
CA
PHE
A
235
9.913
52.829
44.669
1.00
17.15


ATOM
129
CB
PHE
A
235
9.458
52.167
43.370
1.00
15.92


ATOM
130
CG
PHE
A
235
10.063
50.804
43.165
1.00
14.51


ATOM
131
CD1
PHE
A
235
11.226
50.638
42.442
1.00
14.09


ATOM
132
CD2
PHE
A
235
9.429
49.693
43.697
1.00
13.27


ATOM
133
CE1
PHE
A
235
11.786
49.334
42.283
1.00
12.49


ATOM
134
CE2
PHE
A
235
9.979
48.436
43.514
1.00
14.15


ATOM
135
CZ
PHE
A
235
11.159
48.280
42.812
1.00
11.73


ATOM
136
C
PHE
A
235
11.391
53.211
44.502
1.00
15.85


ATOM
137
O
PHE
A
235
12.309
52.611
45.041
1.00
15.02


ATOM
138
N
TYR
A
236
16.573
54.282
43.750
1.00
15.65


ATOM
139
CA
TYR
A
236
12.920
54.781
43.501
1.00
18.77


ATOM
140
CB
TYR
A
236
12.809
56.087
42.744
1.00
20.15


ATOM
141
CG
TYR
A
236
14.079
56.831
42.453
1.00
20.77


ATOM
142
CD1
TYR
A
236
15.006
56.379
41.554
1.00
23.25


ATOM
143
CE1
TYR
A
236
16.171
57.111
41.294
1.00
25.10


ATOM
144
CD2
TYR
A
236
14.303
58.043
43.094
1.00
22.97


ATOM
145
CE2
TYR
A
236
15.434
58.789
42.840
1.00
23.38


ATOM
146
CZ
TYR
A
236
16.355
58.309
41.944
1.00
24.28


ATOM
147
OH
TYR
A
236
17.490
59.032
41.699
1.00
27.10


ATOM
148
C
TYR
A
236
13.668
55.005
44.807
1.00
18.41


ATOM
149
O
TYR
A
236
14.785
54.538
44.979
1.00
17.82


ATOM
150
N
ARG
A
237
13.029
55.671
45.741
1.00
18.84


ATOM
151
NH2
ARG
A
237
16.164
60.578
45.801
1.00
36.66


ATOM
152
NH1
ARG
A
237
15.513
58.642
46.822
1.00
35.42


ATOM
153
CZ
ARG
A
237
15.208
59.704
46.106
1.00
35.99


ATOM
154
NE
ARG
A
237
13.940
59.862
45.712
1.00
36.11


ATOM
155
CD
ARG
A
237
12.867
58.910
45.981
1.00
32.12


ATOM
156
CG
ARG
A
237
12.655
58.442
47.386
1.00
28.99


ATOM
157
CB
ARG
A
237
12.578
56.978
47.698
1.00
22.94


ATOM
158
CA
ARG
A
237
13.566
56.021
47.029
1.00
21.89


ATOM
159
C
ARG
A
237
13.824
54.847
47.959
1.00
22.82


ATOM
160
O
ARG
A
237
14.874
54.759
48.586
1.00
22.33


ATOM
161
N
TYR
A
238
12.826
53.995
48.165
1.00
20.93


ATOM
162
CA
TYR
A
238
12.807
52.950
49.142
1.00
22.79


ATOM
163
CB
TYR
A
238
11.438
52.835
49.835
1.00
25.02


ATOM
164
CG
TYR
A
238
11.052
54.133
50.502
1.00
28.43


ATOM
165
CD1
TYR
A
238
10.191
55.011
49.873
1.00
30.38


ATOM
166
CE1
TYR
A
238
9.827
56.214
50.439
1.00
32.45


ATOM
167
CD2
TYR
A
238
11.570
54.501
51.729
1.00
30.38


ATOM
168
CE2
TYR
A
238
11.228
55.709
52.309
1.00
32.79


ATOM
169
CZ
TYR
A
238
10.384
56.572
51.647
1.00
33.85


ATOM
170
OH
TYR
A
238
10.043
57.784
52.208
1.00
34.86


ATOM
171
C
TYR
A
238
13.222
51.579
48.683
1.00
22.48


ATOM
172
O
TYR
A
238
13.682
50.772
49.509
1.00
24.69


ATOM
173
N
MET
A
239
13.171
51.306
47.405
1.00
20.92


ATOM
174
CA
MET
A
239
13.680
50.048
46.893
1.00
18.57


ATOM
175
CB
MET
A
239
12.667
49.374
45.965
1.00
18.57


ATOM
176
CG
MET
A
239
11.394
48.971
46.729
1.00
18.44


ATOM
177
SD
MET
A
239
13.677
47.664
47.929
1.00
17.64


ATOM
178
CE
MET
A
239
12.084
46.309
46.855
1.00
16.38


ATOM
179
C
MET
A
239
14.975
50.292
46.121
1.00
17.52


ATOM
180
O
MET
A
239
15.826
49.422
46.133
1.00
16.58


ATOM
181
N
GLY
A
240
15.067
51.440
45.447
1.00
16.74


ATOM
182
CA
GLY
A
240
16.198
51.733
44.602
1.00
16.82


ATOM
183
C
GLY
A
240
17.334
52.497
45.232
1.00
20.60


ATOM
184
O
GLY
A
240
18.280
52.875
44.516
1.00
20.21


ATOM
185
N
ARG
A
241
17.242
52.871
46.503
1.00
20.89


ATOM
186
CA
ARG
A
241
18.300
53.628
47.162
1.00
24.17


ATOM
187
CB
ARG
A
241
19.609
52.806
47.126
1.00
26.15


ATOM
188
CG
ARG
A
241
19.504
51.488
47.875
1.00
29.48


ATOM
189
CD
ARG
A
241
20.771
50.648
47.896
1.00
31.73


ATOM
190
NE
ARG
A
241
21.417
50.785
49.228
1.00
32.75


ATOM
191
CZ
ARG
A
241
22.188
51.837
49.428
1.00
33.64


ATOM
192
NH1
ARG
A
241
22.361
52.722
48.450
1.00
35.35


ATOM
193
NH2
ARG
A
241
22.752
52.014
50.598
1.00
32.64


ATOM
194
C
ARG
A
241
18.497
55.001
46.543
1.00
25.05


ATOM
195
O
ARG
A
241
19.574
55.585
46.696
1.00
21.63


ATOM
196
N
GLY
A
242
17.470
55.529
45.831
1.00
22.70


ATOM
197
CA
GLY
A
242
17.603
56.784
45.110
1.00
20.94


ATOM
198
C
GLY
A
242
18.622
56.667
44.003
1.00
20.36


ATOM
199
O
GLY
A
242
19.255
57.656
43.639
1.00
20.42


ATOM
200
N
GLY
A
243
18.841
55.486
43.445
1.00
19.57


ATOM
201
CA
GLU
A
243
19.832
55.277
42.418
1.00
19.51


ATOM
202
CB
GLU
A
243
20.951
54.324
42.832
1.00
21.04


ATOM
203
CG
GLU
A
243
21.992
54.818
43.816
1.00
22.54


ATOM
204
CD
GLU
A
243
22.782
53.747
44.543
1.00
24.67


ATOM
205
OE1
GLU
A
243
23.740
54.097
45.292
1.00
24.23


ATOM
206
OE2
GLU
A
243
22.512
52.535
44.451
1.00
22.83


ATOM
207
C
GLU
A
243
19.104
54.717
41.197
1.00
19.62


ATOM
208
O
GLU
A
243
18.414
53.698
41.291
1.00
18.85


ATOM
209
N
GLU
A
244
19.324
55.341
40.075
1.00
19.48


ATOM
210
CA
GLU
A
244
18.699
54.904
38.833
1.00
22.19


ATOM
211
CB
GLU
A
244
18.928
55.950
37.739
1.00
25.49


ATOM
212
CG
GLU
A
244
18.502
55.433
36.371
1.00
29.88


ATOM
213
CD
GLU
A
244
18.409
56.498
35.310
1.00
32.59


ATOM
214
OE1
GLU
A
244
18.205
57.691
35.608
1.00
33.16


ATOM
215
OE2
GLU
A
244
18.528
56.090
34.136
1.00
35.02


ATOM
216
C
GLU
A
244
19.176
53.524
38.424
1.00
21.10


ATOM
217
O
GLU
A
244
18.360
52.654
38.029
1.00
17.68


ATOM
218
N
SER
A
245
20.466
53.247
38.644
1.00
18.06


ATOM
219
CA
SER
A
245
21.001
51.960
38.207
1.00
20.29


ATOM
220
CB
SER
A
245
22.549
51.953
38.270
1.00
21.06


ATOM
221
OG
SER
A
245
22.833
52.394
39.607
1.00
21.74


ATOM
222
C
SER
A
245
20.409
50.844
39.056
1.00
17.46


ATOM
223
O
SER
A
245
19.970
49.834
38.536
1.00
18.81


ATOM
224
N
THR
A
246
20.355
51.020
40.343
1.00
15.88


ATOM
225
CA
THR
A
246
19.821
50.027
41.275
1.00
18.13


ATOM
226
CB
THR
A
246
20.051
50.546
42.689
1.00
19.42


ATOM
227
OG1
THR
A
246
21.459
50.877
42.861
1.00
21.14


ATOM
228
CG2
THR
A
246
19.692
49.547
43.761
1.00
19.86


ATOM
229
C
THR
A
246
18.337
49.757
41.014
1.00
16.92


ATOM
230
O
THR
A
246
17.915
48.619
41.068
1.00
14.90


ATOM
231
N
THR
A
247
17.545
50.799
40.800
1.00
17.19


ATOM
232
CA
THR
A
247
16.108
50.689
40.560
1.00
16.84


ATOM
233
CB
THR
A
247
15.458
52.076
40.443
1.00
16.21


ATOM
234
OG1
THR
A
247
15.860
52.839
41.581
1.00
14.61


ATOM
235
CG2
THR
A
247
13.920
52.069
40.449
1.00
14.87


ATOM
236
C
THR
A
247
15.848
49.892
39.308
1.00
15.69


ATOM
237
O
THR
A
247
15.088
48.922
39.295
1.00
14.94


ATOM
238
N
THR
A
248
16.502
50.305
38.232
1.00
16.92


ATOM
239
CA
THR
A
248
16.382
49.685
36.926
1.00
16.92


ATOM
240
CB
THR
A
248
17.322
50.415
35.963
1.00
17.93


ATOM
241
OG1
THR
A
248
16.875
51.787
35.915
1.00
18.06


ATOM
242
CG2
THR
A
248
17.381
49.792
34.586
1.00
19.15


ATOM
243
C
THR
A
248
16.712
48.202
36.972
1.00
18.22


ATOM
244
O
THR
A
248
16.073
47.313
36.427
1.00
14.91


ATOM
245
N
ASN
A
249
17.857
47.907
37.593
1.00
17.46


ATOM
246
CA
ASN
A
249
18.342
46.545
37.700
1.00
17.81


ATOM
247
CB
ASN
A
249
19.723
46.472
38.349
1.00
19.11


ATOM
248
CG
ASN
A
249
20.854
47.016
37.499
1.00
22.53


ATOM
249
OD1
ASN
A
249
20.753
47.173
36.283
1.00
22.82


ATOM
250
ND2
ASN
A
249
21.989
47.306
33.157
1.00
21.73


ATOM
251
C
ASN
A
249
17.364
45.662
33.478
1.00
15.16


ATOM
252
O
ASN
A
249
17.157
44.510
38.066
1.00
13.94


ATOM
253
N
TYR
A
250
16.650
46.170
39.578
1.00
14.10


ATOM
254
CA
TYR
A
250
15.888
45.426
40.360
1.00
15.67


ATOM
255
CB
TYR
A
250
16.393
46.239
41.546
1.00
16.52


ATOM
256
CG
TYR
A
250
14.527
45.444
42.501
1.00
18.76


ATOM
257
CD1
TYR
A
250
15.109
44.778
43.571
1.00
20.38


ATOM
258
CE1
TYR
A
250
14.344
44.031
44.447
1.00
21.56


ATOM
259
CD2
TYR
A
250
13.138
45.344
42.332
1.00
18.76


ATOM
260
CE2
TYR
A
250
12.377
44.600
43.203
1.00
19.63


ATOM
261
CZ
TYR
A
250
12.985
43.943
44.248
1.00
22.22


ATOM
262
OH
TYR
A
250
12.250
43.189
45.134
1.00
24.91


ATOM
263
C
TYR
A
250
14.683
45.029
39.472
1.00
14.95


ATOM
264
O
TYR
A
250
14.234
43.893
39.546
1.00
11.83


ATOM
265
N
LEU
A
251
14.133
46.031
38.758
1.00
13.07


ATOM
266
CA
LEU
A
251
12.977
45.742
37.899
1.00
12.72


ATOM
267
CB
LEU
A
251
12.271
47.059
37.519
1.00
12.66


ATOM
268
CG
LEU
A
251
11.696
47.800
38.734
1.00
14.96


ATOM
269
CD1
LEU
A
251
11.038
49.099
38.363
1.00
18.53


ATOM
270
CD2
LEU
A
251
10.717
46.914
39.501
1.00
19.00


ATOM
271
C
LEU
A
251
13.288
44.885
36.700
1.00
11.35


ATOM
272
O
LEU
A
251
12.518
43.962
36.349
1.00
10.33


ATOM
273
N
ILE
A
252
14.429
45.093
36.050
1.00
10.29


ATOM
274
CA
ILE
A
252
14.832
44.209
34.944
1.00
12.09


ATOM
275
CB
ILE
A
252
16.209
44.654
34.372
1.00
13.58


ATOM
276
CG2
ILE
A
252
16.848
43.570
33.523
1.00
14.17


ATOM
277
CG1
ILE
A
252
16.059
45.964
33.581
1.00
16.57


ATOM
278
CD1
ILE
A
252
17.351
46.450
32.902
1.00
18.53


ATOM
279
C
ILE
A
252
14.938
42.791
35.448
1.00
10.51


ATOM
280
O
ILE
A
252
14.592
41.830
34.755
1.00
12.14


ATOM
281
N
GLU
A
253
15.508
42.598
36.641
1.00
9.27


ATOM
282
CA
GLU
A
253
15.743
41.263
37.159
1.00
10.71


ATOM
283
CB
GLU
A
253
16.762
41.233
38.306
1.00
12.25


ATOM
284
CG
GLU
A
253
18.217
41.412
37.830
1.00
12.76


ATOM
285
CD
GLU
A
253
19.215
41.029
38.924
1.00
15.62


ATOM
286
CE1
GLU
A
253
19.091
40.009
39.615
1.00
14.92


ATOM
287
OE2
GLU
A
253
20.134
41.798
39.207
1.00
14.69


ATOM
288
C
GLU
A
253
14.422
40.619
37.605
1.00
9.88


ATOM
289
O
GLU
A
253
14.195
39.441
37.388
1.00
7.43


ATOM
290
N
LEU
A
254
13.559
41.420
38.230
1.00
10.47


ATOM
291
CA
LEU
A
254
12.266
40.858
38.649
1.00
10.04


ATOM
292
CB
LEU
A
254
11.537
41.807
39.572
1.00
9.52


ATOM
293
CG
LEU
A
254
10.103
41.493
40.022
1.00
10.99


ATOM
294
CD1
LEU
A
254
9.778
42.322
41.239
1.00
11.71


ATOM
295
CD2
LEU
A
254
9.106
41.854
33.918
1.00
11.46


ATOM
296
C
LEU
A
254
11.481
40.463
37.408
1.00
9.41


ATOM
297
O
LEU
A
254
10.959
39.343
37.426
1.00
10.16


ATOM
298
N
ILE
A
255
11.399
41.269
36.369
1.00
11.15


ATOM
299
CA
ILE
A
255
10.590
40.910
35.180
1.00
11.06


ATOM
300
CB
ILE
A
255
10.480
42.108
34.194
1.00
10.34


ATOM
301
CG2
ILE
A
255
9.910
41.651
32.851
1.00
12.31


ATOM
302
CG1
ILE
A
255
9.646
43.216
34.796
1.00
10.06


ATOM
303
CD1
ILE
A
255
8.235
42.810
35.286
1.00
10.96


ATOM
304
C
ILE
A
255
11.113
39.671
34.495
1.00
11.34


ATOM
305
O
ILE
A
255
10.466
38.704
34.055
1.00
8.95


ATOM
306
N
ASP
A
256
12.458
39.596
34.420
1.00
10.09


ATOM
307
CA
ASP
A
256
13.108
38.362
33.953
1.00
11.00


ATOM
308
CB
ASP
A
256
14.621
38.617
33.890
1.00
12.60


ATOM
309
CG
ASP
A
256
15.320
37.358
33.434
1.00
16.54


ATOM
310
OD1
ASP
A
256
15.159
37.033
32.249
1.00
17.04


ATOM
311
OD2
ASP
A
256
15.977
36.731
34.290
1.00
18.15


ATOM
312
C
ASP
A
256
12.763
37.124
34.779
1.00
10.53


ATOM
313
O
ASP
A
256
12.485
36.036
34.246
1.00
11.14


ATOM
314
N
ARG
A
257
12.719
37.177
36.087
1.00
11.51


ATOM
315
CA
ARG
A
257
12.362
36.025
36.523
1.00
11.03


ATOM
316
CB
ARG
A
257
12.646
36.291
38.375
1.00
11.04


ATOM
317
CG
ARG
A
257
14.194
36.302
38.743
1.00
9.97


ATOM
318
CD
ARG
A
257
14.347
36.333
40.258
1.00
9.34


ATOM
319
NE
ARG
A
257
13.581
37.392
40.951
1.00
9.56


ATOM
320
CZ
ARG
A
257
14.058
38.613
41.124
1.00
10.48


ATOM
321
NH1
ARG
A
257
15.283
38.961
40.677
1.00
8.64


ATOM
322
NH2
ARG
A
257
13.363
39.539
41.718
1.00
8.45


ATOM
323
C
ARG
A
257
10.868
35.673
36.655
1.00
10.99


ATOM
324
O
ARG
A
257
10.495
34.509
36.580
1.00
10.38


ATOM
325
N
VAL
A
258
10.033
36.685
36.635
1.00
7.90


ATOM
326
CA
VAL
A
258
8.600
36.497
36.295
1.00
9.48


ATOM
327
CB
VAL
A
258
7.877
37.856
36.335
1.00
8.97


ATOM
328
CG1
VAL
A
258
6.398
37.717
35.905
1.00
7.38


ATOM
329
CG2
VAL
A
258
7.915
38.447
37.733
1.00
7.76


ATOM
330
C
VAL
A
258
8.469
35.851
34.931
1.00
9.20


ATOM
331
O
VAL
A
258
7.769
34.858
34.706
1.00
11.73


ATOM
332
N
ASP
A
259
9.193
36.330
33.947
1.00
10.44


ATOM
333
CA
ASP
A
259
9.196
35.817
32.585
1.00
11.92


ATOM
334
CB
ASP
A
259
10.101
36.614
31.655
1.00
12.64


ATOM
335
CG
ASP
A
259
10.059
36.157
30.219
1.00
17.49


ATOM
336
OD1
ASP
A
259
8.962
36.007
29.644
1.00
16.26


ATOM
337
OD2
ASP
A
259
11.145
35.932
29.637
1.00
20.54


ATOM
338
C
ASP
A
259
9.618
34.346
32.546
1.00
13.21


ATOM
339
O
ASP
A
259
9.021
33.572
31.783
1.00
11.13


ATOM
340
N
ASP
A
260
10.546
33.904
33.412
1.00
12.46


ATOM
341
OD2
ASP
A
260
14.081
33.042
35.067
1.00
19.42


ATOM
342
OD1
ASP
A
260
13.629
33.074
32.936
1.00
15.68


ATOM
343
CG
ASP
A
260
13.335
32.789
34.098
1.00
16.09


ATOM
344
CB
ASP
A
260
11.972
32.171
34.451
1.00
13.52


ATOM
345
CA
ASP
A
260
10.912
32.498
33.403
1.00
11.20


ATOM
346
C
ASP
A
260
9.647
31.669
33.761
1.00
13.45


ATOM
347
O
ASP
A
260
9.461
30.565
33.241
1.00
11.34


ATOM
348
N
ILE
A
261
8.867
32.202
34.720
1.00
10.81


ATOM
349
CA
ILE
A
261
7.643
31.469
35.052
1.00
11.86


ATOM
350
CB
ILE
A
261
6.910
32.167
36.198
1.00
13.06


ATOM
351
CG2
ILE
A
261
5.538
31.612
36.416
1.00
12.50


ATOM
252
CG1
ILE
A
261
7.825
31.986
37.422
1.00
16.02


ATOM
353
CD1
ILE
A
261
7.242
32.547
38.701
1.00
17.40


ATOM
354
C
ILE
A
261
6.738
31.396
33.815
1.00
10.07


ATOM
355
O
ILE
A
261
6.351
30.273
33.480
1.00
11.72


ATOM
356
N
TYR
A
262
6.434
32.522
33.232
1.00
8.70


ATOM
357
CA
TYR
A
262
5.515
32.515
32.082
1.00
11.55


ATOM
358
CB
TYR
A
262
5.275
33.937
31.548
1.00
11.91


ATOM
359
CG
TYR
A
262
4.257
34.650
32.411
1.00
12.15


ATOM
360
CD1
TYR
A
262
4.554
35.110
33.670
1.00
12.29


ATOM
361
CE1
TYR
A
262
3.598
35.746
34.457
1.00
12.53


ATOM
362
CD2
TYR
A
262
2.940
34.799
31.941
1.00
14.52


ATOM
363
CE2
TYR
A
262
1.989
35.420
32.716
1.00
14.04


ATOM
364
CZ
TYR
A
262
2.315
35.905
33.956
1.00
14.14


ATOM
365
OH
TYR
A
262
1.368
36.538
34.724
1.00
12.39


ATOM
366
C
TYR
A
262
5.982
31.682
30.932
1.00
11.66


ATOM
367
O
TYR
A
262
5.202
30.842
30.446
1.00
11.39


ATOM
368
N
ARG
A
263
7.231
31.887
30.478
1.00
10.78


ATOM
369
CA
ARG
A
263
7.771
31.380
29.333
1.00
14.61


ATOM
370
CB
ARG
A
263
9.236
31.623
29.117
1.00
18.66


ATOM
371
CG
ARG
A
263
9.634
32.729
28.194
1.00
21.81


ATOM
372
CD
ARG
A
263
11.103
32.655
27.718
1.00
25.82


ATOM
373
NE
ARG
A
263
11.932
31.745
28.516
1.00
27.30


ATOM
374
CZ
ARG
A
263
12.427
32.092
29.708
1.00
28.71


ATOM
375
NH1
ARG
A
263
12.225
33.329
30.166
1.00
29.09


ATOM
376
NH2
ARG
A
263
13.087
33.212
30.435
1.00
27.05


ATOM
377
C
ARG
A
263
7.751
29.674
29.425
1.00
15.13


ATOM
378
O
ARG
A
263
7.596
28.973
28.384
1.00
17.45


ATOM
379
N
ASN
A
264
8.019
29.078
30.591
1.00
12.82


ATOM
380
CA
ASN
A
264
8.003
27.677
30.834
1.00
14.56


ATOM
381
CB
ASN
A
264
8.878
27.204
32.013
1.00
17.95


ATOM
382
CG
ASN
A
264
10.323
27.555
31.654
1.00
19.62


ATOM
383
OD1
ASN
A
264
10.776
27.002
30.654
1.00
23.35


ATOM
384
ND2
ASN
A
264
10.957
28.464
32.335
1.00
19.81


ATOM
385
C
ASN
A
264
6.582
27.144
31.076
1.00
16.00


ATOM
386
O
ASN
A
264
6.449
25.944
31.293
1.00
14.82


ATOM
387
N
THR
A
265
5.566
28.017
31.073
1.00
13.74


ATOM
388
CA
THR
A
265
4.221
27.425
31.290
1.00
13.37


ATOM
389
CB
THR
A
265
3.309
28.463
31.935
1.00
14.37


ATOM
390
OG1
THR
A
265
3.800
28.787
33.238
1.00
11.71


ATOM
391
CG2
THR
A
265
1.866
27.953
32.101
1.00
12.84


ATOM
392
C
THR
A
265
3.675
26.917
29.965
1.00
12.82


ATOM
393
O
THR
A
265
3.698
27.828
28.968
1.00
14.37


ATOM
394
N
ALA
A
266
3.134
25.708
29.970
1.00
13.65


ATOM
395
CA
ALA
A
266
2.432
25.151
28.820
1.00
14.19


ATOM
396
CB
ALA
A
266
2.737
23.645
28.812
1.00
14.17


ATOM
397
C
ALA
A
266
0.937
25.431
28.997
1.00
11.04


ATOM
398
O
ALA
A
266
0.250
24.682
29.675
1.00
10.22


ATOM
399
N
TRP
A
267
0.426
26.539
28.524
1.00
11.35


ATOM
400
CA
TRP
A
267
−0.962
26.949
28.736
1.00
13.04


ATOM
401
CB
TRP
A
267
−1.183
28.301
28.045
1.00
11.63


ATOM
402
CG
TRP
A
267
−0.186
29.330
28.523
1.00
10.70


ATOM
403
CD2
TRP
A
267
−0.205
29.920
29.819
1.00
8.77


ATOM
404
CE2
TRP
A
267
0.904
30.814
29.863
1.00
12.19


ATOM
405
CE3
TRP
A
267
−1.007
29.828
30.931
1.00
9.72


ATOM
406
CD1
TRP
A
267
0.865
29.846
27.849
1.00
10.38


ATOM
407
NE1
TRP
A
267
1.531
30.754
28.652
1.00
11.35


ATOM
408
CZ2
TRP
A
267
1.187
31.580
30.989
1.00
10.57


ATOM
409
CZ3
TRP
A
267
−0.718
30.580
32.066
1.00
11.82


ATOM
410
CH2
TRP
A
267
0.395
31.439
32.071
1.00
9.78


ATOM
411
C
TRP
A
267
−2.007
25.919
28.298
1.00
14.01


ATOM
412
O
TRP
A
267
−3.089
25.832
28.915
1.00
14.19


ATOM
413
N
ASP
A
268
−1.688
25.091
27.326
1.00
11.86


ATOM
414
CA
ASP
A
268
−2.615
24.026
26.899
1.00
13.82


ATOM
415
CB
ASP
A
268
−2.765
24.051
25.382
1.00
13.92


ATOM
416
CG
ASP
A
268
−1.517
23.691
24.619
1.00
16.74


ATOM
417
OD1
ASP
A
268
−0.422
23.699
25.244
1.00
16.49


ATOM
418
OD2
ASP
A
268
−1.561
23.395
23.404
1.00
15.38


ATOM
419
C
ASP
A
268
−2.165
22.661
27.367
1.00
15.26


ATOM
420
O
ASP
A
268
−2.554
21.608
26.834
1.00
13.18


ATOM
421
N
ASN
A
269
−1.225
22.609
28.329
1.00
14.90


ATOM
422
CA
ASN
A
269
−0.596
21.391
28.792
1.00
15.45


ATOM
423
CB
ASN
A
269
−1.547
20.454
29.549
1.00
17.28


ATOM
424
CG
ASN
A
269
−2.190
21.182
30.719
1.00
18.96


ATOM
425
OD1
ASN
A
269
−1.464
21.670
31.560
1.00
20.34


ATOM
426
ND2
ASN
A
269
−3.500
21.321
30.788
1.00
18.93


ATOM
427
C
ASN
A
269
0.108
20.556
27.711
1.00
14.79


ATOM
428
O
ASN
A
269
0.330
19.352
27.859
1.00
14.35


ATOM
429
N
ALA
A
270
0.523
21.193
26.654
1.00
14.55


ATOM
430
CA
ALA
A
270
1.203
20.593
25.533
1.00
17.42


ATOM
431
CB
ALA
A
270
0.189
20.155
24.481
1.00
15.76


ATOM
432
C
ALA
A
270
2.239
21.573
25.004
1.00
16.67


ATOM
433
O
ALA
A
270
3.183
21.866
25.757
1.00
19.13


ATOM
434
N
GLY
A
271
2.141
22.004
23.765
1.00
16.01


ATOM
435
CA
GLY
A
271
3.174
22.837
23.177
1.00
18.64


ATOM
436
C
GLY
A
271
2.951
24.321
23.125
1.00
17.56


ATOM
437
O
GLY
A
271
3.768
25.075
22.589
1.00
18.20


ATOM
438
N
PHE
A
272
1.844
24.831
23.659
1.00
17.81


ATOM
439
CA
PHE
A
272
1.538
26.263
23.614
1.00
16.42


ATOM
440
CB
PHE
A
272
0.047
26.539
23.710
1.00
16.73


ATOM
441
CG
PHE
A
272
−0.389
27.890
23.205
1.00
17.94


ATOM
442
CD1
PHE
A
272
−0.462
28.168
21.858
1.00
19.17


ATOM
443
CD2
PHE
A
272
−0.716
28.894
24.100
1.00
18.80


ATOM
444
CE1
PHE
A
272
−0.813
29.421
23.407
1.00
18.87


ATOM
445
CE2
PHE
A
272
−1.120
30.139
23.664
1.00
18.81


ATOM
446
CZ
PHE
A
272
−1.142
30.404
22.310
1.00
19.11


ATOM
447
C
PHE
A
272
2.305
26.889
24.796
1.00
16.83


ATOM
448
O
PHE
A
272
1.786
27.138
25.860
1.00
14.19


ATOM
449
N
LYS
A
273
3.584
27.067
24.561
1.00
17.93


ATOM
450
CA
LYS
A
273
4.522
27.543
25.546
1.00
21.35


ATOM
451
CB
LYS
A
273
5.236
26.296
26.080
1.00
24.32


ATOM
452
CG
LYS
A
273
6.157
25.698
25.023
1.00
27.94


ATOM
453
CD
LYS
A
273
6.625
24.300
25.389
1.00
31.29


ATOM
454
CE
LYS
A
273
7.307
24.300
26.732
1.00
32.80


ATOM
455
NZ
LYS
A
273
6.347
24.136
27.857
1.00
33.38


ATOM
456
C
LYS
A
273
5.479
28.518
24.906
1.00
19.96


ATOM
457
O
LYS
A
273
5.444
28.763
23.706
1.00
18.61


ATOM
458
N
GLY
A
274
6.382
29.094
25.709
1.00
20.59


ATOM
459
CA
GLY
A
274
7.323
30.058
25.166
1.00
17.10


ATOM
460
C
GLY
A
274
6.701
31.449
25.153
1.00
17.80


ATOM
461
O
GLY
A
274
7.272
32.334
24.547
1.00
17.48


ATOM
462
N
TYR
A
275
5.527
31.675
25.763
1.00
15.67


ATOM
463
CA
TYR
A
275
4.892
32.965
25.302
1.00
16.24


ATOM
464
CB
TYR
A
275
3.340
32.874
25.854
1.00
15.81


ATOM
465
CG
TYR
A
275
2.838
32.446
24.503
1.00
17.73


ATOM
466
CD1
TYR
A
275
2.784
31.102
24.175
1.00
17.51


ATOM
467
CE1
TYR
A
275
2.384
30.722
22.919
1.00
20.42


ATOM
468
CD2
TYR
A
275
2.524
33.418
23.543
1.00
18.48


ATOM
469
CE2
TYR
A
275
2.140
33.017
22.279
1.00
20.02


ATOM
470
CZ
TYR
A
275
2.065
31.690
21.989
1.00
19.42


ATOM
471
OH
TYR
A
275
1.670
31.304
20.737
1.00
23.70


ATOM
472
C
TYR
A
275
5.317
33.689
27.087
1.00
15.60


ATOM
473
O
TYR
A
275
5.270
33.077
28.160
1.00
15.87


ATOM
474
N
GLY
A
276
5.638
34.959
26.991
1.00
17.04


ATOM
475
CA
GLY
A
276
5.978
35.692
28.390
1.00
17.48


ATOM
476
C
GLY
A
276
5.988
37.183
28.020
1.00
19.17


ATOM
477
O
GLY
A
276
5.226
37.781
27.278
1.00
16.76


ATOM
478
N
ILE
A
277
6.893
37.805
28.811
1.00
18.66


ATOM
479
CA
ILE
A
277
6.938
39.245
28.907
1.00
17.89


ATOM
480
CB
ILE
A
277
6.413
39.745
30.256
1.00
19.63


ATOM
481
CG2
ILE
A
277
4.925
39.409
30.421
1.00
21.02


ATOM
482
CG1
ILE
A
277
7.212
39.101
31.390
1.00
20.19


ATOM
483
CD1
ILE
A
277
6.754
39.439
32.779
1.00
20.94


ATOM
484
C
ILE
A
277
8.385
39.741
28.763
1.00
18.46


ATOM
485
O
ILE
A
277
9.318
39.076
29.168
1.00
16.61


ATOM
486
N
GLN
A
278
8.505
40.919
28.219
1.00
17.96


ATOM
487
CA
GLN
A
278
9.743
41.629
28.051
1.00
19.65


ATOM
488
CB
GLN
A
278
10.224
41.684
26.624
1.00
25.01


ATOM
489
CG
GLN
A
278
11.692
41.405
26.382
1.00
28.24


ATOM
490
CD
GLN
A
278
11.580
40.059
25.643
1.00
32.63


ATOM
491
OE1
GLN
A
278
11.660
40.060
24.422
1.00
33.32


ATOM
492
NE2
GLN
A
278
11.331
39.078
26.502
1.00
34.14


ATOM
493
C
GLN
A
278
9.499
43.122
28.316
1.00
17.44


ATOM
494
O
GLN
A
278
8.589
43.689
27.693
1.00
14.22


ATOM
495
N
ILE
A
279
10.537
43.709
28.900
1.00
13.53


ATOM
496
CA
ILE
A
279
10.471
45.146
29.090
1.00
15.82


ATOM
497
CB
ILE
A
279
11.441
45.658
30.183
1.00
15.54


ATOM
498
CG2
ILE
A
279
11.402
47.166
30.140
1.00
15.97


ATOM
499
CG1
ILE
A
279
11.007
45.083
31.520
1.00
16.27


ATOM
500
CD1
ILE
A
279
11.940
45.388
32.661
1.00
17.52


ATOM
501
C
ILE
A
279
10.745
45.847
27.771
1.00
16.97


ATOM
502
O
ILE
A
279
11.741
45.578
27.115
1.00
16.40


ATOM
503
N
GLU
A
280
9.824
46.719
27.370
1.00
17.63


ATOM
504
CA
GLU
A
280
10.019
47.523
26.185
1.00
20.86


ATOM
505
CB
GLU
A
280
8.744
47.778
25.395
1.00
23.07


ATOM
506
CG
GLU
A
280
8.890
48.784
24.268
1.00
29.11


ATOM
507
CD
GLU
A
280
9.843
48.327
23.189
1.00
32.61


ATOM
508
OE1
GLU
A
280
10.187
47.124
23.154
1.00
36.14


ATOM
509
OE2
GLU
A
280
10.293
49.127
22.343
1.00
34.84


ATOM
510
C
GLU
A
280
10.599
48.892
26.605
1.00
18.21


ATOM
511
O
GLU
A
280
11.426
49.511
25.941
1.00
16.53


ATOM
512
N
GLU
A
281
10.088
49.380
27.716
1.00
18.36


ATOM
513
NE2
GLN
A
281
11.497
53.112
26.056
1.00
34.24


ATOM
514
OE1
GLN
A
281
10.702
55.093
26.755
1.00
36.11


ATOM
515
CD
GLN
A
281
10.798
53.869
26.901
1.00
33.14


ATOM
516
CG
GLN
A
281
10.120
53.163
28.056
1.00
29.67


ATOM
517
CB
GLN
A
281
9.611
51.793
27.640
1.00
24.17


ATOM
518
CA
GLN
A
281
10.509
50.675
28.207
1.00
21.85


ATOM
519
C
GLN
A
281
10.385
50.730
29.723
1.00
22.08


ATOM
520
O
GLN
A
281
9.444
50.170
30.275
1.00
19.43


ATOM
521
N
ILE
A
282
11.379
51.377
30.337
1.00
19.26


ATOM
522
CA
ILE
A
282
11.340
51.564
31.756
1.00
20.21


ATOM
523
CB
ILE
A
282
12.456
50.838
32.501
1.00
23.17


ATOM
524
CG2
ILE
A
282
12.567
51.331
33.942
1.00
22.63


ATOM
525
CG1
ILE
A
282
12.183
49.337
32.486
1.00
24.53


ATOM
526
CD1
ILE
A
282
13.292
48.530
33.126
1.00
27.43


ATOM
527
C
ILE
A
282
13.408
53.062
32.033
1.00
20.13


ATOM
528
O
ILE
A
282
12.183
53.826
31.441
1.00
21.53


ATOM
529
N
ARG
A
283
10.595
53.478
32.972
1.00
18.99


ATOM
530
CA
ARG
A
283
10.541
54.878
33.353
1.00
20.71


ATOM
531
CB
ARG
A
283
9.159
55.499
33.116
1.00
23.74


ATOM
532
CG
ARG
A
283
8.779
55.516
31.645
1.00
28.61


ATOM
533
CD
ARG
A
283
9.030
56.887
31.041
1.00
33.16


ATOM
534
NE
ARG
A
283
9.596
56.759
29.712
1.00
37.40


ATOM
535
CZ
ARG
A
283
9.199
57.449
28.659
1.00
40.44


ATOM
536
NH1
ARG
A
283
8.191
58.311
28.783
1.00
41.71


ATOM
537
NH2
ARG
A
283
9.800
57.245
27.492
1.00
41.03


ATOM
538
C
ARG
A
283
10.826
54.930
34.844
1.00
20.40


ATOM
539
O
ARG
A
283
10.049
54.339
35.566
1.00
17.37


ATOM
540
N
ILE
A
284
11.881
55.634
35.220
1.00
18.94


ATOM
541
CA
ILE
A
284
12.127
55.779
36.655
1.00
19.58


ATOM
542
CB
ILE
A
284
13.582
55.519
37.053
1.00
20.09


ATOM
543
CG2
ILE
A
284
13.684
55.477
38.573
1.00
20.97


ATOM
544
CG1
ILE
A
284
14.178
54.254
36.460
1.00
20.86


ATOM
545
CD1
ILE
A
284
13.442
52.976
36.774
1.00
20.01


ATOM
546
C
ILE
A
284
11.792
57.228
37.002
1.00
19.71


ATOM
547
O
ILE
A
284
12.399
58.147
36.427
1.00
19.08


ATOM
548
N
LEU
A
285
10.816
57.413
37.849
1.00
19.33


ATOM
549
CA
LEU
A
285
10.379
58.729
38.276
1.00
20.90


ATOM
550
CB
LEU
A
285
8.881
58.729
38.557
1.00
20.57


ATOM
551
CG
LEU
A
285
8.020
58.220
37.391
1.00
18.92


ATOM
552
CD1
LEU
A
285
6.569
58.488
37.719
1.00
19.77


ATOM
553
CD2
LEU
A
285
8.426
58.759
36.039
1.00
18.79


ATOM
554
C
LEU
A
285
11.153
59.078
39.542
1.00
22.65


ATOM
555
O
LEU
A
285
10.861
58.536
40.585
1.00
21.09


ATOM
556
N
LYS
A
286
12.179
59.897
39.370
1.00
23.47


ATOM
557
CA
LYS
A
286
13.101
60.223
40.443
1.00
25.88


ATOM
558
CB
LYS
A
286
14.400
60.777
39.830
1.00
24.64


ATOM
559
CG
LYS
A
286
15.057
59.703
38.969
1.00
26.69


ATOM
560
CD
LYS
A
286
16.105
60.262
38.032
1.00
28.58


ATOM
561
CE
LYS
A
286
17.308
59.334
37.986
1.00
28.89


ATOM
562
NZ
LYS
A
286
18.328
59.807
37.012
1.00
29.92


ATOM
563
C
LYS
A
286
12.515
61.157
41.473
1.00
26.73


ATOM
564
O
LYS
A
286
12.944
61.136
42.622
1.00
28.60


ATOM
565
N
SER
A
287
12.543
61.980
41.133
1.00
25.80


ATOM
566
CA
SER
A
287
10.969
62.865
42.158
1.00
26.18


ATOM
567
CB
SER
A
287
11.627
64.249
42.056
1.00
26.60


ATOM
568
OG
SER
A
287
11.272
64.767
40.796
1.00
28.18


ATOM
569
C
SER
A
287
9.471
62.857
41.977
1.00
24.89


ATOM
570
O
SER
A
287
8.996
62.358
40.947
1.00
25.47


ATOM
571
N
PRO
A
288
8.739
63.268
42.989
1.00
26.04


ATOM
572
CD
PRO
A
288
9.222
63.876
44.247
1.00
27.14


ATOM
573
CA
PRO
A
288
7.294
61.276
42.938
1.00
26.70


ATOM
574
CB
PRO
A
288
6.831
63.561
44.339
1.00
26.05


ATOM
575
CG
PRO
A
288
8.010
63.972
45.128
1.00
27.69


ATOM
576
C
PRO
A
288
6.826
64.313
41.928
1.00
27.00


ATOM
577
O
PRO
A
288
7.522
65.301
41.666
1.00
27.28


ATOM
578
N
GLN
A
289
5.681
64.051
41.341
1.00
25.80


ATOM
579
CA
GLN
A
289
5.123
64.976
40.376
1.00
27.15


ATOM
580
CB
GLN
A
289
4.021
64.214
39.628
1.00
27.78


ATOM
581
CG
GLN
A
289
3.246
65.040
38.617
1.00
27.92


ATOM
582
CD
GLN
A
289
4.207
65.636
37.616
1.00
28.41


ATOM
583
OE1
GLN
A
289
4.970
64.944
36.966
1.00
28.03


ATOM
584
NE2
GLN
A
289
4.179
66.966
37.505
1.00
32.04


ATOM
585
C
GLN
A
289
4.553
66.194
41.093
1.00
27.84


ATOM
586
O
GLN
A
289
3.693
66.017
41.943
1.00
27.12


ATOM
587
N
GLU
A
290
4.962
67.414
40.766
1.00
30.72


ATOM
588
OE2
GLU
A
290
4.477
72.113
38.486
1.00
39.70


ATOM
589
OE1
GLU
A
290
4.067
72.564
39.857
1.00
40.48


ATOM
590
CD
GLU
A
290
5.336
71.724
39.305
1.00
39.53


ATOM
591
CG
GLU
A
290
5.461
70.253
39.660
1.00
37.94


ATOM
592
CB
GLU
A
290
5.094
69.910
41.084
1.00
35.71


ATOM
593
CA
GLU
A
290
4.384
68.595
41.401
1.00
33.44


ATOM
594
C
GLU
A
290
2.912
68.679
40.978
1.00
32.66


ATOM
595
O
GLU
A
290
2.615
68.487
39.807
1.00
32.60


ATOM
596
N
VAL
A
291
2.027
68.929
41.928
1.00
32.52


ATOM
597
CA
VAL
A
291
0.589
68.960
41.608
1.00
34.53


ATOM
598
CB
VAL
A
291
0.016
67.667
42.214
1.00
34.68


ATOM
599
CG1
VAL
A
291
−0.992
67.828
43.317
1.00
33.99


ATOM
600
CG2
VAL
A
291
−0.509
66.742
41.114
1.00
33.97


ATOM
601
C
VAL
A
291
−0.040
70.265
42.070
1.00
36.93


ATOM
602
O
VAL
A
291
0.296
70.786
43.141
1.00
35.77


ATOM
603
N
LYS
A
292
−0.879
70.860
41.231
1.00
38.91


ATOM
604
NZ
LYS
A
292
0.250
74.239
36.361
1.00
47.09


ATOM
605
CE
LYS
A
292
−0.459
74.753
37.563
1.00
45.89


ATOM
606
CD
LYS
A
292
−1.298
73.665
38.215
1.00
45.49


ATOM
607
CG
LYS
A
292
−1.226
73.759
39.722
1.00
44.08


ATOM
608
CB
LYS
A
292
−2.197
72.809
40.397
1.00
42.31


ATOM
609
CA
LYS
A
292
−1.595
72.078
41.589
1.00
41.28


ATOM
610
C
LYS
A
292
−2.701
71.697
42.557
1.00
41.79


ATOM
611
O
LYS
A
292
−3.085
70.535
42.624
1.00
42.72


ATOM
612
N
PRO
A
293
−3.192
72.668
43.305
1.00
42.21


ATOM
613
CD
PRO
A
293
−2.802
74.096
43.247
1.00
42.59


ATOM
614
CA
PRO
A
293
−4.279
72.420
44.237
1.00
41.91


ATOM
615
CB
PRO
A
293
−4.605
73.784
44.806
1.00
41.79


ATOM
616
CG
PRO
A
293
−3.481
74.676
44.450
1.00
41.90


ATOM
617
C
PRO
A
293
−5.441
71.807
43.474
1.00
41.40


ATOM
618
O
PRO
A
293
−5.696
72.212
42.339
1.00
41.02


ATOM
619
N
GLY
A
294
−6.059
70.755
44.003
1.00
40.85


ATOM
620
CA
GLY
A
294
−7.176
70.133
43.332
1.00
41.30


ATOM
621
C
GLY
A
294
−6.832
69.033
42.332
1.00
40.98


ATOM
622
O
GLY
A
294
−7.688
68.185
42.061
1.00
41.17


ATOM
623
N
GLU
A
295
−5.636
69.051
41.753
1.00
39.55


ATOM
624
OE2
GLU
A
295
−2.049
69.989
38.852
1.00
44.47


ATOM
625
OE1
GLU
A
295
−3.356
71.223
37.568
1.00
44.87


ATOM
626
CD
GLU
A
295
−3.176
70.330
38.422
1.00
44.01


ATOM
627
CG
GLU
A
295
−4.422
69.647
38.946
2.00
42.26


ATOM
628
CB
GLU
A
295
−4.099
68.521
39.886
1.00
39.91


ATOM
629
CA
GLU
A
295
−5.214
68.044
40.813
1.00
38.60


ATOM
630
C
GLU
A
295
−4.641
66.825
41.552
1.00
36.59


ATOM
631
O
GLU
A
295
−4.281
66.871
42.720
1.00
36.85


ATOM
632
N
LYS
A
296
−4.418
65.777
40.773
1.00
33.95


ATOM
633
CA
LYS
A
296
−3.782
64.575
41.294
1.00
30.68


ATOM
634
CB
LYS
A
296
−4.755
63.656
41.996
1.00
31.56


ATOM
635
CG
LYS
A
296
−5.992
63.312
41.185
1.00
32.22


ATOM
636
CD
LYS
A
296
−7.149
62.924
42.075
1.00
32.13


ATOM
637
CE
LYS
A
296
−8.161
62.034
41.381
1.00
33.43


ATOM
638
NZ
LYS
A
296
−8.106
62.091
39.904
1.00
34.90


ATOM
639
C
LYS
A
296
−3.028
63.883
40.167
1.00
28.79


ATOM
640
O
LYS
A
296
−3.275
64.112
38.986
1.00
27.50


ATOM
641
N
HIS
A
297
−1.999
63.335
40.580
1.00
25.20


ATOM
642
CA
HIS
A
297
−1.216
62.396
39.584
1.00
20.71


ATOM
643
CB
HIS
A
297
−0.148
63.267
38.981
1.00
20.06


ATOM
644
CG
HIS
A
297
0.824
62.612
38.054
1.00
18.56


ATOM
645
CD2
HIS
A
297
1.808
61.741
38.309
1.00
15.40


ATOM
646
ND1
HIS
A
297
0.863
62.878
36.701
1.00
18.13


ATOM
647
CE1
HIS
A
297
1.844
62.180
36.160
1.00
17.97


ATOM
648
NE2
HIS
A
297
2.416
61.463
37.105
1.00
19.72


ATOM
649
C
HIS
A
297
−0.730
61.151
40.292
1.00
19.15


ATOM
650
O
HIS
A
297
−0.477
61.256
41.493
1.00
18.54


ATOM
651
N
TYR
A
298
−0.557
60.030
39.580
1.00
18.21


ATOM
652
CA
TYR
A
298
−0.155
58.824
40.330
1.00
16.80


ATOM
653
CB
TYR
A
298
−0.193
57.594
39.437
1.00
16.24


ATOM
654
CG
TYR
A
298
0.940
57.509
38.444
1.00
17.23


ATOM
655
CD1
TYR
A
298
2.077
56.755
38.742
1.00
15.56


ATOM
656
CE1
TYR
A
298
3.094
56.667
37.821
1.00
15.21


ATOM
657
CD2
TYR
A
298
0.881
53.384
37.236
1.00
16.74


ATOM
658
CE2
TYR
A
298
1.913
58.098
36.337
1.00
16.91


ATOM
659
CZ
TYR
A
298
3.022
57.325
36.636
1.00
16.49


ATOM
660
OH
TYR
A
298
4.046
57.260
35.719
1.00
18.10


ATOM
661
C
TYR
A
298
1.185
58.981
41.029
1.00
16.63


ATOM
662
O
TYR
A
298
1.351
58.330
42.073
1.00
16.70


ATOM
663
N
ASN
A
299
2.112
59.766
40.523
1.00
16.99


ATOM
664
CA
ASN
A
299
3.423
60.011
41.085
1.00
18.59


ATOM
665
CB
ASN
A
299
4.463
60.166
39.965
1.00
18.92


ATOM
666
CG
ASN
A
299
5.890
60.214
40.494
1.00
18.76


ATOM
667
OD1
ASN
A
299
6.205
59.456
41.412
1.00
18.23


ATOM
668
ND2
ASN
A
299
6.748
61.070
39.950
1.00
19.19


ATOM
669
C
ASN
A
299
3.513
61.224
42.009
1.00
20.06


ATOM
670
O
ASN
A
299
4.606
61.723
42.362
1.00
18.80


ATOM
671
N
MET
A
300
2.395
61.732
42.509
1.00
20.80


ATOM
672
CA
MET
A
300
2.449
62.886
43.417
1.00
22.77


ATOM
673
CB
MET
A
300
1.115
63.568
43.608
1.00
23.16


ATOM
674
CG
MET
A
300
0.029
62.931
44.436
1.00
25.10


ATOM
675
SD
MET
A
300
−1.590
63.723
44.020
1.00
28.00


ATOM
676
CE
MET
A
300
−2.640
62.839
45.144
1.00
24.04


ATOM
677
C
MET
A
300
3.012
62.458
44.767
1.00
21.89


ATOM
678
O
MET
A
300
2.833
61.314
45.160
1.00
18.53


ATOM
679
N
ALA
A
301
3.369
63.413
45.606
1.00
22.83


ATOM
680
CA
ALA
A
301
3.872
63.134
46.926
1.00
23.87


ATOM
681
CB
ALA
A
301
4.450
64.429
47.484
1.00
23.72


ATOM
682
C
ALA
A
301
2.841
62.580
47.893
1.00
24.63


ATOM
683
O
ALA
A
301
3.085
61.615
48.637
1.00
23.46


ATOM
684
N
LYS
A
302
1.652
63.178
47.913
1.00
26.09


ATOM
685
CA
LYS
A
302
0.645
62.719
48.859
1.00
26.00


ATOM
686
CB
LYS
A
302
−0.215
63.890
49.329
1.00
28.38


ATOM
687
CG
LYS
A
302
0.554
65.188
49.528
1.00
29.29


ATOM
688
CD
LYS
A
302
1.697
65.125
50.505
1.00
30.98


ATOM
689
CE
LYS
A
302
2.522
66.407
50.512
1.00
32.65


ATOM
690
NZ
LYS
A
302
2.617
67.085
49.191
1.00
33.62


ATOM
691
C
LYS
A
302
−0.198
61.580
48.291
1.00
25.55


ATOM
692
O
LYS
A
302
−0.295
61.399
47.087
1.00
24.72


ATOM
693
N
SER
A
303
−0.793
60.835
49.202
1.00
24.45


ATOM
694
CA
SER
A
303
−1.621
59.696
48.836
1.00
25.50


ATOM
695
CB
SER
A
303
−1.434
58.619
49.878
1.00
26.64


ATOM
696
OG
SER
A
303
−1.869
59.030
51.149
1.00
31.03


ATOM
697
C
SER
A
303
−3.052
60.182
48.666
1.00
25.87


ATOM
698
O
SER
A
303
−3.396
61.256
49.185
1.00
22.73


ATOM
699
N
TYR
A
304
−3.814
59.454
47.855
1.00
24.98


ATOM
700
CA
TYR
A
304
−5.181
59.862
47.550
1.00
24.27


ATOM
701
CB
TYR
A
304
−5.140
60.449
46.132
1.00
25.45


ATOM
702
CG
TYR
A
304
−6.466
61.015
45.686
1.00
28.35


ATOM
703
CD1
TYR
A
304
−6.762
62.357
45.929
1.00
29.08


ATOM
704
CE1
TYR
A
304
−7.978
62.891
45.552
1.00
29.59


ATOM
705
CD2
TYR
A
304
−7.426
60.214
45.085
1.00
27.54


ATOM
706
CE2
TYR
A
304
−8.630
60.754
44.702
1.00
29.33


ATOM
707
CZ
TYR
A
304
−8.893
62.094
44.944
1.00
29.27


ATOM
708
OH
TYR
A
304
−10.103
62.610
44.578
1.00
32.08


ATOM
709
C
TYR
A
304
−6.192
58.769
47.721
1.00
25.14


ATOM
710
O
TYR
A
304
−5.707
57.735
47.336
1.000
20.08


ATOM
711
N
PRO
A
305
−7.356
59.000
48.279
1.00
26.60


ATOM
712
CD
PRO
A
305
−8.386
58.001
48.459
1.00
25.22


ATOM
713
CA
PRO
A
305
−7.989
60.240
48.637
1.00
27.02


ATOM
714
CB
PRO
A
305
−9.492
60.083
48.491
1.00
25.75


ATOM
715
CG
PRO
A
305
−9.707
58.646
48.789
1.00
25.74


ATOM
716
C
PRO
A
305
−7.625
60.782
50.007
1.00
28.63


ATOM
717
O
PRO
A
305
−7.922
61.915
50.430
1.00
28.68


ATOM
718
N
ASN
A
306
−6.988
59.904
50.783
1.00
29.14


ATOM
719
CA
ASN
A
306
−6.713
60.273
52.173
1.00
30.26


ATOM
720
CB
ASN
A
306
−7.350
59.232
53.075
1.00
32.58


ATOM
721
CG
ASN
A
306
−8.766
58.861
52.676
1.00
35.48


ATOM
722
OD1
ASN
A
306
−9.661
59.712
52.612
1.00
36.24


ATOM
723
ND2
ASN
A
306
−8.992
57.588
52.368
1.00
36.01


ATOM
724
C
ASN
A
306
−5.229
60.477
52.375
1.00
29.94


ATOM
725
O
ASN
A
306
−4.444
59.536
52.439
1.00
28.29


ATOM
726
N
GLU
A
307
−4.819
61.724
52.507
1.00
29.94


ATOM
727
OE2
GLU
A
307
−2.295
66.669
51.130
1.00
41.44


ATOM
728
OE1
GLU
A
307
−2.711
66.223
53.238
1.00
41.35


ATOM
729
CD
GLU
A
307
−2.656
65.896
52.037
1.00
40.02


ATOM
730
CG
GLU
A
307
−3.034
64.464
51.678
1.00
38.20


ATOM
731
CB
GLU
A
307
−3.401
63.683
52.914
1.00
33.77


ATOM
732
CA
GLU
A
307
−3.461
62.152
52.717
1.00
32.32


ATOM
733
C
GLU
A
307
−2.770
61.594
53.949
1.00
30.24


ATOM
734
O
GLU
A
307
−1.542
61.522
53.870
1.00
30.44


ATOM
735
N
GLU
A
308
−3.513
61.273
54.984
1.00
29.39


ATOM
736
OE2
GLU
A
308
−6.099
61.320
55.501
1.00
38.47


ATOM
737
OE1
GLU
A
308
−7.129
59.531
56.089
1.00
37.95


ATOM
738
CD
GLU
A
308
−6.176
60.330
56.250
1.00
36.70


ATOM
739
CG
GLU
A
308
−5.168
60.057
57.322
1.00
35.39


ATOM
740
CB
GLU
A
308
−3.931
60.913
57.384
1.00
33.10


ATOM
741
CA
GLU
A
308
−2.950
60.795
56.224
1.00
29.98


ATOM
742
C
GLU
A
308
−2.487
59.353
56.093
1.00
28.21


ATOM
743
O
GLU
A
308
−1.607
58.963
56.857
1.00
26.31


ATOM
744
N
LYS
A
309
−3.004
58.626
55.094
1.00
24.19


ATOM
745
CA
LYS
A
309
−2.648
57.216
55.015
1.00
24.20


ATOM
746
CB
LYS
A
309
−3.711
56.413
54.263
1.00
24.89


ATOM
747
CG
LYS
A
309
−5.098
56.344
54.884
1.00
27.73


ATOM
748
CD
LYS
A
309
−5.089
56.571
56.361
1.00
31.22


ATOM
749
CE
LYS
A
309
−6.317
56.792
57.162
1.00
32.52


ATOM
750
NZ
LYS
A
309
−6.638
55.694
58.107
1.00
34.53


ATOM
751
C
LYS
A
309
−1.285
57.012
54.387
1.00
21.98


ATOM
752
O
LYS
A
309
−0.832
57.851
53.636
1.00
22.27


ATOM
753
N
ASP
A
310
−0.675
55.855
54.593
1.00
20.75


ATOM
754
CA
ASP
A
310
0.605
55.530
53.953
1.00
20.70


ATOM
755
CB
ASP
A
310
1.130
54.173
54.501
1.00
20.15


ATOM
756
CG
ASP
A
310
2.615
54.085
54.167
1.00
22.21


ATOM
757
OD1
ASP
A
310
3.335
54.893
54.831
1.00
24.55


ATOM
758
OD2
ASP
A
310
3.040
53.306
53.292
1.00
18.20


ATOM
759
C
ASP
A
310
0.474
55.419
52.450
1.00
19.43


ATOM
760
O
ASP
A
310
1.385
55.706
51.651
1.00
20.19


ATOM
761
N
ALA
A
311
−0.727
55.044
51.990
1.00
18.69


ATOM
762
CA
ALA
A
311
−0.947
54.834
50.572
1.00
17.44


ATOM
763
CB
ALA
A
311
−0.991
53.296
50.429
1.00
16.55


ATOM
764
C
ALA
A
311
−2.302
55.316
50.025
1.00
16.60


ATOM
765
O
ALA
A
311
−3.221
55.655
50.751
1.00
12.08


ATOM
766
N
TRP
A
312
−2.339
55.302
48.711
1.00
17.19


ATOM
767
CA
TRP
A
312
−3.555
55.615
47.963
1.00
15.85


ATOM
768
CB
TRP
A
312
−3.236
55.569
46.483
1.00
14.37


ATOM
769
CG
TRP
A
312
−2.713
56.757
45.760
1.00
16.10


ATOM
770
CD2
TRP
A
312
−3.413
57.526
44.772
1.00
16.24


ATOM
771
CE2
TRP
A
312
−2.554
58.554
44.342
1.00
17.46


ATOM
772
CE1
TRP
A
312
−4.685
57.427
44.204
1.00
17.59


ATOM
773
CD1
TRP
A
312
−1.492
57.360
45.884
1.00
15.52


ATOM
774
NE1
TRP
A
312
−1.381
58.440
45.050
1.00
16.75


ATOM
775
CZ2
TRP
A
312
−2.900
59.475
43.357
1.00
17.80


ATOM
776
CZ3
TRP
A
312
−5.022
58.348
43.228
1.00
15.80


ATOM
777
CH2
TRP
A
312
−4.154
59.345
42.828
1.00
17.23


ATOM
778
C
TRP
A
312
−4.562
54.502
41.204
1.00
16.18


ATOM
779
O
TRP
A
312
−4.185
53.393
48.559
1.00
14.62


ATOM
780
N
ASP
A
313
−5.841
54.750
47.906
1.00
17.14


ATOM
781
CA
ASP
A
313
−6.817
53.682
47.741
1.00
17.42


ATOM
782
CB
ASP
A
313
−8.170
54.298
47.343
1.00
19.70


ATOM
783
CG
ASP
A
313
−9.106
53.244
46.797
1.00
22.89


ATOM
784
OD1
ASP
A
313
−9.073
52.935
45.598
1.00
24.60


ATOM
785
OD2
ASP
A
313
−9.841
52.697
47.623
1.00
26.78


ATOM
786
C
ASP
A
313
−6.273
52.903
46.539
1.00
14.58


ATOM
787
O
ASP
A
313
−6.033
53.570
45.533
1.00
14.85


ATOM
788
N
VAL
A
314
−6.101
51.596
46.588
1.00
15.33


ATOM
789
CA
VAL
A
314
−5.434
50.915
45.475
1.00
14.25


ATOM
790
CB
VAL
A
314
−5.067
49.478
45.891
1.00
13.94


ATOM
791
CG1
VAL
A
314
−6.266
48.578
46.107
1.00
12.58


ATOM
792
CG2
VAL
A
314
−4.090
48.891
44.864
1.00
12.94


ATOM
793
C
VAL
A
314
−6.110
50.966
44.129
1.00
14.22


ATOM
794
O
VAL
A
314
−5.480
51.152
43.099
1.00
13.01


ATOM
795
N
LYS
A
315
−7.435
50.819
44.092
1.00
16.35


ATOM
796
NZ
LYS
A
315
−12.342
48.884
46.668
1.00
27.78


ATOM
797
CE
LYS
A
315
−11.908
48.279
45.365
1.00
26.99


ATOM
798
CD
LYS
A
315
−11.499
49.287
44.334
1.00
24.72


ATOM
799
CG
LYS
A
315
−10.084
43.278
43.775
1.00
21.52


ATOM
800
CB
LYS
A
315
−9.700
50.621
43.204
1.00
18.30


ATOM
801
CA
LYS
A
315
−8.223
50.882
42.870
1.00
17.01


ATOM
802
C
LYS
A
315
−8.111
52.273
42.255
1.00
15.42


ATOM
803
O
LYS
A
315
−7.967
52.432
41.065
1.00
14.82


ATOM
804
N
MET
A
316
−8.189
53.317
43.095
1.00
16.67


ATOM
805
CA
MET
A
316
−8.023
54.673
42.531
1.00
16.96


ATOM
806
CB
MET
A
316
−8.396
55.717
43.579
1.00
19.66


ATOM
807
CG
MET
A
316
−9.874
55.516
43.966
1.00
21.49


ATOM
808
SD
MET
A
316
−10.303
56.858
45.216
1.00
25.95


ATOM
809
CE
MET
A
316
−11.921
56.212
45.655
1.00
23.70


ATOM
810
C
MET
A
316
−6.624
54.927
41.996
1.00
16.13


ATOM
811
O
MET
A
316
−6.463
55.672
41.038
1.00
16.38


ATOM
812
N
LEU
A
317
−5.583
54.315
42.552
1.00
15.29


ATOM
813
CA
LEU
A
317
−4.218
54.490
42.078
1.00
13.26


ATOM
814
CB
LEU
A
317
−3.200
53.915
43.097
1.00
11.74


ATOM
815
CG
LEU
A
317
−1.733
54.036
42.672
1.00
12.04


ATOM
816
CD1
LEU
A
317
−1.323
55.505
42.512
1.00
10.99


ATOM
817
CD2
LEU
A
317
−0.861
53.326
43.698
1.00
11.54


ATOM
818
C
LEU
A
317
−4.079
53.785
40.755
1.00
12.38


ATOM
819
O
LEU
A
317
−3.526
54.334
39.819
1.00
14.48


ATOM
820
N
LEU
A
318
−4.637
52.580
40.616
1.00
12.87


ATOM
821
CA
LEU
A
318
−4.561
51.890
39.326
1.00
12.84


ATOM
822
CB
LEU
A
318
−5.112
50.457
39.453
1.00
12.79


ATOM
823
CG
LEU
A
318
−4.966
49.629
38.170
1.00
14.82


ATOM
824
CD1
LEU
A
318
−3.531
49.542
37.700
1.00
15.86


ATOM
825
CD2
LEU
A
318
−5.558
48.241
38.355
1.00
14.73


ATOM
826
C
LEU
A
318
−5.230
52.673
38.218
1.00
12.07


ATOM
827
O
LEU
A
318
−4.780
52.829
37.099
1.00
12.74


ATOM
828
N
GLU
A
319
−6.420
53.193
38.511
1.00
15.24


ATOM
829
OE2
GLU
A
319
−11.483
52.210
39.220
1.00
28.26


ATOM
830
OE1
GLU
A
319
−10.797
54.093
40.042
1.00
29.42


ATOM
831
CD
GLU
A
319
−10.674
53.181
39.153
1.00
27.45


ATOM
832
CG
GLU
A
319
−9.561
53.233
38.177
1.00
24.55


ATOM
833
CB
GLU
A
319
−8.553
54.375
38.270
1.00
18.18


ATOM
834
CA
GLU
A
319
−7.199
54.025
37.614
1.00
15.25


ATOM
835
C
GLU
A
319
−6.421
55.288
37.289
1.00
14.06


ATOM
836
O
GLU
A
319
−6.317
55.697
36.141
1.00
13.57


ATOM
837
N
GLN
A
320
−5.879
55.947
38.303
1.00
14.48


ATOM
838
CA
GLN
A
320
−5.086
57.164
38.073
1.00
15.95


ATOM
839
CB
GLN
A
320
−4.631
57.772
39.413
1.00
17.37


ATOM
840
CG
GLN
A
320
−3.969
59.147
39.262
1.00
20.30


ATOM
841
CD
GLN
A
320
−4.917
60.189
38.681
1.00
20.82


ATOM
842
OE1
GLN
A
320
−6.069
60.198
39.101
1.00
22.55


ATOM
843
NE2
GLN
A
320
−4.480
61.016
37.768
1.00
20.50


ATOM
844
C
GLN
A
320
−3.896
56.849
37.206
1.00
15.14


ATOM
845
O
GLN
A
320
−3.545
57.572
36.274
1.00
16.35


ATOM
846
N
PHE
A
321
−3.178
55.751
37.535
1.00
14.19


ATOM
847
CA
PHE
A
321
−1.997
55.416
36.728
1.00
13.62


ATOM
848
CB
PHE
A
321
−1.389
54.100
37.277
1.00
14.84


ATOM
849
CG
PHE
A
321
−0.286
53.531
36.462
1.00
14.25


ATOM
850
CD1
PHE
A
321
0.874
54.232
36.256
1.00
16.53


ATOM
851
CD2
PHE
A
321
−0.407
52.275
35.889
1.00
15.71


ATOM
852
C61
PHE
A
321
1.915
53.714
35.499
1.00
16.96


ATOM
853
C62
PHE
A
321
0.594
51.737
35.109
1.00
16.98


ATOM
854
CZ
PHE
A
321
1.760
52.464
34.920
1.00
19.64


ATOM
855
C
PHE
A
321
−2.367
55.265
35.284
1.00
15.37


ATOM
856
O
PHE
A
321
−1.743
55.838
34.391
1.00
17.95


ATOM
857
N
SER
A
322
−3.440
54.502
35.011
1.00
15.65


ATOM
858
CA
SER
A
322
−3.862
54.261
33.650
1.00
16.47


ATOM
859
CB
SER
A
322
−5.052
53.312
33.545
1.00
17.62


ATOM
860
CG
SER
A
322
−4.956
52.111
34.281
1.00
21.90


ATOM
861
C
SER
A
322
−4.219
55.608
32.980
1.00
15.02


ATOM
862
O
SER
A
322
−3.836
55.773
31.839
1.00
15.73


ATOM
863
N
PHE
A
323
−4.855
56.499
33.694
1.00
15.76


ATOM
864
CA
PHE
A
323
−5.163
57.831
33.153
1.00
17.15


ATOM
865
CB
PHE
A
323
−5.953
58.697
34.136
1.00
18.22


ATOM
866
CG
PHE
A
323
−6.374
60.050
33.604
1.00
20.68


ATOM
867
CD1
PHE
A
323
−5.660
61.195
33.861
1.00
21.45


ATOM
868
CD2
PHE
A
323
−7.524
60.161
32.852
1.00
22.31


ATOM
869
CE1
PHE
A
323
−6.032
62.425
33.329
1.00
22.60


ATOM
870
CE2
PHE
A
323
−7.945
61.384
32.325
1.00
24.15


ATOM
871
CZ
PHE
A
323
−7.175
62.502
32.558
1.00
23.26


ATOM
872
C
PHE
A
323
−3.897
58.570
32.756
1.00
18.05


ATOM
873
O
PHE
A
323
−3.807
59.053
31.648
1.00
15.95


ATOM
874
N
ASP
A
324
−2.913
58.698
33.662
1.00
19.20


ATOM
875
CA
ASP
A
324
−1.748
59.521
33.405
1.00
20.57


ATOM
876
CB
ASP
A
324
−0.994
59.740
34.742
1.00
23.05


ATOM
877
CG
ASP
A
324
−1.773
60.624
35.687
1.00
23.08


ATOM
878
OD1
ASP
A
324
−1.894
60.419
36.896
1.00
22.69


ATOM
879
OD2
ASP
A
324
−2.335
61.620
35.188
1.00
26.34


ATOM
880
C
ASP
A
324
−0.746
58.999
32.402
1.00
21.82


ATOM
881
O
ASP
A
324
−0.058
59.793
31.764
1.00
21.73


ATOM
882
N
ILE
A
325
−0.672
57.679
32.240
1.00
21.33


ATOM
883
CA
ILE
A
325
0.264
57.038
31.339
1.00
22.61


ATOM
884
CB
ILE
A
325
0.922
55.889
32.161
1.00
25.69


ATOM
885
CG2
ILE
A
325
0.154
54.579
32.043
1.00
24.65


ATOM
886
CG1
ILE
A
325
2.370
55.730
31.765
1.00
26.90


ATOM
887
CD1
ILE
A
325
3.369
56.465
32.631
1.00
27.55


ATOM
888
C
ILE
A
325
−0.394
56.551
30.073
1.00
22.34


ATOM
889
O
ILE
A
325
0.238
55.950
29.209
1.00
19.22


ATOM
890
N
ALA
A
326
−1.663
56.970
23.849
1.00
21.30


ATOM
891
CA
ALA
A
326
−2.412
56.538
28.677
1.00
21.14


ATOM
892
CB
ALA
A
326
−3.743
57.301
28.568
1.00
20.96


ATOM
893
C
ALA
A
326
−1.701
56.616
27.350
1.00
20.02


ATOM
894
O
ALA
A
326
−1.716
55.660
26.557
1.00
18.13


ATOM
895
N
GLU
A
327
−1.087
57.750
27.055
1.00
21.17


ATOM
896
OE2
GLU
A
327
1.606
59.498
22.827
1.00
38.00


ATOM
897
OE1
GLU
A
327
−0.468
59.073
22.310
1.00
37.16


ATOM
898
CD
GLU
A
327
0.389
59.482
23.114
1.00
35.40


ATOM
889
CG
GLU
A
327
−0.062
59.993
24.456
1.00
33.57


ATOM
900
CB
GLU
A
327
0.333
59.223
25.685
1.00
26.72


ATOM
901
CA
GLU
A
327
−0.310
57.845
25.805
1.00
23.82


ATOM
902
C
GLU
A
327
0.748
56.760
25.705
1.00
20.97


ATOM
903
O
GLU
A
327
0.932
56.156
24.626
1.00
20.68


ATOM
904
N
GLU
A
328
1.536
56.501
26.758
1.00
20.00


ATOM
905
OE2
GLU
A
328
6.485
57.857
28.558
1.00
20.00


ATOM
906
OE1
GLU
A
328
5.550
56.151
29.650
1.00
20.00


ATOM
907
CD
GLU
A
328
5.561
56.965
28.651
1.00
20.00


ATOM
908
CG
GLU
A
328
4.474
56.875
27.579
1.00
20.00


ATOM
909
CB
GLU
A
328
3.625
55.608
27.694
1.00
20.00


ATOM
910
CA
GLU
A
328
2.584
55.483
26.582
1.00
20.00


ATOM
911
C
GLU
A
328
1.966
54.088
26.663
1.00
20.00


ATOM
912
O
GLU
A
328
2.420
53.176
25.932
1.00
20.00


ATOM
913
N
ALA
A
329
0.930
53.900
27.438
1.00
19.57


ATOM
914
CA
ALA
A
329
0.280
52.586
27.501
1.00
21.09


ATOM
915
CB
ALA
A
329
−0.828
52.628
28.545
1.00
20.52


ATOM
916
C
ALA
A
329
−0.292
52.148
26.167
1.00
21.74


ATOM
917
O
ALA
A
329
−0.460
50.963
25.860
1.00
22.92


ATOM
918
N
SER
A
330
−0.593
53.077
25.263
1.00
22.47


ATOM
919
CA
SER
A
330
−1.185
52.807
23.972
1.00
23.55


ATOM
920
CB
SER
A
330
−1.669
54.151
23.397
1.00
23.31


ATOM
921
OG
SER
A
330
−0.614
54.856
22.781
1.00
25.74


ATOM
922
C
SER
A
330
−0.209
52.129
23.038
1.00
23.79


ATOM
923
O
SER
A
330
−0.545
51.533
22.032
1.00
23.93


ATOM
924
N
LYS
A
331
1.073
52.141
23.385
1.00
20.00


ATOM
925
NZ
LYS
A
331
4.948
57.241
21.295
1.00
20.00


ATOM
926
CE
LYS
A
331
3.827
56.290
21.276
1.00
20.00


ATOM
927
CD
LYS
A
331
4.162
54.958
21.950
1.00
20.00


ATOM
928
CG
LYS
A
331
2.995
53.972
21.928
1.00
20.00


ATOM
929
CB
LYS
A
331
3.327
52.639
22.588
1.00
20.00


ATOM
930
CA
LYS
A
331
2.147
51.613
22.574
1.00
20.00


ATOM
933
C
LYS
A
331
2.659
50.261
22.982
1.00
20.00


ATOM
932
O
LYS
A
331
3.484
49.683
22.278
1.00
20.00


ATOM
933
N
VAL
A
332
2.207
49.748
24.112
1.00
21.24


ATOM
934
CA
VAL
A
332
2.660
48.458
24.592
1.00
19.62


ATOM
935
CB
VAL
A
332
3.467
48.639
25.296
1.00
20.18


ATOM
936
CG1
VAL
A
332
4.816
49.290
25.660
1.00
19.67


ATOM
937
CG2
VAL
A
332
2.651
49.433
26.897
1.00
18.82


ATOM
938
C
VAL
A
332
1.495
47.533
24.905
1.00
18.19


ATOM
939
O
VAL
A
332
0.344
47.965
24.964
1.00
18.61


ATOM
940
N
CYS
A
333
1.816
46.274
25.098
1.00
16.72


ATOM
941
CA
CYS
A
333
0.869
45.245
25.475
1.00
18.08


ATOM
942
CB
CYS
A
333
1.522
43.872
25.365
1.00
20.13


ATOM
943
SG
CYS
A
333
0.694
42.448
26.048
1.00
23.29


ATOM
944
C
CYS
A
333
0.346
45.494
26.878
1.00
16.83


ATOM
945
O
CYS
A
333
−0.855
45.347
27.075
1.00
15.63


ATOM
946
N
LEU
A
334
1.226
45.820
27.841
1.00
12.87


ATOM
947
CA
LEU
A
334
0.838
46.094
29.187
1.00
12.88


ATOM
948
CB
LEU
A
334
0.857
44.925
30.157
1.00
13.67


ATOM
949
CG
LEU
A
334
0.004
43.686
29.867
1.00
12.92


ATOM
950
CD1
LEU
A
334
0.432
42.513
30.699
1.00
9.29


ATOM
951
CD2
LEU
A
334
−1.465
44.030
30.158
1.00
10.80


ATOM
952
C
LEU
A
334
1.788
47.151
29.816
1.00
14.90


ATOM
953
O
LEU
A
334
2.929
47.313
29.428
1.00
13.88


ATOM
954
N
ALA
A
335
1.203
47.856
30.778
1.00
14.03


ATOM
955
CA
ALA
A
335
1.920
48.854
31.544
1.00
14.38


ATOM
956
CB
ALA
A
335
1.292
50.235
31.381
1.00
15.95


ATOM
957
C
ALA
A
335
1.859
48.404
32.991
1.00
13.27


ATOM
958
O
ALA
A
335
0.794
48.020
33.435
1.00
14.32


ATOM
959
N
HIS
A
336
2.936
48.458
33.750
1.00
12.02


ATOM
960
CA
HIS
A
336
2.886
43.039
35.141
1.00
10.67


ATOM
961
CB
HIS
A
336
3.543
46.555
35.252
1.00
9.55


ATOM
962
CG
HIS
A
336
3.104
45.503
36.449
1.00
12.03


ATOM
963
CD2
HIS
A
336
2.026
45.099
36.601
1.00
9.22


ATOM
964
ND1
HIS
A
336
3.730
45.915
37.686
1.00
11.53


ATOM
965
CE1
HIS
A
336
3.048
45.186
38.533
1.00
8.45


ATOM
966
NE2
HIS
A
336
1.995
44.711
37.891
1.00
12.17


ATOM
967
C
HIS
A
336
3.596
43.039
36.001
1.00
13.40


ATOM
968
O
HIS
A
336
4.669
49.576
35.641
1.00
13.52


ATOM
969
N
LEU
A
337
2.987
49.473
37.104
1.00
12.61


ATOM
970
CA
LEU
A
337
3.514
50.440
38.026
1.00
12.83


ATOM
971
CB
LEU
A
337
2.357
51.336
38.563
1.00
13.25


ATOM
972
CG
LEU
A
337
2.688
52.163
33.816
1.00
14.22


ATOM
973
CD1
LEU
A
337
3.886
53.054
39.540
1.00
14.34


ATOM
974
CD2
LEU
A
337
1.439
53.027
40.232
1.00
12.48


ATOM
975
C
LEU
A
337
4.137
49.730
39.243
1.00
11.76


ATOM
976
O
LEU
A
337
3.486
48.887
39.833
1.00
10.29


ATOM
977
N
PHE
A
338
5.396
50.012
39.548
1.00
11.12


ATOM
978
CA
PHE
A
338
6.001
49.502
40.775
1.00
9.77


ATOM
979
CB
PHE
A
338
7.378
48.877
40.584
1.00
10.95


ATOM
980
CG
PHE
A
338
7.336
47.661
39.688
1.00
10.01


ATOM
981
CD1
PHE
A
338
7.341
47.745
38.336
1.00
6.77


ATOM
982
CD2
PHE
A
338
7.347
46.392
40.263
1.00
10.50


ATOM
983
CE1
PHE
A
338
7.261
46.629
37.530
1.00
8.39


ATOM
984
CE2
PHE
A
338
7.260
45.254
39.504
1.00
7.33


ATOM
985
CZ
PHE
A
338
7.257
45.387
38.135
1.00
9.45


ATOM
986
C
PHE
A
338
6.093
50.673
41.742
1.00
10.02


ATOM
987
O
PHE
A
338
6.621
51.737
41.430
1.00
11.99


ATOM
988
N
THR
A
339
5.501
50.493
42.897
1.00
9.73


ATOM
989
CA
THR
A
339
5.455
51.468
43.940
1.00
12.72


ATOM
990
CB
THR
A
339
4.053
52.092
44.003
1.00
15.30


ATOM
991
OG1
THR
A
339
4.060
53.246
44.828
1.00
16.97


ATOM
992
CG2
THR
A
339
3.048
51.044
44.495
1.00
15.12


ATOM
993
C
THR
A
339
5.886
50.830
45.261
1.00
12.86


ATOM
994
O
THR
A
339
6.169
49.638
45.386
1.00
12.05


ATOM
995
N
TYR
A
340
5.954
51.663
46.268
1.00
11.17


ATOM
996
CA
TYR
A
340
6.323
51.315
47.616
1.00
11.82


ATOM
997
CB
TYR
A
340
7.823
51.632
47.844
1.00
10.81


ATOM
998
CG
TYR
A
340
8.342
51.050
49.121
1.00
11.94


ATOM
999
CD1
TYR
A
340
8.766
49.717
49.157
1.00
13.34


ATOM
1000
CE1
TYR
A
340
9.228
49.144
50.342
1.00
13.22


ATOM
1001
CD2
TYR
A
340
8.375
51.795
50.286
1.00
11.57


ATOM
1002
CE2
TYR
A
340
8.862
51.239
51.481
1.00
13.34


ATOM
1003
CZ
TYR
A
340
9.294
49.929
51.474
1.00
12.53


ATOM
1004
OH
TYR
A
340
9.708
49.349
52.630
1.00
13.01


ATOM
1005
C
TYR
A
340
5.422
52.066
48.560
1.00
12.56


ATOM
1006
O
TYR
A
340
5.784
53.138
49.086
1.00
13.24


ATOM
1007
N
GLN
A
341
4.248
51.479
48.801
1.00
12.63


ATOM
1008
CA
GLN
A
341
3.279
52.124
49.697
1.00
12.73


ATOM
1009
CB
GLN
A
341
2.457
53.199
48.996
1.00
15.96


ATOM
1010
CG
GLN
A
341
1.630
52.745
47.790
1.00
12.86


ATOM
1011
CD
GLN
A
341
1.063
53.915
47.015
1.00
14.37


ATOM
1012
OE1
GLN
A
341
0.019
54.455
47.412
1.00
14.26


ATOM
1013
NE2
GLN
A
341
1.690
54.336
45.913
1.00
12.87


ATOM
1014
C
GLN
A
341
2.409
51.026
50.281
1.00
13.05


ATOM
1015
O
GLN
A
341
2.135
50.001
49.651
1.00
12.36


ATOM
1016
N
ASP
A
342
2.036
51.214
51.518
1.00
11.62


ATOM
1017
CA
ASP
A
342
1.313
50.221
52.293
1.00
12.36


ATOM
1018
CB
ASP
A
342
1.766
50.350
53.748
1.00
11.58


ATOM
1019
CG
ASP
A
342
1.603
49.084
54.533
1.00
14.83


ATOM
1020
OD1
ASP
A
342
1.136
48.053
53.979
1.00
12.25


ATOM
1021
OD2
ASP
A
342
1.976
49.034
55.734
1.00
16.16


ATOM
1022
C
ASP
A
342
−0.202
50.344
52.159
1.00
13.76


ATOM
1023
O
ASP
A
342
−0.850
50.940
53.016
1.00
10.06


ATOM
1024
N
PHE
A
343
−0.705
49.804
51.047
1.00
12.77


ATOM
1025
CA
PHE
A
343
−2.123
49.686
50.828
1.00
13.67


ATOM
1026
CB
PHE
A
343
−2.407
48.846
49.572
1.00
11.23


ATOM
1027
CG
PHE
A
343
−1.813
49.447
48.336
1.00
13.10


ATOM
1028
CD1
PHE
A
343
−2.070
50.761
47.978
1.00
11.42


ATOM
1029
CD2
PHE
A
343
−0.968
48.703
47.519
1.00
11.91


ATOM
1030
CE1
PHE
A
343
−1.494
51.298
46.845
1.00
11.83


ATOM
1031
CE2
PHE
A
343
−0.431
49.235
46.395
1.00
13.17


ATOM
1032
CZ
PHE
A
343
−0.693
50.547
46.011
1.00
11.97


ATOM
1033
C
PHE
A
343
−2.827
49.073
52.018
1.00
13.82


ATOM
1034
O
PHE
A
343
−2.411
48.111
52.663
1.00
11.97


ATOM
1035
N
ASP
A
344
−3.976
49.646
52.364
1.00
14.70


ATOM
1036
CA
ASP
A
344
−4.734
49.159
53.500
1.00
16.30


ATOM
1037
CB
ASP
A
344
−6.066
49.896
53.688
1.00
19.86


ATOM
1038
CG
ASP
A
344
−5.919
51.270
54.287
1.00
24.51


ATOM
1039
OD1
ASP
A
344
−4.851
51.804
54.586
1.00
24.70


ATOM
1040
OD2
ASP
A
344
−6.983
51.916
54.436
1.00
27.18


ATOM
1041
C
ASP
A
344
−5.093
47.675
53.396
1.00
13.85


ATOM
1042
O
ASP
A
344
−5.208
47.157
52.310
1.00
9.77


ATOM
1043
N
MET
A
345
−5.213
47.069
54.564
1.00
13.16


ATOM
1044
CA
MET
A
345
−5.708
45.753
54.800
1.00
17.11


ATOM
1045
CB
MET
A
345
−7.235
45.710
54.450
1.00
23.01


ATOM
1046
CG
MET
A
345
−7.944
46.687
55.406
1.00
28.99


ATOM
1047
SD
MET
A
345
−9.349
45.913
56.215
1.00
39.05


ATOM
1048
CE
MET
A
345
−9.993
47.308
57.172
1.00
36.28


ATOM
1049
C
MET
A
345
−4.992
44.658
54.023
1.00
16.11


ATOM
1050
O
MET
A
345
−5.586
43.729
53.496
1.00
11.01


ATOM
1051
N
GLY
A
346
−3.649
44.811
53.976
1.00
13.02


ATOM
1052
CA
GLY
A
346
−2.848
43.775
53.364
1.00
12.48


ATOM
1053
C
GLY
A
346
−2.754
43.637
51.897
1.00
10.57


ATOM
1054
O
GLY
A
346
−2.092
42.654
51.492
1.00
10.20


ATOM
1055
N
THR
A
347
−3.392
44.516
51.092
1.00
10.34


ATOM
1056
CA
THR
A
347
−3.236
44.419
49.645
1.00
10.83


ATOM
1057
CB
THR
A
347
−4.204
45.426
48.958
1.00
11.57


ATOM
1058
OG1
THR
A
347
−5.515
45.104
49.474
1.00
11.02


ATOM
1059
CG2
THR
A
347
−4.265
45.214
47.479
1.00
9.59


ATOM
1060
C
THR
A
347
−1.836
44.663
49.119
1.00
11.95


ATOM
1061
O
THR
A
347
−1.160
45.651
49.506
1.00
10.72


ATOM
1062
N
LEU
A
348
−1.400
43.853
48.171
1.00
9.29


ATOM
1063
CA
LEU
A
348
−0.082
43.950
47.585
1.00
11.62


ATOM
1064
CB
LEU
A
348
0.550
42.518
47.580
1.00
11.68


ATOM
1065
CG
LEU
A
348
0.940
41.992
48.967
1.00
13.21


ATOM
1066
CD1
LEU
A
348
1.053
40.466
48.924
1.00
13.82


ATOM
1067
CD2
LEU
A
348
2.282
42.599
49.398
1.00
13.80


ATOM
1068
C
LEU
A
348
−0.066
44.478
46.170
1.00
10.00


ATOM
1069
O
LEU
A
348
0.889
45.107
45.724
1.00
10.81


ATOM
1070
N
GLY
A
349
−1.177
44.229
45.417
1.00
10.78


ATOM
1071
CA
GLY
A
349
−1.154
44.718
44.035
1.00
9.96


ATOM
1072
C
GLY
A
349
−2.577
44.686
43.420
1.00
11.05


ATOM
1073
O
GLY
A
349
−3.461
44.195
44.075
1.00
9.57


ATOM
1074
N
LEU
A
250
−2.667
45.177
42.201
1.00
12.61


ATOM
1075
CA
LEU
A
350
−4.033
45.102
41.592
1.00
12.78


ATOM
1076
CB
LEU
A
350
−4.766
46.348
42.090
1.00
13.89


ATOM
1077
CG
LEU
A
350
−6.279
46.356
41.850
1.00
16.31


ATOM
1078
CD1
LEU
A
350
−6.981
45.416
42.807
1.00
17.00


ATOM
1079
CD2
LEU
A
350
−6.786
47.797
41.945
1.00
15.79


ATOM
1080
C
LEU
A
350
−3.881
45.086
40.119
1.00
10.61


ATOM
1081
O
LEU
A
350
−2.867
45.625
39.674
1.00
9.12


ATOM
1082
N
ALA
A
351
−4.815
44.544
35.319
1.00
8.13


ATOM
1083
CA
ALA
A
351
−4.645
44.560
37.896
1.00
9.68


ATOM
1084
CB
ALA
A
351
−3.807
43.358
37.429
1.00
8.30


ATOM
1085
C
ALA
A
351
−6.006
44.393
37.158
1.00
8.00


ATOM
1086
O
ALA
A
351
−6.781
43.671
37.749
1.00
8.17


ATOM
1087
N
TYR
A
352
−6.102
44.923
35.997
1.00
10.56


ATOM
1088
CA
TYR
A
352
−7.378
44.669
35.243
1.00
11.99


ATOM
1089
CB
TYR
A
352
−7.517
45.727
34.152
1.00
13.49


ATOM
1090
CG
TYR
A
352
−7.816
47.102
34.704
1.00
16.49


ATOM
1091
CD1
TYR
A
352
−9.085
47.388
35.198
1.00
18.25


ATOM
1092
CE1
TYR
A
352
−9.369
48.643
35.704
1.00
18.58


ATOM
1093
CD2
TYR
A
352
−6.835
48.096
34.726
1.00
15.80


ATOM
1094
CE2
TYR
A
352
−7.121
49.344
35.231
1.00
17.33


ATOM
1095
CZ
TYR
A
352
−8.385
49.612
35.726
1.00
19.62


ATOM
1096
OH
TYE
A
352
−8.671
50.865
36.229
1.00
20.81


ATOM
1097
C
TYR
A
352
−7.306
43.297
34.623
1.00
11.61


ATOM
1098
O
TYR
A
352
−6.226
42.856
34.133
1.00
9.99


ATOM
1099
N
VAL
A
353
−8.414
42.569
34.618
1.00
9.19


ATOM
1100
CA
VAL
A
353
−8.433
41.240
34.027
1.00
9.63


ATOM
1101
CB
VAL
A
353
−9.532
40.388
34.675
1.00
12.16


ATOM
1102
CG1
VAL
A
353
−9.580
38.963
34.168
1.00
11.71


ATOM
1103
CG2
VAL
A
353
−9.337
40.459
36.180
1.00
11.77


ATOM
1104
C
VAL
A
353
−8.597
41.233
32.532
1.00
12.50


ATOM
1105
O
VAL
A
353
−9.522
41.869
32.012
1.00
12.29


ATOM
1106
N
GLY
A
354
−7.759
40.476
31.830
1.00
10.94


ATOM
1107
CA
GLY
A
354
−7.781
40.328
30.400
1.00
14.31


ATOM
1108
C
GLY
A
354
−8.927
39.377
29.976
1.00
14.67


ATOM
1109
O
GLY
A
354
−9.497
38.711
30.814
1.00
13.50


ATOM
1110
N
SER
A
355
−9.183
39.300
28.685
1.00
15.31


ATOM
1111
CA
SER
A
355
−10.226
38.340
28.254
1.00
18.47


ATOM
1112
CB
SER
A
355
−11.596
29.039
28.449
1.00
19.00


ATOM
1113
OG
SER
A
355
−12.631
38.360
27.760
1.00
21.32


ATOM
1114
C
SER
A
355
−9.959
38.049
26.808
1.00
17.63


ATOM
1115
O
SER
A
355
−9.378
38.937
26.168
1.00
18.38


ATOM
1116
N
PRO
A
356
−10.461
36.952
26.271
1.00
19.06


ATOM
1117
CD
PRO
A
356
−11.125
35.862
27.017
1.00
18.95


ATOM
1118
CA
PRO
A
356
−10.370
36.661
24.859
1.00
21.26


ATOM
1119
CB
PRO
A
356
−10.771
35.200
24.707
1.00
20.19


ATOM
1120
CG
PRO
A
356
−11.451
34.834
25.974
1.00
20.51


ATOM
1121
C
PRO
A
356
−11.357
37.502
24.051
1.00
24.27


ATOM
1122
O
PRO
A
356
−11.249
37.622
22.833
1.00
25.16


ATOM
1123
N
ARG
A
357
−12.369
38.028
24.714
1.00
27.47


ATOM
1124
NH2
ARG
A
357
−14.829
39.823
29.846
1.00
45.75


ATOM
1125
NH1
ARG
A
357
−15.278
41.187
28.059
1.00
45.46


ATOM
1126
CZ
ARG
A
357
−15.278
39.980
28.609
1.00
43.96


ATOM
1127
NE
ARG
A
357
−15.708
38.909
27.965
1.00
41.93


ATOM
1128
CD
ARG
A
357
−16.239
38.818
26.627
1.00
38.04


ATOM
1129
CG
ARG
A
357
−15.252
38.219
25.641
1.00
34.46


ATOM
1130
CB
ARG
A
357
−14.476
39.345
24.961
1.00
32.97


ATOM
1131
CA
ARG
A
357
−13.386
33.812
24.032
1.00
31.58


ATOM
1132
C
ARG
A
357
−12.777
39.943
23.231
1.00
33.38


ATOM
1133
O
ARG
A
357
−11.979
40.784
23.635
1.00
32.52


ATOM
1134
CB
ALA
A
358
−13.971
40.872
19.874
1.00
35.32


ATOM
1135
C
ALA
A
358
−12.904
42.350
21.524
1.00
36.30


ATOM
1136
O
ALA
A
358
−11.940
43.090
21.425
1.00
37.79


ATOM
1137
N
ALA
A
358
−13.235
39.948
21.981
1.00
35.10


ATOM
1138
CA
ALA
A
358
−12.901
40.933
20.979
1.00
36.40


ATOM
1139
N
ASN
A
359
−14.027
42.745
22.100
1.00
36.18


ATOM
1140
ND2
ASN
A
359
−17.589
44.247
20.981
1.00
38.54


ATOM
1141
OD1
ASN
A
359
−15.577
44.791
20.178
1.00
40.48


ATOM
1142
CG
ASN
A
359
−16.290
44.493
21.132
1.00
39.04


ATOM
1143
CB
ASN
A
359
−15.760
44.367
22.540
1.00
37.70


ATOM
1144
CA
ASN
A
359
−14.263
44.061
22.641
1.00
36.27


ATOM
1145
C
ASN
A
359
−13.834
44.198
24.094
1.00
35.65


ATOM
1146
O
ASN
A
359
−14.157
45.182
24.751
1.00
35.92


ATOM
1147
N
SER
A
360
−13.119
43.218
24.615
1.00
34.08


ATOM
1148
OG
SER
A
360
−10.429
42.540
26.749
1.00
34.50


ATOM
1149
CB
SER
A
360
−11.683
42.108
26.257
1.00
33.68


ATOM
1150
CA
SER
A
360
−12.647
43.261
25.982
1.00
32.95


ATOM
1151
C
SER
A
360
−11.907
44.577
26.260
1.00
30.62


ATOM
1152
O
SER
A
360
−11.073
45.055
25.505
1.00
29.59


ATOM
1153
N
HIS
A
361
−12.244
45.128
27.405
1.00
28.43


ATOM
1154
CD2
HIS
A
361
−14.316
47.743
26.576
1.00
37.21


ATOM
1155
NE2
HIS
A
361
−14.610
48.664
25.596
1.00
37.98


ATOM
1156
CE1
HIS
A
361
−13.624
49.531
25.503
1.00
37.94


ATOM
1157
ND1
HIS
A
361
−12.729
49.221
26.413
1.00
38.32


ATOM
1158
CG
HIS
A
361
−13.138
43.108
27.110
1.00
36.46


ATOM
1159
CB
HIS
A
361
−12.374
47.488
28.234
1.00
33.76


ATOM
1160
CA
HIS
A
361
−11.550
45.275
27.920
1.00
30.24


ATOM
1161
C
HIS
A
361
−10.928
45.653
29.193
1.00
29.98


ATOM
1162
O
HIS
A
361
−11.660
45.080
30.014
1.00
33.02


ATOM
1163
N
GLY
A
362
−9.625
45.543
29.184
1.00
25.53


ATOM
1164
CA
GLY
A
362
−8.942
45.064
30.372
1.00
20.70


ATOM
1165
C
GLY
A
362
−7.829
44.108
29.983
1.00
16.68


ATOM
1166
O
GLY
A
362
−7.986
43.330
29.056
1.00
12.10


ATOM
1167
N
GLY
A
363
−6.695
44.301
30.672
1.00
13.81


ATOM
1168
CA
GLY
A
363
−5.648
43.339
30.406
1.00
14.18


ATOM
1169
C
GLY
A
363
−4.908
43.513
29.110
1.00
13.66


ATOM
1170
O
GLY
A
363
−4.808
44.608
28.557
1.00
12.16


ATOM
1171
N
VAL
A
364
−4.310
42.413
28.673
1.00
14.17


ATOM
1172
CG2
VAL
A
364
−4.030
40.030
27.062
1.00
15.53


ATOM
1173
CG1
VAL
A
364
−1.902
40.628
28.266
1.00
15.36


ATOM
1174
CB
VAL
A
364
−2.897
41.047
27.174
1.00
18.71


ATOM
1175
CA
VAL
A
364
−3.455
42.442
27.502
1.00
17.47


ATOM
1176
C
VAL
A
364
−4.138
43.070
26.294
1.00
22.13


ATOM
1177
O
VAL
A
364
−5.313
42.870
26.039
1.00
18.74


ATOM
1178
N
CYS
A
365
−3.323
43.852
25.611
1.00
26.09


ATOM
1179
SG
CYS
A
365
−3.257
42.201
22.935
1.00
38.70


ATOM
1180
CB
CYS
A
365
−4.184
43.720
23.283
1.00
34.15


ATOM
1181
CA
CYS
A
365
−3.608
44.572
24.400
1.00
32.02


ATOM
1182
C
CYS
A
365
−4.433
45.808
24.718
1.00
32.84


ATOM
1183
O
CYS
A
365
−5.505
45.800
25.307
1.00
33.41


ATOM
1184
N
PRO
A
366
−3.826
46.943
24.391
1.00
34.94


ATOM
1185
CG
PRO
A
366
−2.315
48.596
23.731
1.00
34.57


ATOM
1186
CD
PRO
A
366
−2.542
47.119
23.698
1.00
34.14


ATOM
1187
CB
PRO
A
366
−3.403
49.216
24.501
1.00
35.23


ATOM
1188
CA
PRO
A
366
−4.515
48.220
24.644
1.00
35.75


ATOM
1189
C
PRO
A
366
−5.714
48.244
23.715
1.00
36.16


ATOM
1190
O
PRO
A
366
−5.574
47.917
22.548
1.00
38.73


ATOM
1191
N
LYS
A
367
−6.905
48.420
24.211
1.00
36.55


ATOM
1192
NZ
LYS
A
367
−11.060
46.083
19.713
1.00
39.83


ATOM
1193
CE
LYS
A
367
−10.945
46.830
20.990
1.00
39.58


ATOM
1194
CD
LYS
A
367
−10.461
45.989
22.141
1.00
39.79


ATOM
1195
CG
LYS
A
367
−9.071
46.373
22.617
1.00
39.82


ATOM
1196
CB
LYS
A
367
−9.031
47.227
23.867
1.00
36.78


ATOM
1197
CA
LYS
A
367
−8.228
48.530
23.676
1.00
37.98


ATOM
1198
C
LYS
A
367
−8.995
49.679
24.375
1.00
36.54


ATOM
1199
O
LYS
A
367
−9.725
49.528
25.366
1.00
33.85


ATOM
1200
N
ALA
A
368
−8.855
50.888
23.839
1.00
35.07


ATOM
1201
CA
ALA
A
368
−9.376
52.113
24.400
1.00
32.73


ATOM
1202
CB
ALA
A
368
−9.170
53.209
23.330
1.00
34.00


ATOM
1203
C
ALA
A
368
−10.770
52.317
24.933
1.00
32.95


ATOM
1204
O
ALA
A
368
−11.784
51.928
24.364
1.00
32.14


ATOM
1205
N
TYR
A
369
−10.878
53.117
25.991
1.00
31.03


ATOM
1206
CA
TYR
A
369
−12.087
53.643
26.567
1.00
32.06


ATOM
1207
CB
TYR
A
369
−12.264
53.583
28.057
1.00
34.85


ATOM
1208
CG
TYR
A
369
−13.026
52.465
28.689
1.00
37.47


ATOM
1209
CD1
TYR
A
369
−12.349
51.435
29.321
1.00
38.45


ATOM
1210
CE1
TYR
A
369
−13.025
50.390
29.914
1.00
39.73


ATOM
1211
CD2
TYR
A
369
−14.410
52.415
28.669
1.00
39.08


ATOM
1212
CE2
TYR
A
369
−15.096
51.380
29.271
1.00
40.46


ATOM
1213
CZ
TYR
A
369
−14.397
50.369
29.891
1.00
41.04


ATOM
1214
OH
TYR
A
369
−15.067
49.320
30.483
1.00
42.68


ATOM
1215
C
TYR
A
369
−11.953
55.158
26.287
1.00
32.03


ATOM
1216
O
TYR
A
369
−10.842
55.634
26.529
1.00
28.95


ATOM
1217
N
TYR
A
370
−12.996
55.828
25.851
1.00
32.03


ATOM
1218
OH
TYR
A
370
−13.216
63.382
23.761
1.00
38.96


ATOM
1219
CD2
TYR
A
370
−14.752
60.205
24.698
1.00
36.28


ATOM
1220
CE2
TYR
A
370
−14.597
61.568
24.490
1.00
36.78


ATOM
1221
CZ
TYR
A
370
−13.409
62.034
23.975
1.00
37.70


ATOM
1222
CE1
TYR
A
370
−12.383
61.168
23.662
1.00
36.85


ATOM
1223
CD1
TYR
A
370
−12.563
59.820
23.871
1.00
35.73


ATOM
1224
CG
TYR
A
370
−13.741
59.312
24.388
1.00
35.35


ATOM
1225
CB
TYR
A
370
−13.896
57.816
24.613
1.00
34.74


ATOM
1226
CA
TYR
A
370
−12.850
57.254
25.574
1.00
33.23


ATOM
1227
C
TYR
A
370
−12.982
57.999
26.897
1.00
33.56


ATOM
1228
O
TYR
A
370
−13.819
57.580
27.684
1.00
33.28


ATOM
1229
N
SER
A
371
−12.169
59.015
27.125
1.00
35.61


ATOM
1230
OG
SER
A
371
−10.952
60.534
30.263
1.00
37.79


ATOM
1231
CB
SER
A
371
−10.994
59.623
29.183
1.00
39.02


ATOM
1232
CA
SER
A
371
−12.297
59.726
28.389
1.00
38.04


ATOM
1233
C
SER
A
371
−12.666
61.187
28.201
1.00
39.91


ATOM
1234
O
SER
A
371
−11.843
62.022
27.853
1.00
38.57


ATOM
1235
N
PRO
A
372
−13.931
61.484
28.820
1.00
43.18


ATOM
1236
CG
PRO
A
372
−16.243
61.324
28.452
1.00
44.76


ATOM
1237
CD
PRO
A
372
−15.008
60.574
28.867
1.00
44.03


ATOM
1238
CB
PRO
A
372
−15.900
62.772
28.425
1.00
45.09


ATOM
1239
CA
PRO
A
372
−14.403
62.878
28.437
1.00
45.43


ATOM
1240
C
PRO
A
372
−13.833
63.366
29.760
1.00
46.59


ATOM
1241
O
PRO
A
372
−14.102
62.743
30.789
1.00
47.64


ATOM
1242
N
VAL
A
373
−12.978
64.362
25.767
1.00
48.18


ATOM
1243
CG2
VAL
A
373
−13.693
65.070
32.937
1.00
48.74


ATOM
1244
CG1
VAL
A
373
−11.354
64.454
33.270
1.00
48.15


ATOM
1245
CB
VAL
A
373
−12.534
64.295
32.314
1.00
48.02


ATOM
1246
CA
VAL
A
373
−12.176
64.754
30.916
1.00
47.53


ATOM
1247
C
VAL
A
373
−10.843
64.081
30.527
1.00
47.84


ATOM
1248
O
VAL
A
373
−10.706
62.871
30.685
1.00
48.07


ATOM
1249
N
GLY
A
374
−9.966
64.870
29.936
1.00
46.71


ATOM
1250
CA
GLY
A
374
−8.687
64.329
29.474
1.00
45.92


ATOM
1251
C
GLY
A
374
−8.718
64.327
27.946
1.00
44.34


ATOM
1252
O
GLY
A
374
−7.703
64.386
27.276
1.00
43.53


ATOM
1253
N
LYS
A
375
−9.937
64.227
27.433
1.00
20.00


ATOM
1254
NZ
LYS
A
375
−11.621
70.469
25.481
1.00
20.00


ATOM
1255
CE
LYS
A
375
−11.822
69.108
25.996
1.00
20.00


ATOM
1256
CD
LYS
A
375
−10.786
68.111
25.474
1.00
20.00


ATOM
1257
CG
LYS
A
375
−10.999
66.697
26.013
1.00
20.00


ATOM
1258
CB
LYS
A
375
−9.976
65.697
25.486
1.00
20.00


ATOM
1259
CA
LYS
A
375
−10.201
64.262
26.011
1.00
20.00


ATOM
1260
C
LYS
A
375
−9.308
63.297
25.260
1.00
20.00


ATOM
1261
O
LYS
A
375
−8.529
63.725
24.411
1.00
20.00


ATOM
1262
N
LYS
A
376
−9.385
62.003
25.604
1.00
20.00


ATOM
1263
NZ
LYS
A
376
−3.285
64.692
24.559
1.00
20.00


ATOM
1264
CE
LYS
A
376
−4.696
64.381
24.290
1.00
20.00


ATOM
1265
CD
LYS
A
376
−5.139
63.045
24.890
1.00
20.00


ATOM
1266
CG
LYS
A
376
−6.606
62.726
24.608
1.00
20.00


ATOM
1267
CB
LYS
A
376
−7.050
61.390
25.194
1.00
20.00


ATOM
1268
CA
LYS
A
376
−8.531
61.050
24.897
1.00
20.00


ATOM
1269
C
LYS
A
376
−8.810
59.601
25.286
1.00
20.00


ATOM
1270
O
LYS
A
376
−9.696
59.281
26.077
1.00
20.00


ATOM
1271
N
ASN
A
377
−8.050
53.726
24.640
1.00
29.74


ATOM
1272
CA
ASN
A
377
−8.240
57.295
24.862
1.00
29.33


ATOM
1273
CB
ASN
A
377
−7.825
56.539
23.612
1.00
29.66


ATOM
1274
CG
ASN
A
377
−8.743
56.803
22.433
1.00
30.76


ATOM
1275
OD1
ASN
A
377
−9.964
56.948
22.559
1.00
29.66


ATOM
1276
ND2
ASN
A
377
−8.128
56.865
21.249
1.00
31.26


ATOM
1277
C
ASN
A
377
−7.486
56.848
26.098
1.00
28.35


ATOM
1278
O
ASN
A
377
−6.411
57.376
26.306
1.00
26.83


ATOM
1279
N
ILE
A
378
−8.123
56.055
26.952
1.00
26.88


ATOM
1280
CA
ILE
A
378
−7.431
55.408
25.039
1.00
28.08


ATOM
1281
CB
ILE
A
378
−7.802
55.780
29.473
1.00
29.37


ATOM
1282
CG2
ILE
A
378
−7.624
57.282
29.706
1.00
28.66


ATOM
1283
CG1
ILE
A
378
−9.217
55.317
29.789
1.00
31.06


ATOM
1284
CD1
ILE
A
378
−9.563
55.101
31.261
1.00
32.92


ATOM
1285
C
ILE
A
378
−7.567
53.887
27.882
1.00
26.65


ATOM
1286
O
ILE
A
378
−8.559
53.283
27.473
1.00
25.21


ATOM
1287
N
TYR
A
379
−6.456
53.246
28.250
1.00
25.14


ATOM
1288
CA
TYR
A
379
−6.298
51.805
28.141
1.00
23.62


ATOM
1289
CB
TYR
A
379
−5.057
51.473
27.299
1.00
25.30


ATOM
1290
CG
TYR
A
379
−5.076
52.202
25.979
1.00
27.60


ATOM
1291
CD1
TYR
A
379
−4.644
53.523
25.919
1.00
28.62


ATOM
1292
CE1
TYR
A
379
−4.683
54.224
24.736
1.00
30.42


ATOM
1293
CD2
TYR
A
379
−5.571
51.619
24.836
1.00
28.58


ATOM
1294
CE2
TYR
A
379
−5.582
52.298
23.534
1.00
29.43


ATOM
1295
CZ
TYR
A
379
−5.141
53.597
23.603
1.00
30.50


ATOM
1296
OH
TYR
A
379
−5.162
54.325
22.441
1.00
33.44


ATOM
1297
C
TYR
A
379
−6.141
51.154
29.498
1.00
22.07


ATOM
1298
O
TYR
A
379
−5.164
51.460
30.204
1.00
22.84


ATOM
1299
N
LEU
A
380
−6.941
50.122
29.768
1.00
16.20


ATOM
1300
CA
LEU
A
380
−6.831
49.396
30.998
1.00
17.68


ATOM
1301
CB
LEU
A
380
−8.233
49.019
31.490
1.00
19.14


ATOM
1302
CG
LEU
A
380
−9.204
50.207
31.624
1.00
21.74


ATOM
1303
CD1
LEU
A
380
−10.479
49.690
32.285
1.00
22.06


ATOM
1304
CD2
LEU
A
380
−8.614
51.364
32.411
1.00
20.08


ATOM
1305
C
LEU
A
380
−5.903
48.191
30.845
1.00
13.92


ATOM
1306
O
LEU
A
380
−6.249
47.139
31.351
1.00
12.26


ATOM
1307
N
ASN
A
381
−4.762
48.385
30.190
1.00
14.40


ATOM
1308
CA
ASN
A
381
−3.798
47.282
30.009
1.00
15.71


ATOM
1309
CB
ASN
A
381
−3.148
47.364
28.646
1.00
13.12


ATOM
1310
CG
ASN
A
381
−2.442
48.681
28.373
1.00
13.93


ATOM
1311
OD1
ASN
A
381
−2.614
49.693
29.057
1.00
15.98


ATOM
1312
ND2
ASN
A
381
−1.584
48.766
27.386
1.00
13.77


ATOM
1313
C
ASN
A
381
−2.732
47.428
31.111
1.00
15.34


ATOM
1314
O
ASN
A
381
−1.538
47.496
30.826
1.00
19.25


ATOM
1315
N
SER
A
382
−3.178
47.587
32.318
1.00
14.28


ATOM
1316
CA
SER
A
382
−2.363
47.953
33.462
1.00
16.49


ATOM
1317
CB
SER
A
382
−2.722
49.449
33.712
1.00
19.36


ATOM
1318
OG
SER
A
382
−4.021
49.622
34.261
1.00
19.22


ATOM
1319
C
SER
A
382
−2.534
47.168
34.720
1.00
13.50


ATOM
1320
O
SER
A
382
−3.491
46.443
34.986
1.00
14.79


ATOM
1321
N
GLY
A
383
−1.543
47.226
35.602
1.00
12.08


ATOM
1322
CA
GLY
A
383
−1.460
46.552
36.865
1.00
7.68


ATOM
1323
C
GLY
A
383
−0.407
47.250
37.737
1.00
9.13


ATOM
1324
O
GLY
A
383
0.356
48.018
37.167
1.00
7.23


ATOM
1325
N
LEU
A
384
−0.406
46.961
39.018
1.00
9.60


ATOM
1326
CA
LEU
A
384
0.596
47.604
39.860
1.00
10.98


ATOM
1327
CB
LEU
A
384
0.108
48.911
40.437
1.00
10.87


ATOM
1328
CG
LEU
A
384
−1.098
48.840
41.372
1.00
12.55


ATOM
1329
CD1
LEU
A
384
−0.751
48.583
42.819
1.00
11.84


ATOM
1330
CD2
LEU
A
384
−1.824
50.197
41.305
1.00
14.27


ATOM
1331
C
LEU
A
384
0.963
46.614
40.982
1.00
11.40


ATOM
1332
O
LEU
A
384
0.191
45.705
41.269
1.00
12.17


ATOM
1333
N
THR
A
385
2.174
46.774
41.470
1.00
10.30


ATOM
1334
CA
THR
A
385
2.773
45.977
42.535
1.00
10.05


ATOM
1335
CB
THR
A
385
3.958
45.170
41.969
1.00
11.82


ATOM
1336
OG1
THR
A
385
3.463
44.161
41.100
1.00
12.53


ATOM
1337
CG2
THR
A
385
4.842
44.430
42.991
1.00
7.93


ATOM
1338
C
THR
A
385
3.429
46.936
43.546
1.00
10.37


ATOM
1339
O
THR
A
385
4.154
47.869
43.150
1.00
10.04


ATOM
1340
N
SER
A
386
3.153
46.751
44.806
1.00
10.16


ATOM
1341
CA
SER
A
386
3.835
47.470
45.853
1.00
12.08


ATOM
1342
CB
SER
A
386
2.913
47.978
46.925
1.00
12.65


ATOM
1343
OG
SER
A
386
3.625
48.590
47.976
1.00
12.90


ATOM
1344
C
SER
A
386
4.773
46.445
46.540
1.00
11.71


ATOM
1345
O
SER
A
386
4.348
45.314
46.714
1.00
11.70


ATOM
1346
N
THR
A
387
5.929
46.899
46.978
1.00
13.21


ATOM
1347
CA
THR
A
387
6.861
46.004
47.677
1.00
11.54


ATOM
1348
CB
THR
A
387
8.258
45.976
47.083
1.00
12.46


ATOM
1349
OG1
THR
A
387
8.794
47.305
46.902
1.00
12.52


ATOM
1350
CG2
THR
A
387
8.193
45.224
45.771
1.00
9.84


ATOM
1351
C
THR
A
387
6.917
46.429
49.137
1.00
12.59


ATOM
1352
O
THR
A
387
7.750
45.916
49.857
1.00
9.86


ATOM
1353
N
LYS
A
388
5.888
47.176
49.559
1.00
10.11


ATOM
1354
CA
LYS
A
388
5.781
47.451
50.983
1.00
11.18


ATOM
1355
CB
LYS
A
388
5.844
48.928
51.315
1.00
10.27


ATOM
1356
CG
LYS
A
388
5.598
49.163
52.809
1.00
11.78


ATOM
1357
CD
LYS
A
388
5.570
50.665
53.086
1.00
12.59


ATOM
1358
CE
LYS
A
388
5.610
50.846
54.616
1.00
12.42


ATOM
1359
NZ
LYS
A
388
5.400
52.289
54.915
1.00
12.86


ATOM
1360
C
LYS
A
388
4.466
46.836
51.470
1.00
12.79


ATOM
1361
O
LYS
A
388
3.445
47.068
50.803
1.00
13.47


ATOM
1362
N
ASN
A
389
4.490
46.117
52.561
1.00
11.20


ATOM
1363
CA
ASN
A
389
3.235
45.595
53.114
1.00
13.05


ATOM
1364
CB
ASN
A
389
2.797
44.247
52.498
1.00
9.98


ATOM
1365
CG
ASN
A
389
1.328
43.929
52.695
1.00
13.57


ATOM
1366
OD1
ASN
A
389
0.562
44.523
53.020
1.00
11.41


ATOM
1367
ND2
ASN
A
389
0.828
42.697
52.544
1.00
11.87


ATOM
1368
C
ASN
A
389
3.401
45.431
54.605
1.00
12.01


ATOM
1369
O
ASN
A
389
4.389
44.832
55.045
1.00
12.68


ATOM
1370
N
TYR
A
390
2.463
45.891
55.415
1.00
9.33


ATOM
1371
CA
TYR
A
390
2.544
45.725
56.834
1.00
11.32


ATOM
1372
CB
TYR
A
390
2.395
44.317
57.360
1.00
13.01


ATOM
1373
CG
TYR
A
390
1.034
43.646
57.138
1.00
17.63


ATOM
1374
CD1
TYR
A
390
0.888
42.699
56.135
1.00
17.99


ATOM
1375
CE1
TYR
A
390
−0.324
42.059
55.906
1.00
18.34


ATOM
1376
CD2
TYR
A
390
−0.059
43.050
57.918
1.00
17.56


ATOM
1377
CE2
TYR
A
390
−1.295
43.344
57.684
1.00
19.81


ATOM
1378
CZ
TYR
A
390
−1.408
42.399
56.685
1.00
18.72


ATOM
1379
OH
TYR
A
390
−2.599
41.770
56.456
1.00
18.16


ATOM
1380
C
TYR
A
390
3.875
46.390
57.342
1.00
11.32


ATOM
1381
O
TYR
A
390
4.444
45.867
58.262
1.00
10.06


ATOM
1382
N
GLY
A
391
4.202
47.568
56.849
1.00
12.38


ATOM
1383
CA
GLY
A
391
5.264
48.396
57.395
1.00
13.46


ATOM
1384
C
GLY
A
391
6.671
47.822
57.226
1.00
14.75


ATOM
1385
O
GLY
A
391
7.615
48.218
57.920
1.00
13.47


ATOM
1386
N
LYS
A
392
6.864
47.001
56.213
1.00
14.18


ATOM
1387
NZ
LYS
A
392
6.391
42.087
59.901
1.00
31.24


ATOM
1388
CE
LYS
A
392
6.545
43.004
58.726
1.00
30.06


ATOM
1389
CD
LYS
A
392
7.980
43.237
58.298
1.00
27.75


ATOM
1390
CG
LYS
A
392
8.231
44.701
57.942
1.00
25.41


ATOM
1391
CB
LYS
A
392
8.133
44.929
56.460
1.00
20.56


ATOM
1392
CA
LYS
A
392
8.133
46.376
55.909
1.00
15.94


ATOM
1393
C
LYS
A
392
8.265
46.221
54.399
1.00
14.65


ATOM
1394
O
LYS
A
392
7.242
46.070
53.676
1.00
12.21


ATOM
1395
N
THR
A
393
9.481
45.969
53.965
1.00
9.88


ATOM
1396
CA
THR
A
393
9.744
45.629
52.574
1.00
10.28


ATOM
1397
CB
THR
A
393
11.178
45.988
52.156
1.00
10.31


ATOM
1398
OG1
THR
A
393
11.412
47.397
52.330
1.00
9.91


ATOM
1399
CG2
THR
A
393
11.393
45.631
50.693
1.00
7.93


ATOM
1400
C
THR
A
393
9.450
44.139
52.450
1.00
11.39


ATOM
1401
O
THR
A
393
9.872
43.332
53.278
1.00
11.16


ATOM
1402
N
ILE
A
394
8.715
43.737
51.398
1.00
8.47


ATOM
1403
CA
ILE
A
394
8.413
42.305
51.297
1.00
8.59


ATOM
1404
CB
ILE
A
394
7.223
42.076
50.329
1.00
7.43


ATOM
1405
CG2
ILE
A
394
6.044
42.929
50.867
1.00
5.89


ATOM
1406
CG1
ILE
A
394
7.562
42.401
48.910
1.00
7.72


ATOM
1407
CD1
ILE
A
394
6.413
42.268
47.877
1.00
9.17


ATOM
1408
C
ILE
A
394
9.657
41.573
50.761
1.00
9.33


ATOM
1409
O
ILE
A
394
10.482
42.262
50.170
1.00
8.55


ATOM
1410
N
LEU
A
395
9.689
40.276
50.913
1.00
7.97


ATOM
1411
CA
LEU
A
395
10.808
39.499
50.347
1.00
11.81


ATOM
1412
CB
LEU
A
395
10.545
37.998
50.620
1.00
12.21


ATOM
1413
CG
LEU
A
395
10.370
37.651
52.090
1.00
13.09


ATOM
1414
CD1
LEU
A
395
10.246
36.140
52.313
1.00
10.90


ATOM
1415
CD2
LEU
A
395
11.569
38.245
52.832
1.00
13.70


ATOM
1416
C
LEU
A
395
10.920
39.603
48.860
1.00
13.57


ATOM
1417
O
LEU
A
395
9.864
39.692
48.193
1.00
11.36


ATOM
1418
N
THR
A
396
12.089
39.426
48.281
1.00
9.31


ATOM
1419
CA
THR
A
396
12.273
39.345
46.840
1.00
11.95


ATOM
1420
CB
THR
A
396
13.746
39.021
46.476
1.00
14.52


ATOM
1421
OG1
THR
A
396
14.575
40.034
47.090
1.00
16.31


ATOM
1422
CG2
THR
A
396
13.983
39.148
44.996
1.00
16.49


ATOM
1423
C
THR
A
396
11.376
38.264
46.208
1.00
12.19


ATOM
1424
O
THR
A
396
10.790
38.544
45.152
1.00
11.09


ATOM
1425
N
LYS
A
397
11.286
37.104
46.840
1.00
9.73


ATOM
1426
CA
LYS
A
397
10.451
36.033
46.298
1.00
12.22


ATOM
1427
CB
LYS
A
397
10.630
34.680
44.935
1.00
11.19


ATOM
1428
CG
LYS
A
397
10.365
34.491
48.402
1.00
10.22


ATOM
1429
CD
LYS
A
397
10.459
32.971
48.678
1.00
12.87


ATOM
1430
CE
LYS
A
397
9.904
32.634
50.049
1.00
10.59


ATOM
1431
NZ
LYS
A
397
10.430
31.409
50.690
1.00
13.72


ATOM
1432
C
LYS
A
397
8.946
36.390
46.379
1.00
11.16


ATOM
1433
O
LYS
A
397
8.250
35.937
45.488
1.00
10.09


ATOM
1434
N
GLU
A
398
8.588
37.196
47.346
1.00
10.22


ATOM
1435
CA
GLU
A
398
7.207
37.628
47.475
1.00
13.12


ATOM
1436
CB
GLU
A
398
6.931
38.233
48.857
1.00
11.64


ATOM
1437
CG
GLU
A
398
6.951
37.079
49.876
1.00
15.45


ATOM
1438
CD
GLU
A
398
6.952
37.662
51.284
1.00
15.72


ATOM
1439
OE1
GLU
A
398
7.139
38.861
51.557
1.00
15.77


ATOM
1440
OE2
GLU
A
398
6.722
36.861
52.186
1.00
17.81


ATOM
1441
C
GLU
A
398
6.875
38.628
46.374
1.00
14.23


ATOM
1442
O
GLU
A
398
5.819
38.496
45.746
1.00
11.36


ATOM
1443
N
ALA
A
399
7.791
39.566
46.144
1.00
11.71


ATOM
1444
CA
ALA
A
399
7.603
40.571
45.121
1.00
10.93


ATOM
1445
CB
ALA
A
399
8.705
41.611
45.021
1.00
10.46


ATOM
1446
C
ALA
A
399
7.464
39.901
43.737
1.00
11.66


ATOM
1447
O
ALA
A
399
6.535
40.310
43.047
1.00
8.52


ATOM
1448
N
ASP
A
400
5.259
38.892
43.411
1.00
10.58


ATOM
1449
CA
ASP
A
400
8.092
38.272
42.164
1.00
11.27


ATOM
1450
CB
ASP
A
400
9.061
37.001
41.994
1.00
13.33


ATOM
1451
CG
ASP
A
400
10.525
37.443
41.936
1.00
15.25


ATOM
1452
OD1
ASP
A
400
10.787
38.685
41.868
1.00
11.52


ATOM
1453
OD2
ASP
A
400
11.331
36.459
41.963
1.00
15.55


ATOM
1454
C
ASP
A
400
6.682
37.543
42.061
1.00
10.74


ATOM
1455
O
ASP
A
400
6.102
37.681
40.959
1.00
11.54


ATOM
1456
N
LEU
A
401
6.184
37.034
43.153
1.00
9.91


ATOM
1457
CA
LEU
A
401
4.860
36.399
43.132
1.00
12.48


ATOM
1458
CB
LEU
A
401
4.618
35.610
44.411
1.00
13.67


ATOM
1459
CG
LEU
A
401
5.551
34.464
44.805
1.00
19.11


ATOM
1460
CD1
LEU
A
401
5.596
34.451
46.337
1.00
20.83


ATOM
1461
CD2
LEU
A
401
5.072
33.125
44.302
1.00
19.44


ATOM
1462
C
LEU
A
401
3.724
37.434
42.994
1.00
11.96


ATOM
1463
O
LEU
A
401
2.701
37.092
42.388
1.00
9.62


ATOM
1464
N
VAL
A
402
3.849
38.626
43.576
1.00
9.23


ATOM
1465
CA
VAL
A
402
2.656
39.664
43.347
1.00
10.16


ATOM
1466
CB
VAL
A
402
3.222
40.976
44.086
1.00
11.53


ATOM
1467
CG1
VAL
A
402
2.219
42.096
43.805
1.00
10.53


ATOM
1468
CG2
VAL
A
402
3.254
40.598
45.565
1.00
8.46


ATOM
1469
C
VAL
A
402
2.701
40.016
41.882
1.00
12.23


ATOM
1470
O
VAL
A
402
1.581
40.096
41.336
1.00
9.50


ATOM
1471
N
THR
A
403
3.821
40.359
41.261
1.00
8.92


ATOM
1472
CA
THR
A
403
3.845
40.764
39.883
1.00
8.22


ATOM
1473
CB
THR
A
403
5.220
41.259
39.386
1.00
6.99


ATOM
1474
OG1
THR
A
403
5.612
42.325
40.255
1.00
6.97


ATOM
1475
CG2
THR
A
403
5.221
41.841
37.998
1.00
6.87


ATOM
1476
C
THR
A
403
3.381
39.610
38.992
1.00
9.35


ATOM
1477
O
THR
A
403
2.693
39.954
38.016
1.00
5.99


ATOM
1478
N
THR
A
404
3.855
38.407
39.301
1.00
6.34


ATOM
1479
CA
THR
A
404
3.382
37.249
38.521
1.00
7.96


ATOM
1480
CB
THR
A
404
3.962
35.946
39.104
1.00
8.71


ATOM
1481
OG1
THR
A
404
5.404
35.959
38.945
1.00
8.46


ATOM
1482
CG2
THR
A
404
3.448
34.743
38.303
1.00
8.11


ATOM
1483
C
THR
A
404
1.842
37.175
38.572
1.00
6.99


ATOM
1484
O
THR
A
404
1.211
36.979
37.529
1.00
6.33


ATOM
1485
N
HIS
A
405
1.298
37.277
39.751
1.00
6.76


ATOM
1486
CA
HIS
A
405
−0.132
37.232
40.003
1.00
9.62


ATOM
1487
CB
HIS
A
405
−0.383
37.343
41.495
1.00
7.56


ATOM
1488
CG
HIS
A
405
−1.828
37.311
41.919
1.00
6.65


ATOM
1489
CD2
HIS
A
405
−2.801
38.292
41.862
1.00
4.31


ATOM
1490
ND1
HIS
A
405
−2.389
36.204
42.467
1.00
7.16


ATOM
1491
CE1
HIS
A
405
−3.664
36.486
42.798
1.00
9.20


ATOM
1492
NE2
HIS
A
405
−3.937
37.722
42.413
1.00
9.52


ATOM
1493
C
HIS
A
405
−0.867
38.376
39.290
1.00
9.96


ATOM
1494
O
HIS
A
405
−1.836
38.080
38.597
1.00
9.05


ATOM
1495
N
GLU
A
406
−0.414
39.612
39.416
1.00
9.09


ATOM
1496
CA
GLU
A
406
−1.106
40.730
38.755
1.00
11.72


ATOM
1497
CB
GLU
A
406
−0.532
42.078
39.207
1.00
12.02


ATOM
1498
CG
GLU
A
406
−0.582
42.239
40.701
1.00
11.63


ATOM
1499
CD
GLU
A
406
−1.940
42.013
41.321
1.00
12.61


ATOM
1500
CE1
GLU
A
406
−2.985
42.048
40.632
1.00
12.02


ATOM
1501
CE2
GLU
A
406
−1.910
41.759
42.535
1.00
12.54


ATOM
1502
C
GLU
A
406
−1.087
40.659
37.256
1.00
13.24


ATOM
1503
O
GLU
A
406
−2.110
40.827
36.529
1.00
10.09


ATOM
1504
N
LEU
A
407
0.115
40.341
36.745
1.00
9.35


ATOM
1505
CA
LEU
A
407
0.259
40.106
35.318
1.00
11.31


ATOM
1506
CB
LEU
A
407
1.702
39.802
34.937
1.00
13.34


ATOM
1507
CG
LEU
A
407
2.671
40.844
34.384
1.00
17.06


ATOM
1508
CD1
LEU
A
407
2.232
42.279
34.412
1.00
15.35


ATOM
1509
CD2
LEU
A
407
4.112
40.690
34.878
1.00
15.89


ATOM
1510
C
LEU
A
407
−0.675
38.971
34.886
1.00
8.96


ATOM
1511
O
LEU
A
407
−1.105
38.869
33.720
1.00
9.09


ATOM
1512
N
GLY
A
408
−0.837
37.972
35.732
1.00
7.26


ATOM
1513
CA
GLY
A
408
−1.649
36.774
35.444
1.00
7.95


ATOM
1514
C
GLY
A
408
−3.107
37.247
35.182
1.00
8.27


ATOM
1515
O
GLY
A
408
−3.776
36.757
34.277
1.00
7.64


ATOM
1516
N
HIS
A
409
−3.565
38.171
36.030
1.00
10.19


ATOM
1517
CA
HIS
A
409
−4.873
38.777
35.752
1.00
11.21


ATOM
1518
CB
HIS
A
409
−5.162
39.320
36.713
1.00
8.68


ATOM
1519
CG
HIS
A
409
−5.605
39.404
38.018
1.00
10.30


ATOM
1520
CD2
HIS
A
409
−5.193
39.710
39.255
1.00
9.44


ATOM
1521
ND1
HIS
A
409
−6.606
38.454
38.114
1.00
10.06


ATOM
1522
CE1
HIS
A
409
−6.833
38.237
39.402
1.00
12.63


ATOM
1523
NE2
HIS
A
409
−5.961
38.972
40.132
1.00
12.50


ATOM
1524
C
HIS
A
409
−4.918
39.414
34.381
1.00
12.04


ATOM
1525
O
HIS
A
409
−5.853
39.223
33.615
1.00
12.02


ATOM
1526
N
ASN
A
410
−3.910
40.235
34.085
1.00
11.36


ATOM
1527
CA
ASN
A
410
−3.859
40.925
32.820
1.00
10.24


ATOM
1528
CB
ASN
A
410
−2.594
41.750
32.616
1.00
10.71


ATOM
1529
CG
ASN
A
410
−2.499
43.027
33.424
1.00
12.40


ATOM
1530
OD1
ASN
A
410
−1.369
43.394
33.748
1.00
9.72


ATOM
1531
ND2
ASN
A
410
−3.598
43.762
33.714
1.00
9.17


ATOM
1532
C
ASN
A
410
−3.953
39.918
31.675
1.00
12.78


ATOM
1533
O
ASN
A
410
−4.538
40.276
30.652
1.00
9.40


ATOM
1534
N
PHE
A
411
−3.292
38.782
31.796
1.00
9.09


ATOM
1535
CA
PHE
A
411
−3.280
37.693
30.872
1.00
10.91


ATOM
1536
CB
PHE
A
411
−2.105
36.703
31.101
1.00
10.93


ATOM
1537
CG
PHE
A
411
−0.840
37.086
30.375
1.00
13.69


ATOM
1538
CD1
PHE
A
411
−0.102
38.216
30.730
1.00
15.12


ATOM
1539
CD2
PHE
A
411
−0.309
−36.297
29.389
1.00
15.69


ATOM
1540
CE1
PHE
A
411
1.076
38.546
30.052
1.00
13.51


ATOM
1541
CE2
PHE
A
411
0.862
36.617
28.723
1.00
15.64


ATOM
1542
CZ
PHE
A
411
1.556
37.782
29.051
1.00
14.12


ATOM
1543
C
PHE
A
411
−4.606
36.903
30.849
1.00
10.27


ATOM
1544
O
PHE
A
411
−4.684
36.100
29.931
1.00
9.02


ATOM
1545
N
GLY
A
412
−5.578
37.150
31.701
1.00
11.88


ATOM
1546
CA
GLY
A
412
−6.912
36.517
31.563
1.00
11.02


ATOM
1547
C
GLY
A
412
−7.360
35.734
32.748
1.00
12.85


ATOM
1548
O
GLY
A
412
−8.496
35.256
32.898
1.00
11.80


ATOM
1549
N
ALA
A
413
−6.418
35.577
33.737
1.00
9.39


ATOM
1550
CA
ALA
A
413
−6.759
34.738
34.860
1.00
8.60


ATOM
1551
CB
ALA
A
413
−5.523
34.078
35.504
1.00
6.06


ATOM
1552
C
ALA
A
413
−7.520
35.451
35.966
1.00
9.94


ATOM
1553
O
ALA
A
413
−7.216
36.584
36.300
1.00
9.19


ATOM
1554
N
GLU
A
414
−8.476
34.694
36.530
1.00
9.61


ATOM
1555
CA
GLU
A
414
−9.172
35.158
37.731
1.00
12.27


ATOM
1556
CB
GLU
A
414
−10.666
34.812
37.677
1.00
14.74


ATOM
1557
CG
GLU
A
414
−11.293
35.591
36.517
1.00
16.17


ATOM
1558
CD
GLU
A
414
−11.696
36.987
36.834
1.00
20.61


ATOM
1559
OE1
GLU
A
414
−11.520
37.544
37.933
1.00
21.11


ATOM
1560
OE2
GLU
A
414
−12.266
37.646
35.920
1.00
24.06


ATOM
1561
C
GLU
A
414
−8.509
34.457
38.920
1.00
12.40


ATOM
1562
O
GLU
A
414
−7.455
33.841
38.757
1.00
12.29


ATOM
1563
N
HIS
A
415
−9.108
34.478
40.104
1.00
11.96


ATOM
1564
CA
HIS
A
415
−8.512
33.849
41.259
1.00
13.28


ATOM
1565
CB
HIS
A
415
−9.093
34.484
43.514
1.00
12.84


ATOM
1566
CG
HIS
A
415
−8.513
35.841
42.716
1.00
11.55


ATOM
1567
CD2
HIS
A
415
−7.240
36.265
42.433
1.00
11.21


ATOM
1568
ND1
HIS
A
415
−9.180
36.899
43.276
1.00
10.77


ATOM
1569
CE1
HIS
A
415
−8.380
37.944
43.314
1.00
9.60


ATOM
1570
NE2
HIS
A
415
−7.174
37.576
42.791
1.00
11.71


ATOM
1571
C
HIS
A
415
−8.789
32.362
41.293
1.00
14.34


ATOM
1572
O
HIS
A
415
−9.851
32.007
40.751
1.00
10.53


ATOM
1573
N
ASP
A
416
−7.855
31.567
41.826
1.00
10.07


ATOM
1574
CA
ASP
A
416
−8.239
30.158
41.962
1.00
11.05


ATOM
1575
CB
ASP
A
416
−6.978
29.338
42.310
1.00
13.78


ATOM
1576
CG
ASP
A
416
−5.913
29.387
41.229
1.00
14.67


ATOM
1577
OD1
ASP
A
416
−6.267
29.373
40.039
1.00
13.81


ATOM
1578
OD2
ASP
A
416
−4.717
29.403
41.608
1.00
16.01


ATOM
1579
C
ASP
A
416
−9.254
29.930
43.052
1.00
10.40


ATOM
1580
O
ASP
A
416
−9.169
30.468
44.159
1.00
11.17


ATOM
1581
N
PRO
A
417
−10.296
29.111
42.805
1.00
10.30


ATOM
1582
CD
PRO
A
417
−10.544
28.473
41.502
1.00
12.83


ATOM
1583
CA
PRO
A
417
−11.275
28.774
43.805
1.00
12.54


ATOM
1584
CB
PRO
A
417
−12.495
28.328
42.975
1.00
13.91


ATOM
1585
CG
PRO
A
417
−11.940
27.894
41.674
1.00
15.31


ATOM
1586
C
PRO
A
417
−10.837
27.603
44.689
1.00
13.42


ATOM
1587
O
PRO
A
417
−10.002
26.839
44.276
1.00
14.77


ATOM
1588
N
ASP
A
418
−11.346
27.376
45.860
1.00
14.02


ATOM
1589
CA
ASP
A
418
−11.086
26.217
46.694
1.00
20.43


ATOM
1590
CB
ASP
A
418
−11.375
26.531
48.172
1.00
22.42


ATOM
1591
CG
ASP
A
418
−10.416
27.595
48.658
1.00
25.60


ATOM
1592
OD1
ASP
A
418
−9.221
27.416
48.429
1.00
27.33


ATOM
1593
OD2
ASP
A
418
−10.724
28.666
49.204
1.00
29.81


ATOM
1594
C
ASP
A
418
−11.917
25.061
46.257
1.00
23.39


ATOM
1595
O
ASP
A
418
−13.034
25.354
45.640
1.00
23.78


ATOM
1596
N
GLY
A
419
−11.533
23.829
46.307
1.00
24.01


ATOM
1597
CA
GLY
A
419
−12.290
22.650
46.050
1.00
28.51


ATOM
1598
C
GLY
A
419
−12.000
21.714
44.916
1.00
31.09


ATOM
1599
O
GLY
A
419
−11.000
21.726
44.169
1.00
31.19


ATOM
1600
N
LEU
A
420
−12.976
20.849
44.625
1.00
32.09


ATOM
1601
CD2
LEU
A
420
−14.406
17.142
44.111
1.00
38.06


ATOM
1602
CD1
LEU
A
420
−16.571
18.444
44.050
1.00
37.27


ATOM
1603
CG
LEU
A
420
−15.061
18.507
44.238
1.00
36.91


ATOM
1604
CB
LEU
A
420
−14.424
19.470
43.224
1.00
36.82


ATOM
1605
CA
LEU
A
420
−12.969
19.843
43.591
1.00
35.26


ATOM
1606
C
LEU
A
420
−12.193
20.130
42.331
1.00
36.08


ATOM
1607
O
LEU
A
420
−11.638
19.221
41.701
1.00
37.02


ATOM
1608
N
ALA
A
421
−12.053
21.380
41.907
1.00
36.27


ATOM
1609
CB
ALA
A
421
−11.478
23.254
40.472
1.00
37.17


ATOM
1610
CA
ALA
A
421
−11.309
21.755
40.742
1.00
36.49


ATOM
1611
C
ALA
A
421
−9.841
21.381
40.794
1.00
35.18


ATOM
1612
O
ALA
A
421
−9.253
21.402
39.702
1.00
36.10


ATOM
1613
N
GLU
A
422
−9.183
21.102
41.907
1.00
32.65


ATOM
1614
OE2
GLU
A
422
−8.104
20.106
37.709
1.00
41.16


ATOM
1615
CE1
GLU
A
422
−6.137
19.284
37.500
1.00
39.97


ATOM
1616
CD
GLU
A
422
−6.983
19.889
38.198
1.00
38.24


ATOM
1617
CG
GLU
A
422
−6.628
20.311
39.582
1.00
35.89


ATOM
1618
CB
GLU
A
422
−7.426
19.813
40.760
1.00
31.03


ATOM
1619
CA
GLU
A
422
−7.761
20.769
41.914
1.00
29.38


ATOM
1620
C
GLU
A
422
−6.901
22.028
41.779
1.00
24.25


ATOM
1621
O
GLU
A
422
−5.677
21.951
42.645
1.00
21.69


ATOM
1622
N
CYS
A
423
−7.530
23.185
41.837
1.00
19.59


ATOM
1623
CA
CYS
A
423
−6.862
24.457
41.613
1.00
18.31


ATOM
1624
CB
CYS
A
423
−7.819
25.319
40.797
1.00
21.54


ATOM
1625
SG
CYS
A
423
−8.112
24.725
39.090
1.00
22.74


ATOM
1626
C
CYS
A
423
−6.367
25.102
42.893
1.00
16.82


ATOM
1627
O
CYS
A
423
−5.884
26.233
42.855
1.00
14.86


ATOM
1628
N
ALA
A
424
−6.516
24.451
44.029
1.00
15.16


ATOM
1629
CA
ALA
A
424
−5.974
24.991
45.288
1.00
16.52


ATOM
1630
CB
ALA
A
424
−6.940
25.972
45.924
1.00
15.07


ATOM
1631
C
ALA
A
424
−5.603
23.812
46.165
1.00
15.42


ATOM
1632
O
ALA
A
424
−6.206
23.507
47.182
1.00
16.31


ATOM
1633
N
PRO
A
425
−4.545
23.118
45.774
1.00
16.63


ATOM
1634
CD
PRO
A
425
−3.694
23.394
44.593
1.00
14.62


ATOM
1635
CA
PRO
A
425
−4.096
21.935
46.484
1.00
18.01


ATOM
1636
CB
PRO
A
425
−2.965
21.392
45.635
1.00
17.36


ATOM
1637
CG
PRO
A
425
−3.064
22.047
44.301
1.00
16.07


ATOM
1638
C
PRO
A
425
−3.655
22.217
47.908
1.00
19.52


ATOM
1639
O
PRO
A
425
−3.304
23.325
48.294
1.00
16.80


ATOM
1640
N
ASN
A
426
−3.670
21.143
48.707
1.00
21.90


ATOM
1641
ND2
ASN
A
426
−6.177
19.346
50.674
1.00
32.22


ATOM
1642
OD1
ASN
A
426
−5.934
21.437
51.378
1.00
30.53


ATOM
1643
CG
ASN
A
426
−5.407
20.380
51.018
1.00
30.42


ATOM
1644
CB
ASN
A
426
−3.898
20.167
50.928
1.00
27.25


ATOM
1645
CA
ASN
A
426
−3.224
21.249
50.088
1.00
24.17


ATOM
1646
C
ASN
A
426
−1.695
21.270
50.121
1.00
22.87


ATOM
1647
O
ASN
A
426
−1.014
21.025
49.127
1.00
19.72


ATOM
1648
N
GLU
A
427
−1.148
21.695
51.247
1.00
24.03


ATOM
1649
OE2
GLU
A
427
3.209
21.859
55.259
1.00
39.86


ATOM
1650
OE1
GLU
A
427
2.503
23.818
54.605
1.00
37.70


ATOM
1651
CD
GLU
A
427
2.640
22.595
54.427
1.00
37.41


ATOM
1652
CG
GLU
A
427
2.167
21.979
53.132
1.00
36.42


ATOM
1653
CB
GLU
A
427
0.679
22.110
52.857
1.00
32.16


ATOM
1654
CA
GLU
A
427
0.305
21.775
51.409
1.00
29.42


ATOM
1655
C
GLU
A
427
0.998
20.507
50.975
1.00
29.51


ATOM
1656
O
GLU
A
427
1.971
20.497
50.213
1.00
29.26


ATOM
1657
N
ASP
A
428
0.488
19.358
51.414
1.00
31.72


ATOM
1658
OD2
ASP
A
428
−1.918
16.341
52.011
1.00
41.88


ATOM
1659
OD1
ASP
A
428
−1.452
18.328
52.816
1.00
37.31


ATOM
1660
CG
ASP
A
428
−1.103
17.267
52.267
1.00
38.88


ATOM
1661
CB
ASP
A
428
0.320
16.958
51.853
1.00
36.50


ATOM
1662
CA
ASP
A
428
1.042
19.054
51.077
1.00
32.85


ATOM
1663
C
ASP
A
428
1.081
17.735
49.610
1.00
32.15


ATOM
1664
O
ASP
A
428
1.827
16.851
49.173
1.00
32.63


ATOM
1665
N
GLN
A
429
0.302
18.414
48.772
1.00
29.90


ATOM
1666
NE2
GLN
A
429
−0.844
15.151
46.445
1.00
35.05


ATOM
1667
OE1
GLN
A
429
−0.895
15.061
48.694
1.00
36.32


ATOM
1668
CD
GLN
A
429
−1.190
15.629
47.636
1.00
35.53


ATOM
1669
CG
GLN
A
429
−1.923
16.955
47.621
1.00
32.82


ATOM
1670
CB
GLN
A
429
−1.138
18.032
46.865
1.00
30.20


ATOM
1671
CA
GLN
A
429
0.307
18.190
47.347
1.00
26.44


ATOM
1672
C
GLN
A
429
1.041
19.302
46.621
1.00
22.82


ATOM
1673
O
GLN
A
429
0.832
19.463
45.426
1.00
21.67


ATOM
1674
N
GLY
A
430
1.812
20.142
47.320
1.00
18.52


ATOM
1675
CA
GLY
A
430
2.534
21.185
46.583
1.00
15.09


ATOM
1676
C
GLY
A
430
1.982
22.581
46.889
1.00
14.53


ATOM
1677
O
GLY
A
430
2.582
23.559
46.432
1.00
16.43


ATOM
1678
N
GLY
A
431
0.898
22.745
47.615
1.00
11.39


ATOM
1679
CA
GLY
A
431
0.314
24.011
47.958
1.00
12.94


ATOM
1680
C
GLY
A
431
−0.505
24.702
46.871
1.00
10.35


ATOM
1681
O
GLY
A
431
−0.764
24.181
45.795
1.00
11.85


ATOM
1682
N
LYS
A
432
−0.845
25.936
47.147
1.00
11.65


ATOM
1683
CA
LYS
A
432
−1.637
26.762
46.245
1.00
13.87


ATOM
1684
CB
LYS
A
432
−2.343
27.862
47.049
1.00
16.54


ATOM
1685
CG
LYS
A
432
−3.250
27.146
48.043
1.00
20.67


ATOM
1686
CD
LYS
A
432
−4.058
28.036
48.933
1.00
24.37


ATOM
1687
CE
LYS
A
432
−5.090
27.228
49.718
1.00
25.86


ATOM
1688
NZ
LYS
A
432
−4.539
25.962
50.296
1.00
25.58


ATOM
1689
C
LYS
A
432
−0.810
27.312
45.112
1.00
12.71


ATOM
1690
O
LYS
A
432
0.414
27.398
45.187
1.00
11.37


ATOM
1691
N
TYR
A
433
−1.533
27.713
44.072
1.00
8.62


ATOM
1692
CA
TYR
A
433
−0.997
28.243
42.844
1.00
8.63


ATOM
1693
CB
TYR
A
433
−1.677
27.746
41.591
1.00
0.94


ATOM
1694
CG
TYR
A
433
−1.507
26.270
41.276
1.00
12.81


ATOM
1695
CD1
TYR
A
433
−2.460
25.350
41.653
1.00
12.02


ATOM
1696
CE1
TYR
A
433
−2.310
23.995
41.361
1.00
14.63


ATOM
1697
CD2
TYR
A
433
−0.360
25.813
40.637
1.00
13.00


ATOM
1698
CE2
TYR
A
433
−0.202
24.469
40.333
1.00
14.04


ATOM
1699
CZ
TYR
A
433
−1.180
23.579
40.713
1.00
15.76


ATOM
1700
OH
TYR
A
433
−1.018
22.241
40.429
1.00
18.68


ATOM
1701
C
TYR
A
433
−0.990
29.769
42.955
1.00
6.12


ATOM
1702
O
TYR
A
433
−1.576
30.319
43.866
1.00
7.36


ATOM
1703
N
VAL
A
434
−0.279
30.385
42.031
1.00
8.06


ATOM
1704
CA
VAL
A
434
−0.023
33.820
42.080
1.00
9.13


ATOM
1705
CB
VAL
A
434
1.026
32.189
41.035
1.00
9.24


ATOM
1706
CG1
VAL
A
434
0.473
32.255
39.614
1.00
9.78


ATOM
1707
CG2
VAL
A
434
1.656
33.531
41.432
1.00
9.67


ATOM
1708
C
VAL
A
434
−1.247
32.724
41.971
1.00
9.44


ATOM
1709
O
VAL
A
434
−1.224
33.807
42.521
1.00
8.77


ATOM
1710
N
MET
A
435
−2.348
32.242
41.373
1.00
9.61


ATOM
1711
CA
MET
A
435
−3.580
33.044
41.377
1.00
10.35


ATOM
1712
CB
MET
A
435
−4.313
32.866
40.054
1.00
9.92


ATOM
1713
CG
MET
A
435
−3.514
33.300
38.848
1.00
10.91


ATOM
1714
SD
MET
A
435
−2.789
34.945
38.866
1.00
11.06


ATOM
1715
CE
MET
A
435
−4.229
35.954
39.266
1.00
11.66


ATOM
1716
C
MET
A
435
−4.479
32.835
42.569
1.00
11.89


ATOM
1717
O
MET
A
435
−5.625
33.382
42.578
1.00
10.19


ATOM
1718
N
TYR
A
436
−4.004
32.200
43.636
1.00
9.70


ATOM
1719
CA
TYR
A
436
−4.776
32.133
44.873
1.00
10.59


ATOM
1720
CB
TYR
A
436
−4.154
31.274
45.974
1.00
12.19


ATOM
1721
CG
TYR
A
436
−5.187
30.700
46.929
1.00
12.41


ATOM
1722
CD1
TYR
A
436
−6.086
29.710
46.528
1.00
13.54


ATOM
1723
CE1
TYR
A
436
−7.026
29.190
47.405
1.00
10.84


ATOM
1724
CD2
TYR
A
436
−5.275
31.200
48.218
1.00
12.72


ATOM
1725
CE2
TYR
A
436
−6.216
30.710
49.104
1.00
15.95


ATOM
1726
CZ
TYR
A
436
−7.105
29.725
48.659
1.00
14.43


ATOM
1727
OH
TYR
A
436
−8.012
29.268
49.572
1.00
17.14


ATOM
1728
C
TYR
A
436
−4.977
33.571
45.304
1.00
10.80


ATOM
1729
O
TYR
A
436
−4.106
34.412
45.121
1.00
7.79


ATOM
1730
N
PRO
A
437
−6.178
33.938
45.778
1.00
11.93


ATOM
1731
CD
PRO
A
437
−7.340
33.037
45.939
1.00
11.26


ATOM
1732
CA
PRO
A
437
−6.467
35.326
46.139
1.00
10.62


ATOM
1733
CB
PRO
A
437
−7.962
35.319
46.495
1.00
12.25


ATOM
1734
CG
PRO
A
437
−8.320
33.884
46.714
1.00
12.44


ATOM
1735
C
PRO
A
437
−5.713
35.775
47.385
1.00
10.79


ATOM
1736
O
PRO
A
437
−5.577
36.995
47.602
1.00
11.50


ATOM
1737
N
ILE
A
438
−5.411
34.802
48.243
1.00
11.06


ATOM
1738
CA
ILE
A
438
−4.645
35.046
49.464
1.00
14.21


ATOM
1739
CB
ILE
A
438
−5.154
34.201
50.625
1.00
16.10


ATOM
1740
CG2
ILE
A
438
−4.290
34.449
51.876
1.00
19.74


ATOM
1741
CG1
ILE
A
438
−6.619
34.470
50.967
1.00
19.29


ATOM
1742
CD1
ILE
A
438
−7.175
33.545
52.055
1.00
20.13


ATOM
1743
C
ILE
A
438
−3.173
34.778
49.119
1.00
14.66


ATOM
1744
O
ILE
A
438
−2.796
33.666
48.710
1.00
10.76


ATOM
1745
N
ALA
A
439
−2.342
35.803
49.202
1.00
12.90


ATOM
1746
CB
ALA
A
439
−0.137
36.968
49.129
1.00
13.51


ATOM
1747
CA
ALA
A
439
−0.946
35.702
48.748
1.00
12.56


ATOM
1748
C
ALA
A
439
−0.219
34.450
49.179
1.00
11.82


ATOM
1749
O
ALA
A
439
−0.053
34.221
50.350
1.00
12.72


ATOM
1750
N
VAL
A
440
0.244
33.624
48.232
1.00
12.54


ATOM
1751
CA
VAL
A
440
1.038
32.460
48.610
1.00
13.18


ATOM
1752
CB
VAL
A
440
1.194
31.545
47.405
1.00
13.89


ATOM
1753
CG1
VAL
A
440
−0.203
30.964
47.060
1.00
14.71


ATOM
1754
CG2
VAL
A
440
1.748
32.335
46.225
1.00
14.29


ATOM
1755
C
VAL
A
440
2.422
32.915
49.105
1.00
13.24


ATOM
1756
O
VAL
A
440
2.951
33.937
48.665
1.00
10.97


ATOM
1757
N
SER
A
441
3.009
32.117
49.958
1.00
13.77


ATOM
1758
CA
SER
A
441
4.320
32.449
50.541
1.00
15.67


ATOM
1759
CB
SER
A
441
4.602
31.531
51.741
1.00
14.54


ATOM
1760
OG
SER
A
441
4.895
30.230
51.251
1.00
12.13


ATOM
1761
C
SER
A
441
5.443
32.298
49.543
1.00
14.86


ATOM
1762
O
SER
A
441
6.333
33.042
49.627
1.00
16.15


ATOM
1763
N
GLY
A
442
5.365
31.340
48.626
1.00
15.69


ATOM
1764
CA
GLY
A
442
6.458
31.086
47.680
1.00
15.78


ATOM
1765
C
GLY
A
442
7.329
29.955
48.292
1.00
17.87


ATOM
1766
O
GLY
A
442
8.313
29.533
47.700
1.00
17.88


ATOM
1767
N
ASP
A
443
6.933
29.420
49.433
1.00
16.97


ATOM
1768
CA
ASP
A
443
7.639
28.297
50.053
1.00
19.48


ATOM
1769
CB
ASP
A
443
7.315
28.159
51.522
1.00
20.17


ATOM
1770
CG
ASP
A
443
7.613
29.371
52.357
1.00
23.62


ATOM
1771
OD1
ASP
A
443
8.296
30.306
51.896
1.00
23.81


ATOM
1772
OD2
ASP
A
443
7.119
29.399
53.505
1.00
25.54


ATOM
1773
C
ASP
A
443
7.308
26.945
41.435
1.00
21.78


ATOM
1774
O
ASP
A
443
8.052
25.962
49.619
1.00
20.22


ATOM
1775
N
HIS
A
444
6.163
26.878
48.737
1.00
18.42


ATOM
1776
CA
HIS
A
444
5.734
25.593
48.195
1.00
18.25


ATOM
1777
CB
HIS
A
444
4.263
25.329
48.628
1.00
19.33


ATOM
1778
CG
HIS
A
444
4.010
25.631
50.066
1.00
21.40


ATOM
1779
CD2
HIS
A
444
3.475
26.703
50.697
1.00
21.56


ATOM
1780
ND1
HIS
A
444
4.407
24.766
51.066
1.00
22.82


ATOM
1781
CE1
HIS
A
444
4.098
25.274
52.242
1.00
22.65


ATOM
1782
NE2
HIS
A
444
3.540
26.457
52.047
1.00
23.53


ATOM
1783
C
HIS
A
444
5.869
25.478
46.699
1.00
18.20


ATOM
1784
O
HIS
A
444
5.869
26.430
45.924
1.00
16.89


ATOM
1785
N
GLU
A
445
5.967
24.246
46.228
1.00
18.90


ATOM
1786
OE2
GLU
A
445
7.287
19.466
44.909
1.00
37.32


ATOM
1787
OE1
GLU
A
445
5.382
19.436
43.805
1.00
36.75


ATOM
1788
CD
GLU
A
445
6.406
20.025
44.213
1.00
34.73


ATOM
1789
CG
GLU
A
445
6.551
21.509
43.912
1.00
31.48


ATOM
1790
CB
GLU
A
445
5.641
22.370
44.753
1.00
24.36


ATOM
1791
CA
GLU
A
445
6.094
23.856
44.844
1.00
21.30


ATOM
1792
C
GLU
A
445
5.192
24.573
43.856
1.00
19.12


ATOM
1793
O
GLU
A
445
5.654
25.106
42.852
1.00
18.41


ATOM
1794
N
ASN
A
446
3.886
24.568
44.155
1.00
14.02


ATOM
1795
CA
ASN
A
446
2.931
25.161
43.217
1.00
12.89


ATOM
1796
CB
ASN
A
446
1.558
24.575
43.616
1.00
13.52


ATOM
1797
CG
ASN
A
446
1.492
23.081
43.416
1.00
11.57


ATOM
1798
OD1
ASN
A
446
2.288
22.530
42.688
1.00
14.69


ATOM
1799
ND2
ASN
A
446
0.580
22.359
44.016
1.00
14.47


ATOM
1800
C
ASN
A
446
2.880
26.669
43.236
1.00
12.30


ATOM
1801
O
ASN
A
446
2.299
27.295
42.349
1.00
11.18


ATOM
1802
N
ASN
A
447
3.432
27.299
44.274
1.00
12.22


ATOM
1803
CA
ASN
A
447
3.261
28.692
44.560
1.00
12.81


ATOM
1804
CB
ASN
A
447
3.943
29.244
45.794
1.00
13.02


ATOM
1805
CG
ASN
A
447
3.432
28.721
47.094
1.00
14.61


ATOM
1806
OD1
ASN
A
447
4.151
28.922
48.031
1.00
15.02


ATOM
1807
ND2
ASN
A
447
2.276
28.070
47.103
1.00
13.05


ATOM
1808
C
ASN
A
447
3.662
29.596
43.403
1.00
14.50


ATOM
1809
O
ASN
A
447
2.990
30.597
43.173
1.00
14.90


ATOM
1810
N
LYS
A
448
4.698
29.182
42.678
1.00
15.41


ATOM
1811
CA
LYS
A
448
5.123
30.032
41.582
1.00
19.44


ATOM
1812
CB
LYS
A
448
6.678
30.007
41.496
1.00
20.29


ATOM
1813
CG
LYS
A
448
7.319
30.599
42.725
1.00
22.70


ATOM
1814
CD
LYS
A
448
8.503
31.527
42.408
1.00
25.96


ATOM
1815
CE
LYS
A
448
8.285
32.968
42.835
1.00
24.34


ATOM
1816
NZ
LYS
A
448
8.963
33.438
44.090
1.00
16.70


ATOM
1817
C
LYS
A
448
4.568
29.566
40.271
1.00
19.62


ATOM
1818
O
LYS
A
448
5.136
29.990
39.263
1.00
25.92


ATOM
1819
N
MET
A
449
3.632
28.647
40.230
1.00
13.54


ATOM
1820
CA
MET
A
449
3.122
28.149
38.956
1.00
14.78


ATOM
1821
CB
MET
A
449
3.181
26.610
39.000
1.00
17.23


ATOM
1822
CG
MET
A
449
4.638
26.182
39.231
1.00
23.71


ATOM
1823
SD
MET
A
449
5.557
26.266
37.701
1.00
35.18


ATOM
1824
CE
MET
A
449
6.512
27.753
37.876
1.00
29.45


ATOM
1825
C
MET
A
449
1.660
28.558
38.779
1.00
10.74


ATOM
1826
O
MET
A
449
1.051
28.898
39.776
1.00
7.03


ATOM
1827
N
PHE
A
450
1.104
28.330
37.629
1.00
9.72


ATOM
1828
CA
PHE
A
450
−0.319
28.583
37.393
1.00
11.38


ATOM
1829
CB
PHE
A
450
−0.503
29.170
35.975
1.00
11.13


ATOM
1830
CG
PHE
A
450
−0.071
30.631
35.959
1.00
12.52


ATOM
1831
CD1
PHE
A
450
−0.930
31.655
36.320
1.00
12.19


ATOM
1832
CD2
PHE
A
450
1.207
30.955
35.549
1.00
10.84


ATOM
1833
CE1
PHE
A
450
−0.508
32.973
36.265
1.00
11.08


ATOM
1834
CE2
PHE
A
450
1.624
32.264
35.490
1.00
10.58


ATOM
1835
CZ
PHE
A
450
0.770
33.283
35.856
1.00
10.00


ATOM
1836
C
PHE
A
450
−1.150
27.312
37.490
1.00
11.07


ATOM
1837
O
PHE
A
450
−0.799
26.260
36.954
1.00
9.07


ATOM
1838
N
SER
A
451
−2.323
27.410
38.138
1.00
11.36


ATOM
1839
CA
SER
A
451
−3.268
26.315
38.270
1.00
10.14


ATOM
1840
CB
SER
A
451
−4.487
26.735
39.155
1.00
10.95


ATOM
1841
CG
SER
A
451
−5.179
27.782
38.420
1.00
9.02


ATOM
1842
C
SER
A
451
−3.844
25.958
36.901
1.00
9.35


ATOM
1843
O
SER
A
451
−3.770
26.735
35.963
1.00
9.40


ATOM
1844
N
GLN
A
452
−4.577
24.855
36.824
1.00
12.16


ATOM
1845
CA
GLN
A
452
−5.351
24.521
35.618
1.00
13.47


ATOM
1846
CB
GLN
A
452
−5.964
23.125
35.803
1.00
16.94


ATOM
1847
CG
GLN
A
452
−6.700
22.595
34.601
1.00
21.50


ATOM
1848
CD
GLN
A
452
−5.827
22.669
33.361
1.00
23.04


ATOM
1849
OE1
GLN
A
452
−4.673
22.244
33.400
1.00
21.47


ATOM
1850
NE2
GLN
A
452
−6.377
23.285
32.307
1.00
23.25


ATOM
1851
C
GLN
A
452
−6.430
25.554
35.338
1.00
33.65


ATOM
1852
O
GLN
A
452
−6.638
25.907
34.165
1.00
14.17


ATOM
1853
N
CYS
A
453
−7.045
26.104
36.363
1.00
14.02


ATOM
1854
CA
CYS
A
453
−8.092
27.127
36.197
1.00
17.31


ATOM
1855
CB
CYS
A
453
−8.719
27.417
37.560
1.00
21.49


ATOM
1856
SG
CYS
A
453
−9.533
26.093
38.447
1.00
29.58


ATOM
1857
C
CYS
A
453
−7.500
28.361
35.535
1.00
15.91


ATOM
1858
O
CYS
A
453
−7.993
28.886
34.524
1.00
12.98


ATOM
1859
N
SER
A
454
−6.301
28.786
36.002
1.00
10.78


ATOM
1860
CA
SER
A
454
−5.584
29.258
35.390
1.00
9.42


ATOM
1861
CB
SER
A
454
−4.341
30.410
36.146
1.00
8.01


ATOM
1862
OG
SER
A
454
−4.692
30.709
37.471
1.00
8.77


ATOM
1863
C
SER
A
454
−5.186
29.538
33.979
1.00
9.67


ATOM
1864
O
SER
A
454
−5.237
30.413
33.113
1.00
9.80


ATOM
1865
N
LYS
A
455
−4.691
28.304
33.763
1.00
13.07


ATOM
1866
CA
LYS
A
455
−4.240
27.987
32.421
1.00
12.98


ATOM
1867
CB
LYS
A
455
−3.599
26.587
32.376
1.00
13.14


ATOM
1868
CG
LYS
A
455
−2.146
26.611
32.855
1.00
17.01


ATOM
1869
CD
LYS
A
455
−1.656
25.166
32.882
1.00
19.15


ATOM
1870
CE
LYS
A
455
−0.242
25.104
33.451
1.00
20.39


ATOM
1871
NZ
LYS
A
455
0.195
23.673
33.295
1.00
23.90


ATOM
1872
C
LYS
A
455
−5.367
28.049
31.401
1.00
12.31


ATOM
1873
O
LYS
A
455
−5.180
28.539
30.315
1.00
12.74


ATOM
1874
N
GLN
A
456
−6.529
27.527
31.755
1.00
14.47


ATOM
1875
NE2
GLN
A
456
−10.676
25.407
33.099
1.00
30.34


ATOM
1876
OE1
GLN
A
456
−9.503
23.500
32.899
1.00
29.79


ATOM
1877
CD
GLN
A
456
−9.664
24.686
32.606
1.00
28.31


ATOM
1878
CG
GLN
A
456
−8.670
25.342
31.686
1.00
25.00


ATOM
1879
CB
GLN
A
456
−8.814
26.832
31.511
1.00
19.95


ATOM
1880
CA
GLN
A
456
−7.661
27.516
30.804
1.00
16.41


ATOM
1881
C
GLN
A
456
−7.967
28.542
30.401
1.00
15.24


ATOM
1882
O
GLN
A
456
−7.936
29.330
29.244
1.00
15.99


ATOM
1883
N
SER
A
457
−8.038
29.821
31.393
1.00
14.14


ATOM
1884
CA
SER
A
457
−8.377
31.231
33.194
1.00
14.81


ATOM
1885
CB
SER
A
457
−8.518
31.976
32.530
1.00
15.12


ATOM
1886
OG
SER
A
457
−9.565
31.464
33.315
1.00
16.45


ATOM
1887
C
SER
A
457
−7.354
31.967
30.377
1.00
12.94


ATOM
1888
O
SER
A
457
−7.697
32.696
29.467
1.00
12.19


ATOM
1889
N
ILE
A
458
−6.051
31.825
30.722
1.00
12.21


ATOM
1890
CA
ILE
A
458
−5.038
32.567
29.982
1.00
9.86


ATOM
1891
CB
ILE
A
458
−3.699
32.500
30.795
1.00
11.36


ATOM
1892
CG2
ILE
A
548
−2.555
32.898
29.890
1.00
6.36


ATOM
1893
CG1
ILE
A
458
−3.853
33.384
32.036
1.00
9.88


ATOM
1894
CD1
ILE
A
458
−2.730
33.281
33.059
1.00
11.89


ATOM
1895
C
ILE
A
458
−4.854
32.048
28.573
1.00
9.53


ATOM
1896
O
ILE
A
458
−4.640
32.816
27.634
1.00
9.61


ATOM
1897
N
TYR
A
459
−4.939
30.731
28.423
1.00
9.48


ATOM
1898
CA
TYR
A
459
−4.767
30.100
27.112
1.00
11.60


ATOM
1899
CB
TYR
A
459
−5.038
28.600
27.250
1.00
11.22


ATOM
1900
CG
TYR
A
459
−5.045
27.843
25.943
1.00
16.31


ATOM
1901
CD1
TYR
A
459
−4.013
27.976
25.041
1.00
16.99


ATOM
1902
CE1
TYR
A
459
−4.028
27.303
23.827
1.00
19.40


ATOM
1903
CD2
TYR
A
459
−6.103
26.999
25.626
1.00
18.93


ATOM
1904
CE2
TYR
A
459
−6.108
26.299
24.422
1.00
21.51


ATOM
1905
CZ
TYR
A
459
−5.075
26.458
23.532
1.00
20.71


ATOM
1906
OH
TYR
A
459
−5.095
25.772
22.341
1.00
21.74


ATOM
1907
C
TYR
A
459
−5.720
30.750
26.110
1.00
12.72


ATOM
1908
O
TYR
A
459
−5.334
31.252
25.073
1.00
14.82


ATOM
1909
N
LYS
A
460
−6.974
30.779
26.528
1.00
14.14


ATOM
1910
NZ
LYS
A
460
−10.468
26.961
25.743
1.00
30.41


ATOM
1911
CE
LYS
A
460
−9.733
27.718
24.702
1.00
27.82


ATOM
1912
CD
LYS
A
460
−9.809
29.219
24.921
1.00
26.35


ATOM
1913
CG
LYS
A
460
−9.794
29.689
26.345
1.00
23.26


ATOM
1914
CB
LYS
A
460
−9.375
31.156
26.477
1.00
19.80


ATOM
1915
CA
LYS
A
460
−8.043
31.371
25.721
1.00
18.07


ATOM
1916
C
LYS
A
460
−7.739
32.806
25.384
1.00
16.65


ATOM
1917
O
LYS
A
460
−7.735
33.206
24.228
1.00
16.84


ATOM
1918
N
THR
A
461
−7.225
33.546
26.348
1.00
14.44


ATOM
1919
CA
THR
A
461
−6.847
34.932
26.139
1.00
14.79


ATOM
1920
CB
THR
A
461
−6.597
35.590
27.509
1.00
13.79


ATOM
1921
OG1
THR
A
461
−7.813
35.528
28.254
1.00
13.87


ATOM
1922
CG2
THR
A
461
−6.192
37.054
27.345
1.00
16.01


ATOM
1923
C
THR
A
461
−5.709
35.061
25.159
1.00
14.88


ATOM
1924
O
THR
A
461
−5.830
35.765
24.142
1.00
14.86


ATOM
1925
N
ILE
A
462
−4.569
34.417
25.419
1.00
14.52


ATOM
1926
CA
ILE
A
462
−3.422
34.528
24.542
1.00
17.34


ATOM
1927
CB
ILE
A
462
−2.223
33.642
24.975
1.00
18.43


ATOM
1928
CG2
ILE
A
462
−1.130
33.699
23.904
1.00
20.28


ATOM
1929
CG1
ILE
A
462
−1.643
34.018
26.316
1.00
18.70


ATOM
1930
CD1
ILE
A
462
−0.726
32.967
26.946
1.00
19.10


ATOM
1931
C
ILE
A
462
−3.757
34.102
23.124
1.00
18.59


ATOM
1932
O
ILE
A
462
−3.420
34.813
22.189
1.00
17.11


ATOM
1933
N
GLU
A
463
−4.473
32.979
22.968
1.00
22.82


ATOM
1934
OE2
GLU
A
463
−8.026
23.422
22.532
1.00
41.03


ATOM
1935
OE1
GLU
A
463
−7.006
28.787
20.674
1.00
39.73


ATOM
1936
CD
GLU
A
463
−7.293
29.635
21.536
1.00
39.22


ATOM
1937
CG
GLU
A
463
−6.723
31.032
21.405
1.00
36.15


ATOM
1938
CB
GLU
A
463
−5.228
31.095
21.624
1.00
30.56


ATOM
1939
CA
GLU
A
463
−4.692
32.520
21.587
1.00
26.30


ATOM
1940
C
GLU
A
463
−5.492
33.530
20.800
1.00
27.72


ATOM
1941
O
GLU
A
463
−5.233
33.704
19.607
1.00
29.03


ATOM
1942
N
SER
A
464
−6.399
34.283
23.418
1.00
26.79


ATOM
1943
CA
SER
A
464
−7.190
35.312
20.764
1.00
26.80


ATOM
1944
CB
SER
A
464
−8.395
35.611
21.666
1.00
25.15


ATOM
1945
OG
SER
A
464
−9.060
36.806
21.404
1.00
25.60


ATOM
1946
C
SER
A
464
−6.434
36.623
20.582
1.00
27.79


ATOM
1947
O
SER
A
464
−6.686
37.340
19.612
1.00
27.52


ATOM
1948
N
LYS
A
465
−5.598
36.959
21.560
1.00
25.83


ATOM
1949
CA
LYS
A
465
−4.956
38.267
21.585
1.00
28.04


ATOM
1950
CB
LYS
A
465
−5.065
38.846
22.993
1.00
28.65


ATOM
1951
CG
LYS
A
465
−6.217
39.766
23.316
1.00
30.43


ATOM
1952
CD
LYS
A
465
−7.570
39.136
23.099
1.00
31.72


ATOM
1953
CE
LYS
A
465
−8.699
40.165
23.068
1.00
32.17


ATOM
1954
NZ
LYS
A
465
−8.593
41.165
24.149
1.00
32.20


ATOM
1955
C
LYS
A
465
−3.505
38.293
21.145
1.00
27.28


ATOM
1956
O
LYS
A
465
−3.053
39.353
20.704
1.00
27.45


ATOM
1957
N
ALA
A
466
−2.767
37.193
21.184
1.00
28.49


ATOM
1958
CA
ALA
A
466
−1.373
37.191
20.753
1.00
28.95


ATOM
1959
CB
ALA
A
466
−0.788
35.788
20.750
1.00
27.44


ATOM
1960
C
ALA
A
466
−1.152
37.821
19.385
1.00
30.12


ATOM
1961
O
ALA
A
466
−0.295
38.708
19.256
1.00
28.37


ATOM
1962
N
GLN
A
467
−1.922
37.440
18.373
1.00
30.63


ATOM
1963
NE2
GLN
A
467
0.360
36.582
14.061
1.00
41.77


ATOM
1964
OE1
GLN
A
467
−0.196
35.394
15.846
1.00
42.22


ATOM
1965
CD
GLN
A
467
−0.524
36.191
14.967
1.00
40.84


ATOM
1966
CG
GLN
A
467
−1.903
36.768
14.813
1.00
40.14


ATOM
1967
CB
GLN
A
467
−2.609
37.306
16.027
1.00
36.55


ATOM
1968
CA
GLN
A
467
−1.712
38.007
17.038
1.00
33.94


ATOM
1969
C
GLN
A
467
−1.891
39.519
16.994
1.00
33.19


ATOM
1970
O
GLN
A
467
−1.208
40.231
16.271
1.00
33.32


ATOM
1971
N
GLU
A
468
−2.797
40.063
17.768
1.00
33.44


ATOM
1972
OE2
GLU
A
468
−7.657
40.802
18.969
1.00
44.61


ATOM
1973
OE1
GLU
A
468
−6.465
41.900
20.497
1.00
44.24


ATOM
1974
CD
GLU
A
468
−6.664
41.480
19.332
1.00
44.10


ATOM
1975
CG
GLU
A
468
−5.602
41.832
18.305
1.00
41.64


ATOM
1976
CB
GLU
A
468
−4.238
41.582
18.934
1.00
38.28


ATOM
1977
CA
GLU
A
468
−3.092
41.457
17.917
1.00
35.15


ATOM
1978
C
GLU
A
468
−1.956
42.299
18.485
1.00
33.88


ATOM
1979
O
GLU
A
468
−1.706
43.397
17.980
1.00
32.88


ATOM
1980
N
CYS
A
469
−1.382
41.873
19.618
1.00
32.54


ATOM
1981
CA
CYS
A
469
−0.374
42.738
20.230
1.00
32.43


ATOM
1982
CB
CYS
A
469
−1.019
43.591
21.320
1.00
34.38


ATOM
1983
SG
CYS
A
469
−1.294
42.874
22.918
1.00
36.46


ATOM
1984
C
CYS
A
469
0.888
42.055
20.713
1.00
29.85


ATOM
1985
O
CYS
A
469
1.786
42.811
21.105
1.00
30.62


ATOM
1986
N
PHE
A
470
1.027
40.739
20.624
1.00
26.22


ATOM
1987
CA
PHE
A
470
2.314
40.147
21.073
1.00
25.07


ATOM
1988
CB
PHE
A
470
2.163
38.694
21.471
1.00
21.88


ATOM
1989
CG
PHE
A
470
1.492
38.480
22.808
1.00
21.60


ATOM
1990
CD1
PHE
A
470
0.810
39.497
23.450
1.00
19.78


ATOM
1991
CD2
PHE
A
470
1.556
37.251
23.414
1.00
19.41


ATOM
1992
CE1
PHE
A
470
0.182
39.309
24.658
1.00
20.26


ATOM
1993
CE2
PHE
A
470
0.932
37.046
24.634
1.00
20.13


ATOM
1994
CZ
PHE
A
470
0.257
38.065
25.257
1.00
20.62


ATOM
1995
C
PHE
A
470
3.351
40.383
19.999
1.00
24.85


ATOM
1996
O
PHE
A
470
2.994
40.592
18.836
1.00
23.37


ATOM
1997
N
GLN
A
471
4.610
40.404
20.389
1.00
23.76


ATOM
1998
CA
GLN
A
471
5.714
40.672
19.491
1.00
25.96


ATOM
1999
CB
GLN
A
471
6.350
42.028
19.794
1.00
27.26


ATOM
2000
CG
GLN
A
471
5.453
43.201
19.442
1.00
31.81


ATOM
2001
CD
GLN
A
471
6.014
44.575
19.678
1.00
33.37


ATOM
2002
OE1
GLN
A
471
5.258
45.547
19.668
1.00
35.13


ATOM
2003
NE2
GLN
A
471
7.323
44.723
19.885
1.00
35.41


ATOM
2004
C
GLN
A
471
6.772
39.578
19.615
1.00
25.85


ATOM
2005
O
GLN
A
471
6.668
38.670
20.433
1.00
23.32


ATOM
2006
N
GLU
A
472
7.771
39.683
18.760
1.00
27.21


ATOM
2007
OE2
GLU
A
472
8.898
41.817
17.307
1.00
43.27


ATOM
2008
OE1
GLU
A
472
9.685
41.624
15.282
1.00
44.72


ATOM
2009
CD
GLU
A
472
9.267
41.115
16.344
1.00
42.17


ATOM
2010
CG
GLU
A
472
9.207
39.605
16.387
1.00
39.41


ATOM
2011
CB
GLU
A
472
9.836
38.975
17.600
1.00
34.14


ATOM
2012
CA
GLU
A
472
8.867
38.730
18.759
1.00
30.87


ATOM
2013
C
GLU
A
472
9.656
38.993
20.037
1.00
30.26


ATOM
2014
O
GLU
A
472
9.773
40.161
20.396
1.00
29.23


ATOM
2015
N
ARG
A
473
10.256
37.970
20.584
1.00
31.97


ATOM
2016
CA
ARG
A
473
11.073
38.106
21.778
1.00
34.21


ATOM
2017
CB
ARG
A
473
11.230
36.691
22.340
1.00
34.97


ATOM
2018
CG
ARG
A
473
12.230
36.454
23.443
1.00
37.52


ATOM
2019
CD
ARG
A
473
11.661
35.449
24.436
1.00
39.68


ATOM
2020
NE
ARG
A
473
12.564
35.155
25.532
1.00
41.06


ATOM
2021
CZ
ARG
A
473
12.469
35.726
26.729
1.00
42.18


ATOM
2022
NH1
ARG
A
473
13.327
35.423
27.693
1.00
42.83


ATOM
2023
NH2
ARG
A
473
11.559
36.660
26.960
1.00
42.33


ATOM
2024
C
ARG
A
473
12.451
38.665
21.456
1.00
36.39


ATOM
2025
O
ARG
A
473
13.092
38.294
20.489
1.00
36.44


ATOM
2026
N
SER
A
474
12.918
39.567
22.276
1.00
37.92


ATOM
2027
OG
SER
A
474
15.308
38.413
23.524
1.00
36.38


ATOM
2028
CB
SER
A
474
15.293
39.122
22.290
1.00
37.61


ATOM
2029
CA
SER
A
474
14.200
40.202
22.359
1.00
37.96


ATOM
2030
C
SER
A
474
14.436
41.341
21.403
1.00
39.67


ATOM
2031
O
SER
A
474
13.589
42.259
21.336
1.00
40.16


END









EXAMPLE 5
TACE Inhibitor Design
The TACE x-ray diffraction coordinates were read into a Sybyl v.6.3 (Tripos Associates) software package and the x-ray structure analyzed graphically. The regions within the original x-ray coordinates were corrected for chirality and atom type. The modified x-ray model of TACE was energy minimized until all the TACE structural parameters were at their equilibrium or optimal values. The energy minimized structure was then compared to the original structure to confirm the absence of anomalies.
Sites of specific interaction(s) between TACE and the co-crystallized inhibitor were identified. The inhibitor was then removed from the X-ray complex model, leaving only the TACE structural model.
Candidate inhibitors were chosen based upon the sites of interaction with TACE and the candidate inhibitor in light of the sites of interaction identified previously for the co-crystallized inhibitor. Once specific candidate inhibitor-TACE interactions were determined, docking studies were performed to provide preliminary “modeled” complexes of selected candidate inhibitors with TACE.
Constrained conformational analysis was performed using molecular dynamics (MD) to check the integrity of the modeled TACE-inhibitor complex. Once the complex reached its most favorable conformational state, the structure as proposed by the MD study was analyzed visually to insure that the modeled complex complied with known experimental SAR/QSAR based on measured binding affinities.
The modeled candidate inhibitor-TACE complex was analyzed. The region of the complex associated with the S1′ regions of TACE containing a small solvent exposed channel was chosen as a target region for modification. A single modification, a benzyl group which becomes embedded within the target region, was selected based upon computational and synthetic chemical principles. The benzyl group was oriented on an appropriate zinc chelator core so as to be projected into the S1′S3′ pocket. This modification converts an inhibitor which was generally MMP selective to one which is TACE selective. IC50 data for the inhibitor with a benzyl modification confirm this selectivity.
Structure-based analoging for optimization of inhibitor potency, selectivity and physical drug-like properties was performed in an iterative manner.
EXAMPLE 6
Measuring TACE Inhibition
250 μM peptide substrate (Ac-SPLAQAVRSSSR-NH2) was incubate with 3.7 U/μL TACE in a buffer containing 10 mM TRIS HCl, pH 7.4, 10% glycerol at 25 degrees C. The reaction was quenched with 1% TFA (final concentration) after two hours. The reaction mixture was separated by HPLC on a Hewlett-Packard 1150. The product formation was monitored by absorbance at 220 nm.
The linearity of the reaction was confirmed (r2>0.85). The mean (x±sem) of the control rate was calculated and compared for statistical significance (p<0.05) with drug-tested rates using Dunnett's multiple comparison test. Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression.
From the foregoing description and examples, one skilled in the art can ascertain the essential characteristics of the invention and, without departing from the spirit and scope of the invention, can make changes, modifications, and variations of the invention to adapt it to various uses and conditions. Additionally, the disclosure of all publications and patent applications cited above, including U.S. provisional patent application serial No. 60/073,709 and U.S. provisional patent application serial No. 60/135,499, are expressly incorporated herein by reference in their entireties to the same extent as if each were incorporated by reference individually.

## Claims

1. A method of identifying a compound that associates with tumor necrosis factor-α-converting enzyme (TACE), comprising (A) using atomic coordinates that comprise the coordinates of Table 1 to design an associating compound that forms a bond with a catalytic domain of a TACE polypeptide, (B) synthesizing said compound, and (C) determining in vitro whether said compound associates with said catalytic domain and whether said compound inhibits, meditates, or otherwise regulates TNF-α-converting enzyme activity.

2. The method according to claim 1, wherein said associating compound is an inhibitor, mediator, or other compound that regulates TNF-α-converting enzyme activity.

3. The method of claim 1, wherein said associating compound is a competitive inhibitor, un-competitive inhibitor, or non-competitive inhibitor.

4. The method according to claim 1, wherein the associating compound is designed to incorporate a moiety that chelates zinc.

5. The method according to claim 1, wherein the associating compound is designed to associate with the S1′ region of TNF-α-converting enzyme.

6. The method according to claim 1, wherein the associating compound is designed to associate with the S1′S3′ pocket of TNF-α-converting enzyme.

7. The method according to claim 1, wherein the associating compound is designed to introduce a non-polar group which occupies the S1′ pocket of TNF-α-converting enzyme.

8. The method according to claim 1, wherein the associating compound is designed to introduce a group which lies within the channel joining S1′-S3′ pockets of TNF-α-converting enzyme and which makes appropriate van der Waal contact with the channel.

9. The method according to claim 1, wherein the associating compound is designed to form a hydrogen bond with Leu348 or Gly349 of TNF-α-converting enzyme.

10. The method according to claim 1, wherein the associating compound is designed to form a hydrogen bond with Leu348 or Gly349 on the backbone amide groups of TNF-α-converting enzyme.