# Patent

## Title
Crystal of recombinant interferon with altered spatial configuration, three-dimensional structure and uses thereof

## Abstract

This invention provides crystalline recombinant interferon (rSIFN-co (SEQ ID NO: 1)) having (i) the same amino acid sequence as that of human consensus interferon, and (ii) altered three-dimensional structure as compared to IFN-α2b. The interferon of the present invention exhibits enhanced biological activities. The present invention also provides a structural model of said interferon useful for drug screening and/or drug design, and mimetics of said interferon.

## Background
FIELD OF THE INVENTION
This invention relates in general to crystalline recombinant interferon with altered spatial configuration, its crystallization method and three-dimensional structure thereof, uses of said crystal and its three-dimensional structure, and mimetics of said recombinant interferon.
BACKGROUND OF THE INVENTION
Interferon (IFN) is a kind of soluble protein produced by a variety of cells which has many important biological functions, including anti-viral, anti-tumor, and immunoregulatory functions. Interferons can be divided into type I, type II, and type III interferons according to the differences in the types of producing cells, receptors and biological activities etc. Type I IFNs, which are mostly induced by viruses and synthetic double-stranded RNA, are also known as anti-viral interferons. There are three forms of type I interferons: IFNα, INFβ, IFNω. Type II IFN, also known as immune interferon or IFNγ, is produced by the T cells, and is an important immunoregulatory factor in vivo. Type III interferon is made up of IFN-λ molecules.
In recent years, many companies in the world have engaged in the research of interferon, as exemplified by a number of pertinent patents and disclosure documents. For example, U.S. Pat. Nos. 4,695,623 and 4,897,471 disclosed new types of human interferon polypeptides which have amino acid sequences containing the common or predominant amino acids found in naturally occurring α-interferon polypeptides. That new type of interferon was named IFN-con (consensus interferon α). The disclosed amino acid sequences were named IFN-con1, IFN-con2 and IFN-con3. Genes encoding IFN-cons and gene expression in Escherichia coli were also disclosed. Compared with leukocyte interferon or other type I interferons, studies have shown that recombinant IFN-con has higher anti-viral, anti-proliferative and natural killer cell activities in vitro.
U.S. Pat. No. 5,372,808 disclosed the use of human IFN-con in the treatment of diseases. Compared with previous clinically approved α-interferon such as Intron®A (IFN-α2b, SGP) produced by Schering-Plough, recombinant human IFN-con has been shown to have lower side-effects. By the end of 1997, the FDA had approved the use of human IFN-con, which was produced by Amgen and sold under the brand name Infergen® (interferon alfacon-1) (SEQ ID NO: 1), for clinical treatment of hepatitis C.
Both U.S. Pat. No. 7,364,724 and Chinese Patent Publication No. CN1740197A (incorporated in their entirety as references to this application) disclosed a recombinant interferon (hereafter referred to as “rSIFN-co” (SEQ ID NO: 1)) that has enhanced efficacy, fewer side-effects and can be used in high doses. The said recombinant interferon has the same amino acid sequence as Infergen® (SEQ ID NO: 1), but has different spatial structure and biological efficacy. In addition, the above-mentioned Chinese Patent Publication No. CN1740197A also disclosed the crystal form of said recombinant interferon and its crystallization method thereof; however, the crystals were of poor quality, had loose internal structures and an X-ray diffraction resolution as low as 5 Å such that they were not suitable for obtaining useful structural information from further analysis of the protein spatial structure. It is of great interest to obtain good quality crystals of the said recombinant interferon with altered structure and functions at high X-ray diffraction resolution so as to determine the three-dimensional structure of said recombinant interferon, establish its model, and take advantage of said structure and model to perform drug design and to improve the efficacy of known interferons.
SUMMARY OF THE INVENTION
This invention relates to the crystal of the recombinant interferon disclosed by U.S. Pat. No. 7,364,724 and Chinese Patent Publication No. CN1740197A, and this recombinant interferon comprises the amino acid sequence of SEQ ID NO: 1. Further, this invention provides the crystallization method of this recombinant interferon and the composition comprising said crystal. In addition, this invention provides the three-dimensional structure of this recombinant interferon, which is different from the three-dimensional structure of IFN-α2b published in the art and the three-dimensional structure of Infergen® (SEQ ID NO: 1) from Amgen (U.S.) based on computational modelling. Also provided are uses of said three-dimensional structure for identifying the candidate compound interacting with said interferon, designing mimetics of said interferon and performing rational drug design based on computer. Still further, this invention provides mimetics of said recombinant interferon, composition comprising said mimetics and uses of said crystal, mimetics or composition for preparation of medicament for treatment of viral diseases and/or tumors.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a monocrystal of the recombinant interferon (rSIFN-co (SEQ ID NO: 1)) of the present invention used in crystal structure analysis.
FIG. 2 shows an X-ray diffractogram of the rSIFN-co (SEQ ID NO: 1) crystal (2.6 Å resolution).
FIG. 3 shows a partial 1.0σ electron-density map of 2Fo-Fc format within the crystal structure of rSIFN-co (SEQ ID NO: 1).
FIG. 4 shows a distribution map of the average temperature factors along the amino acid residues for all the atoms of rSIFN-co (SEQ ID NO: 1). (a) A chain; (b) B chain.
FIG. 5 shows the (Φ, Ψ) value distribution on the Ramachandran plot of all the amino acid residues in the model of the rSIFN-co (SEQ ID NO: 1) protein molecular structure. Based on an analysis of 118 structures with resolution of at least 2.0 Å and R-factor no greater than 20%, a good quality model would be expected to have over 90% in the most favoured regions; the statistical data as follows:










Plot statistics

















Residues in most favoured regions [A, B, L]
240
90.6%


Residues in additional allowed regions [a, b, l, p]
24
9.1%


Residues in generously allowed regions [~a, ~b,
1
0.4%


~l, ~p]


Residues in disallowed regions
0
0.0%


Number of non-glycine and non-proline residues
265
100.0%


Number of end-residues (excl. Gly and Pro)
127


Number of glycine residues
18


Number of praline reidues
6


Total number of residues
416









FIG. 6 shows a unit cell packing diagram of rSIFN-co (SEQ ID NO: 1).
FIG. 7 shows the assembled structure of the rSIFN-co (SEQ ID NO: 1) dimers.
FIG. 8 shows the organization of rSIFN-co (SEQ ID NO: 1) crystallographic dimers (FIG. 8a, FIG. 8b) and the root-mean square deviation (RMSD) of α carbon atoms (the boxes represent missing residues) (FIG. 8c).
FIG. 9 shows the monomolecular structure of rSIFN-co (SEQ ID NO: 1) (main chain demonstrated only); (A) Side view; (B) Top view; (C) Topology diagram; (D) Topological organization of the secondary structures.
FIG. 10 shows the sequence alignment between the secondary structures of rSIFN-co (SEQ ID NO: 1) and its amino acid sequence; the gray boxes represent amino acid residues that were not set up in the structure; the blue boxes represent amino acid residues which were set up as Ala or Gly. The solid lines represent two pairs of disulfide linkages and the green subscripts represent one disulfide linkage that has been constructed in the structure.
FIG. 11 shows the sequence alignment of rSIFN-co (SEQ ID NO: 1) protein and homologous IFN polypeptides.
FIG. 12 shows a comparative diagram of the three-dimensional structure of rSIFN-co (SEQ ID NO: 1) and IFN-α2b.
FIG. 13 shows the superimposed image of rSIFN-co (SEQ ID NO: 1) (in red) and IFN-α2b (in yellow).
FIG. 14 shows the comparative differences between the three-dimensional structure of rSIFN-co (SEQ ID NO: 1) and the computational model of Infergen® (SEQ ID NO: 1) from Amgen (U.S.).
FIG. 15 shows (a) the combined model of protein IFN-α and its receptor; (b) the diagram of the functional domain of protein IFN-α (the important functional domain is illustrated by blue ring).
FIG. 16 shows the mean enzyme concentration in blood-time curve after subcutaneous injection of 9 μg rSIFN-co (SEQ ID NO: 1) and 9 μg Infergen® (SEQ ID NO: 1) to 18 subjects.



DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed description of the invention provided to aid those skilled in the art for practicing the present invention.
Recombinant Interferon (rSIFN-co (SEQ ID NO: 1))
The purified recombinant interferon, which has been crystallized in this invention, is obtained from the method disclosed by the examples 1 and 2 of the specification of the U.S. Pat. No. 7,364,724 and/or pages 11-17 of the specification of the Chinese Patent Publication No. CN1740197 Å. The characterization of this recombinant interferon is disclosed in the U.S. Pat. No. 7,364,724 and/or the Chinese Patent Publication No. CN1740197 Å. In one embodiment, the amino acid sequence of the present recombinant interferon, as well as the nucleotide sequence encoding the same, are shown below:










M  C  D   L  P  Q  T   H  S  L   G  N  R   R  A  L  I   L  L  A



 


1
ATGTGCGACC TGCCGCAGAC CCACTCCCTG GGTAACCGTC GTGCTCTGAT CCTGCTGGCT


 



TACACGCTGG ACGGCGTCTG GGTGAGGGAC CCATTGGCAG CACGAGACTA GGACGACCGA


 



Q  M  R   R  I  S  P   F  S  C   L  K  D   R  H  D  F   G  F  P


 


61
CAGATGCGTC GTATCTCCCC GTTCTCCTGC CTGAAAGACC GTCACGACTT CGGTTTCCCG


 



GTCTACGCAG CATAGAGGGG CAAGAGGACG GACTTTCTGG CAGTGCTGAA GCCAAAGGGC


 



Q  E  E   F  D  G  N   Q  F  Q   K  A  Q   A  I  S  V   L  H  E


 


121
CAGGAAGAAT TCGACGGTAA CCAGTTCCAG AAAGCTCAGG CTATCTCCGT TCTGCACGAA


 



GTCCTTCTTA AGCTGCCATT GGTCAAGGTC TTTCGAGTCC GATAGAGGCA AGACGTGCTT


 



M  I  Q   Q  T  F  N   L  F  S   T  K  D   S  S  A  A   W  D  E


 


181
ATGATCCAGC AGACCTTCAA CCTGTTCTCC ACCAAAGACT CCTCCGCTGC TTGGGACGAA


 



TACTAGGTCG TCTGGAAGTT GGACAAGAGG TGGTTTCTGA GGAGGCGACG AACCCTGCTT


 



S  L  L   E  K  F  Y   T  E  L   Y  Q  Q   L  N  D  L   E  A  C


 


241
TCCCTGCTGG AAAAATTCTA CACCGAACTG TACCAGCAGC TGAACGACCT GGAAGCTTGC


 



AGGGACGACC TTTTTAAGAT GTGGCTTGAC ATGGTCGTCG ACTTGCTGGA CCTTCGAACG


 



V  I  Q   E  V  G  V   E  E  T   P  L  M   N  V  D  S   I  L  A


 


301
GTTATCCAGG AAGTTGGTGT TGAAGAAACC CCGCTGATGA ACGTTGACTC CATCCTGGCT


 



CAATAGGTCC TTCAACCACA ACTTCTTTGG GGCGACTACT TGCAACTGAG GTAGGACCGA


 



V  K  K   Y  F  Q  R   I  T  L   Y  L  T   E  K  K  Y   S  P  C


 


361
GTTAAAAAAT ACTTCCAGCG TATCACCCTG TACCTGACCG AAAAAAAATA CTCCCCGTGC


 



CAATTTTTTA TGAAGGTCGC ATAGTGGGAC ATGGACTGGC TTTTTTTTAT GAGGGGCACG


 



A  W  E   V  V  R  A   E  I  M   R  S  F   S  L  S  T   N  L  Q


 


421
GCTTGGGAAG TTGTTCGTGC TGAAATCATG CGTTCCTTCT CCCTGTCCAC CAACCTGCAG


 



CGAACCCTTC AACAAGCACG ACTTTAGTAC GCAAGGAAGA GGGACAGGTG GTTGGACGTC


 



 E  R  L   R  R  K  E (SEQ ID NO: 1)


 


481
GAACGTCTGC GTCGTAAAGA ATAA (SEQ ID NO: 2)


 



CTTGCAGACG CAGCATTTCT TATT (SEQ ID NO: 3)






Moreover, the circular dichroism spectrum (CD) of the present recombinant interferon in ranges of 190-250 nm and 250-320 nm is significantly different from the corresponding CD of INFERGEN® (SEQ ID NO: 1) when determined under the same conditions (see page 3, lines 22-25, example 3 and FIGS. 6A-D of the Chinese Patent Publication No. CN1740197A,).
In addition, the three-dimensional structure of the present recombinant interferon is also different from the three-dimensional structure of IFN-α2b published in the art (see FIG. 12) and the three-dimensional structure of INFERGEN® (SEQ ID NO: 1) based on computational modeling (see KORN, A P et al., Journal of Interferon Research 1994, 14: 1-9). There are obvious differences between the AB loops of the two, and their BC loops also cannot overlap completely (see FIG. 14).
Furthermore, after intramuscular injection of the present recombinant interferon into subjects whose BMI ranged from 18 to 23, the time of blood sample collection was plotted against the concentration of 2-5A oligonucleotidase (also referred to as 2′,5′-OAS) in the serum of the subjects. The chart generally shows a two-peak pattern, and the resulting area under the curve of this chart is significantly greater than that of INFERGEN® (SEQ ID NO: 1) after injection under the same conditions. The half-life period of this recombinant interferon is longer than that of INFERGEN® (SEQ ID NO: 1) after injection into the body.
The experimental results have also confirmed that the present recombinant interferon is more effective than any interferon used clinically at present (including INFERGEN® (SEQ ID NO: 1)). For example, for HBV, the recombinant interferon from this invention is capable of not only inhibiting DNA replication of HBV, but also inhibiting secretion of both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). The efficiency of inhibiting DNA replication of hepatitis B core antigen (HBcAg) by this interferon is about twice that of INFERGEN® (SEQ ID NO: 1). The in vitro pharmacodynamics of the present recombinant interferon shows that it is capable of not only inhibiting the DNA replication of HBV, but also inhibiting secretion of both hepatitis B surface antigen and hepatitis B e antigen. The cytotoxicity of the present recombinant interferon is only 1⁄8 that of the current clinically used interferons, but its antiviral activity is as much as 5-20 times greater; meanwhile, the biological responses of the present recombinant interferon is more effective, more broad-spectrum and longer lasting in the human body.
Furthermore, with respect to prevention of viral diseases or treatment of tumor, the present recombinant interferon shows higher antiviral activity and less side effects compared with any other interferons (including INFERGEN® (SEQ ID NO: 1)). For example, this recombinant interferon possesses not only an antiviral activity 20 times as great as that of the interferons currently in clinical use, but also a more effective anti-tumor (such as breast cancer and cervical cancer) function compared with recombinant human interferon α (including INFERGEN® (SEQ ID NO: 1)). It also shows greatly reduced toxic side effects and can be safely used in large dosages (each dose >10 million IU), making it possible to treat viral diseases or tumors which require large dosages of interferon.
Thus, the present recombinant interferon has a different spatial configuration, enhanced biologic activities and different pharmacokinetics characteristics as compared with INFERGEN® (SEQ ID NO: 1).
As used herein, the terms ‘spatial configuration’, ‘spatial structure’, ‘three-dimensional structure’ and ‘three-dimensional configuration’ can be used interchangeably.
Therefore, in one embodiment, the present recombinant interferon comprises the amino acid sequence of SEQ ID NO: 1 and is encoded by the nucleotide sequence comprising SEQ ID NO: 2. Further, the present recombinant interferon has the amino acid sequence of SEQ ID NO: 1, and is encoded by the nucleotide sequence of SEQ ID NO: 2. In comparison with interferons such as INFERGEN® (SEQ ID NO: 1), which has the amino acid sequence of SEQ ID NO: 1 or the same amino acid sequence as the present recombinant interferon, but is not encoded by the nucleotide sequence of SEQ ID NO: 2, the present recombinant interferon has a different spatial configuration and/or enhanced biologic activities and/or different pharmacokinetics characteristics. For example, the present recombinant interferon has a different spatial configuration and enhanced biologic activities, different spatial configuration and different pharmacokinetics characteristics, or enhanced biologic activities and different pharmacokinetics characteristics. Further, said different spatial configuration includes: the circular dichroism spectrum (CD) of the present recombinant interferon at 190-250 nm and/or 250-320 nm is significantly different from the corresponding CD of INFERGEN® (SEQ ID NO: 1) when determined under the same conditions. The enhanced biological activities include: enhanced antiviral activity, enhanced anti-tumor activity, less side effects and/or could be used in large dosages (e.g. each dose >10 million IU). For example, said enhanced biological activities can be enhanced antiviral activity and enhanced anti-tumor activity and the like. Furthermore, said tumors can be breast cancer and cervical cancer. The different pharmacokinetics characteristics include: after intramuscular injection of the recombinant interferon in subjects whose BMI ranged from 18 to 23, the time of blood sample collection was plotted against the concentration of 2-5A oligonucleotidase in the serum of the subjects, and the resulting area under the curve of this chart is significantly greater and/or the half-life of this recombinant interferon in the body is longer than those of INFERGEN® (SEQ ID NO: 1) after injection under the same conditions
In another embodiment, the present recombinant interferon can be produced by the method comprising the following steps: introducing a nucleotide sequence comprising SEQ ID NO: 2 that encodes the recombinant interferon into an isolated host cell; culturing the host cell under appropriate condition for expression of the recombinant interferon; and harvesting the recombinant interferon, wherein the recombinant interferon has an amino acid sequence of SEQ ID NO: 1, and the recombinant interferon inhibits secretion of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) of Hepatitis B Virus. Further, said host cell is Escherichia coli, such as Escherichia coli LGM 194. Further, the nucleotide sequence comprising SEQ ID NO: 2 is under the control of the promoter PBAD. Further, the harvesting step comprises extraction of the interferon from the fermentation broth, collection of the inclusion bodies, denaturation and renaturation of the harvested interferon. Still further, the harvesting step also comprises separation and purification of the recombinant interferon (see the claims of U.S. Pat. No. 7,364,724).
Crystalline Recombinant Interferon and Crystallization Method Thereof
Crystalline Recombinant Interferon
This invention provides a crystalline recombinant interferon.
In one embodiment, this invention provides a crystalline recombinant interferon comprising the amino acid sequence of SEQ ID NO: 1. Further, this crystal belongs to the trigonal system. In one embodiment, the space group of this crystal is P3121. In some embodiments, the unit cell parameters of this crystal are a=b=77.92 Å, c=125.935 Å, α=β=90°, γ=120°, with a variability of at most 5% in all cell parameters. In some embodiments, said crystal contains two molecules in one asymmetric unit. In some embodiments, said crystal comprises covalently or non-covalently bound metal ions. Further, said mental ions can be magnesium ion, zinc ion and the like, these metal ions can mediate the formation of the interferon dimers in the crystal. In some embodiments, said recombinant interferon is encoded by the nucleotide sequence comprising SEQ ID NO: 2.
In a still further embodiment, this invention provides a crystalline recombinant interferon comprising the amino acid sequence of SEQ ID NO: 1, preferably the recombinant interferon having the amino acid sequence of SEQ ID NO: 1, in which the space group of this crystal is P3121, with two molecules in one asymmetric unit, and the unit cell parameters are a=b=77.92 Å, c=125.935 Å, α=β=90°, γ=120°, with a variability of at most 5% in all cell parameters. Further, such recombinant interferon is encoded by the nucleotide sequence comprising SEQ ID NO: 2, preferably encoded by the nucleotide sequence of SEQ ID NO: 2.
Crystallization Method
This invention provides a method for preparing or culturing the present crystalline recombinant interferon.
In one embodiment, this invention provides a method for preparing or culturing the present crystalline recombinant interferon, comprising the steps of: concentrating the recombinant interferon to about 3-3.5 mg/ml, and leaving it in the crystallization solution containing Li2SO4, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) and MgCl2 for an appropriate period of time to obtain the crystal. Further, said method for culturing crystal is performed at room temperature such as 293K. In some embodiments, this crystal can be cultured by the hanging drop method or the sitting drop method, preferably the hanging drop method (also referred to as hanging drop vapor diffusion method). In some embodiments, said crystallization solution contains about 1.0-about 1.5M Li2SO4, about 0.05-about 0.15M CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) and about 0.01-about 0.03 M MgCl2. In some embodiments, the pH value of the crystallization solution is in the range of about 10.5-about 12.0, preferably about 11.1. In some embodiments, said crystallization solution contains 1.2M Li2SO4, 0.1M CAPS (3-(cyclohexylamino)-1-propanesulfonic acid), pH 11.1, 0.02 M MgCl2. In some embodiments, the method for culturing the crystal includes leaving the crystallization solution containing said recombinant interferon to stand for about 1 day to about 2 weeks, preferably about 2 days to about 10 days, more preferably about 3 days to about 1 week, such as 3 days to 1 week.
X-Ray Crystallographic Analysis
Each of the constituent amino acids of interferon disclosed herein is defined by a set of structural coordinates (also known as “atomic coordinates”). The term “structural coordinates” refers to Cartesian coordinates derived from mathematical equations related to the patterns obtained by the diffraction of a monochromatic beam of x-rays by the atoms (scattering centers) of the present interferon in crystalline form. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are then used to establish the positions of the individual atoms of the interferon protein or protein/ligand complex.
Slight variations in structural coordinates can be generated by mathematically manipulating the interferon or interferon/ligand structural coordinates. For example, the structural coordinates disclosed herein could be manipulated by crystallographic permutation, fractionalization, addition or subtraction of the entire set, inversion, or any combination of the above. Alternatively, modifications in the crystal structure due to mutations, additions, substitutions, and/or deletions of amino acids, or other changes in any of the components that make up the crystal, could also yield variations in structural coordinates. Such slight variations in the individual coordinates will have little effect on the overall configuration. If such variations are within an acceptable standard error as compared to the original coordinates, the resulting three-dimensional shape is considered to be structurally equivalent.
It should be noted that slight variations in individual structural coordinates of the interferon of the present invention are not expected to significantly alter the nature of the entities such as ligands that could associate with the interferon or portion thereof (e.g. the AB or the BC loop). As used herein, the “AB loop” of the present recombinant interferon means the amino acid residues 25-33 of the present recombinant interferon having the amino acid sequence of SEQ ID NO: 1; namely, the AB loop has the amino acid sequence SPFSCLKDR as shown in SEQ ID NO: 4; and the “BC loop” of the present recombinant interferon means the amino acid residues 44-52 of the present recombinant interferon having the amino acid sequence of SEQ ID NO: 1; namely, the BC loop has the amino acid sequence DGNQFQKAQ as shown in SEQ ID NO: 5. In this context, the phrase “associated with” refers to a condition of proximity between a ligand, or portions thereof, and an interferon molecule or portions thereof. The association may be non-covalent, wherein the juxtaposition is energetically favored by hydrogen bonding, van der Waals forces, or electrostatic interactions, or it may be covalent. Thus, for example, a ligand that binds to the binding pocket or region of an interferon would also be expected to bind to or interact with a structurally equivalent binding pocket or region.
In this invention, any molecule or molecular complex, or any portion thereof, that has a root mean square deviation of conserved residue backbone atoms (e.g. N, Cα, C, O, preferably Cα) of less than about 0.65 Å, when superimposed on the relevant backbone atoms described herein, is considered “structurally equivalent”. That is to say, the crystal structures of those portions of the two molecules are substantially identical, within acceptable error. Particularly preferred structurally equivalent molecules or molecular complexes are those that are defined by the entire set of structural coordinates disclosed herein±a root mean square deviation from the conserved backbone atoms of those amino acids of less than about 0.65 Å. More preferably, the root mean square deviation is at most about 0.5 Å, and even more preferably, at most about 0.35 Å. Other embodiments of this invention include a molecular complex defined by the structural coordinates for the AB or the BC loop disclosed herein±a root mean square deviation of less than about 0.65 Å, preferably at most about 0.5 Å, and more preferably at most about 0.35 Å.
The term “root mean square deviation” means the square root of the arithmetic mean of the squares of the deviations. It is a way to express the deviation or variation from a trend or object. In one embodiment, the “root mean square deviation” defines the variation in the backbone of a protein from the backbone of interferon or a portion thereof as defined by the structural coordinates described herein.
X-ray structural coordinates define a unique configuration of points in space. Those skilled in the art would understand that a set of structural coordinates for a protein or a protein/ligand complex, or a portion thereof, defines a relative set of points that, in turn, defines a configuration in three dimensions. A similar or identical configuration can be defined by an entirely different set of coordinates, provided that the distances and angles between coordinates remain essentially the same. In addition, a scalable configuration of points can be defined by increasing or decreasing the distances between coordinates by a scalar factor while keeping the angles essentially the same.
Various computational analyses can be used to determine whether a molecule or a portion thereof is “structurally equivalent”, defined in terms of its three-dimensional structure, to the interferon disclosed herein, or part of it. For example, comparisons between different structures, different conformations of the same structure, or different parts of the same structure can be made by various computational analyses. In one embodiment, such analysis can be divided into four steps: (1) load the structures to be compared; (2) define the atom equivalences in these structures; (3) perform a fitting operation; and (4) analyze the results.
Three-dimensional structure of Recombinant Interferon (rSIFN-co (SEQ ID NO: 1))
This invention provides the three-dimensional structure of the present recombinant interferon.
This three-dimensional structure is different from the three-dimensional structure of IFN-α2b published in the art (see FIG. 12) and the structure of the computational model of INFERGEN® (SEQ ID NO: 1) of U.S. Amgen (see FIG. 14), especially in the AB and BC loops.
In one embodiment, the three-dimensional structure of said recombinant interferon contains the atomic coordinates of recombinant interferon as shown in table 7, said atomic coordinates optionally have a variability of root mean square deviation from the conserved backbone atoms, preferably Cα (also referred to as ‘α carbon atom’), of less than about 0.65 Å, preferably or about 0.5 Å, and more preferably about 0.35 Å.
In one embodiment, in the above-mentioned three-dimensional structure of the recombinant interferon, each monomer of said recombinant interferon is composed of 6 segments of α-helix, a segment of 310 helix, and the connecting peptides between them. The corresponding amino acid residue locations of said 6 segments of the α-helices are 13-20, 50-68, 70-76, 79-100, 114-133, and 138-160; the corresponding amino acid residue location of said segment of 310 helix is 40-43. The folding of the monomer structure belongs to the helical cytokine type, having the following characteristics: after superimposition of the Cα-backbone of said recombinant interferon and the Cα-backbone of IFN-α2b protein using least squares method, the location root-mean-square deviation of Cα in the 25-33 residues (AB loop) of said recombinant interferon and Cα in the corresponding residues of IFN-α2b protein is 3.63 Å±5%.
Preferably, the location root-mean-square deviation of Cα at residue 25 of said recombinant interferon and IFN-α2b protein is 3.291 Å±5%, the location root-mean-square deviation of Cα at residue 26 is 4.779 Å±5%; the location root-mean-square deviation of Cα at residue 27 is 5.090 Å±5%; the location root-mean-square deviation of Cα in the 28 residue is 3.588 Å±5%; the location root-mean-square deviation of Cα at residue 29 is 2.567 Å±5%, the location root-mean-square deviation of Cα at residue 30 is 2.437 Å±5%; the location root-mean-square deviation of Cα at residue 31 is 3.526 Å±5%; the location root-mean-square deviation of Cα at residue 32 is 4.820 Å±5%; and the location root-mean-square deviation of Cα at residue 33 is 2.756 Å±5%.
More preferably, the location root-mean-square deviation of Cα at residues 44-52 (BC loop) of said recombinant interferon and Cα in the corresponding residues of IFN-α2b protein is 2.90 Å±5%. Wherein, the location root-mean-square deviation of Cα at residue 44 of both said recombinant interferon and IFN-α2b protein is 1.614 Å±5%; the location root-mean-square deviation of Cα at residue 45 is 1.383 Å±5%; the location root-mean-square deviation of Cα at residue 46 is 2.735 Å±5%; the location root-mean-square deviation of Cα at residue 47 is 2.709 Å±5%; the location root-mean-square deviation of Cα at residue 48 is 5.018 Å±5%; the location root-mean-square deviation of Cα at residue 49 is 4.140 Å±5%; the location root-mean-square deviation of Cα at residue 50 is 3.809 Å±5%; the location root-mean-square deviation of Cα at residue 51 is 2.970 Å±5%; and the location root-mean-square deviation of Cα at residue 52 is 0.881 Å±5%. The “location root-mean-square deviation” listed above are all root-mean-square deviations of the coordinate positions.
In another aspect, this invention provides a selected portion of the three-dimensional structure of the present recombinant interferon, which contains atomic coordinates of one or more amino acid residues from amino acid residues 25-33 and/or 45-52 in table 7. In some embodiments, the “one or more amino acid residues” described herein include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 amino acid residues. In some embodiments, the “selected portion of said three-dimensional structure” contains the atomic coordinates of the amino acid residues 25-33 and/or 44-52 in table 7. In some embodiments, the “selected portion of the three-dimensional structure” contains the atomic coordinates of at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 amino acid residues in table 7. In some embodiments, said atomic coordinates have a variability of root mean square deviation from the conserved backbone atoms (preferably Cα) of less than about 0.65 Å, preferably about 0.5 Å, and more preferably about 0.35 Å.
In another aspect, this invention provides the protein spatial structure model comprising the three-dimensional structure of the present recombinant interferon. In one embodiment, said protein spatial structure model could be an electron density map, a wire-frame model, a chicken-wire model, a space-filling model, a stick-model, a ribbon model and a molecular surface model and the like.
In still another aspect, the present invention provides a scalable three-dimensional configuration of points, wherein at least a portion of said points are derived from the structural coordinates disclosed herein, or from peptides comprising the AB loop or the BC loop of the present recombinant interferon. In one embodiment, the scalable three-dimensional configuration of points is displayed as a holographic image, a stereo diagram, a model, or a computer-displayed image.
The Application of Three-Dimensional Structure
Screening/Designing Candidate Substance that could Interact with Recombinant Interferon
In one aspect, this invention provides a method for screening/designing candidate compounds that could interact with the present recombinant interferon. Further, said method utilizes the three-dimensional structure of the present recombinant interferon. Still further, said method is based on a computer. In one embodiment, this invention provides a computer-based method for identifying candidate compounds that could interact with recombinant interferon, said method comprises the steps of: (a) providing a three-dimensional structure comprising the atomic coordinates of the recombinant interferon as shown in table 7, said atomic coordinates optionally have a variability of root mean square deviation from the conserved backbone atoms (preferably Cα) of less than about 0.65 Å, preferably about 0.5 Å, and more preferably about 0.35 Å; and (b) selecting a candidate compound that comprises structural features capable of interacting with said three-dimensional structure or selected portion thereof, thereby identifying a candidate compound that could interact with said recombinant interferon. In some embodiments, said structural features are selected from the group consisting of antigenic sites, hydrophilic properties, surface accessibility, and structural motifs. In some embodiments, the selection and identification of candidate compounds in step (b) comprises: (i) generating three-dimensional structures for a plurality of candidate compounds; and (ii) fitting each of the three-dimensional structures of step (i) against the three-dimensional structure of step (a) or selected portion thereof to find the most energetically favorable interaction, thereby identifying a candidate compound that could interact with the recombinant interferon. In some embodiments, said method further comprises the steps of: (c) obtaining or synthesizing the candidate compound; and (d) contacting the candidate compound with said recombinant interferon to determine the ability of the candidate compound to interact with said recombinant interferon. Further, the step of determining the ability of the candidate compound to interact with said recombinant interferon may further comprise measuring the activity of said recombinant interferon when contacted with the candidate compound. Interferon activities to be measured include, for example, antivirus activity, anti-tumor activity, anti-proliferation activity, natural killer cell activation, and immunomodulatory activity. In some embodiments, said candidate compound is a ligand bound to said recombinant interferon or selected portion thereof. For example, said ligand is selected from the group consisting of receptor, modifier, agonist and antagonist, said receptor could be IFNAR1, IFNAR2 or their complex, and said selected portion comprises one or more amino acid residues from the amino acid residues 25-33 (AB loop) and/or 45-52 (BC loop) of said recombinant interferon. Further, said selected portion comprises the amino acid residues 25-33 and/or 44-52 of said recombinant interferon.
In another aspect, the present invention provides a method for determining potential ligands that bind to the present recombinant interferon. In one embodiment, the method includes exposing a crystal disclosed herein to one or more samples comprising potential ligands, and determining whether a ligand-interferon molecular complex is formed.
In another aspect, the present invention provides a method for acquiring structural information to design potential ligands that can form molecular complexes with interferon. In one embodiment, the method includes exposing a crystal disclosed herein to one or more samples comprising potential ligands, and determining whether a ligand-interferon molecular complex is formed.
In another aspect, the present invention provides a computer-assisted method for determining, designing, or making potential modifiers of interferon activity. In one embodiment, the method includes screening a library of chemical or biological entities.
Those skilled in the art can utilize crystallography to screen and identify chemical or biological entities that may become ligands of an interferon (see e.g. in U.S. Pat. No. 6,297,021). For example, a preferred method may include obtaining a crystal of unliganded interferon; exposing the unliganded interferon to one or more test samples that contain potential ligands of the interferon; and determining whether a ligand-interferon molecular complex is formed. The interferon may be exposed to potential ligands by various methods including, but not limited to, soaking an interferon crystal in a solution of one or more potential ligands or co-crystallizing interferon in the presence of one or more potential ligands.
Structural information from said ligand-interferon complexes may preferably be used to design new ligands that bind tighter and more specifically, have desired special biological activities, have better safety profiles or combinations thereof than known ligands. For example, the calculated electron density map directly reveals the binding event, identifies the bound chemical or biological entities, and provides a detailed three-dimensional structure of the ligand-interferon complex. Once a hit is found, a series of analogs or derivatives of the hit may be screened for tighter binding or desired biological activity by traditional screening methods. Optionally, the ligand-interferon complex may be iteratively exposed to additional potential ligands so that two or more hits may preferably be linked together to identify or design a more potent ligand.
Obtaining Structurally Homologous Molecules/Designing Interferon Mimetics
The structural coordinates disclosed herein can be used to aid in obtaining structural information about another crystallized molecule or molecular complex. The method of this invention allows determination of at least a portion of the three-dimensional structure of molecules or molecular complexes which contain one or more structural features that are similar to the structural features of the interferon disclosed herein. These molecules are referred to herein as “structurally homologous”. Similar structural features can include, for example, regions of amino acid identity, conserved active site or binding site motifs and similarly arranged secondary structural elements (e.g., α helices and β sheets). In another embodiment, structural homology is determined by aligning the residues of two amino acid sequences to optimize the number of identical amino acids along the lengths of their sequences; gaps in either or both sequences are permitted in making the alignment in order to optimize the number of identical amino acids; however, the amino acids in each sequence must remain in their proper order. Preferably, a structurally homologous molecule is a protein that has an amino acid sequence sharing at least 65% identity with SEQ ID NO:1. More preferably, a protein that is structurally homologous to the interferon of the present invention includes a contiguous stretch of at least 50 amino acids that shares at least 80% amino acid sequence identity with the analogous portion of SEQ ID NO:1. Methods for generating structural information about the structurally homologous molecule or molecular complex are well-known in the art.
The structural coordinates disclosed herein are also useful for solving the crystallographic structures of related interferons, interferon mutants or interferon homologs complexed with a variety of ligands. This approach enables the determination of the optimal sites for interaction between a ligand and an interferon, e.g. between candidate interferon modifiers and interferon. Potential sites for modification within the various binding sites of the molecules can also be identified. This information provides an additional tool for determining the most efficient binding interactions, for example, increased hydrophobic interactions between an interferon and a ligand.
In one embodiment, the present invention also provides a computer-based method for designing a mimetic of the recombinant interferon, comprising the steps of: (a) generating three-dimensional structures for a plurality of mimetics; and (b) fitting each of the three-dimensional structures of step (a) against the three-dimensional structure comprising the atomic coordinates of the recombinant interferon as shown in table 7 or selected portion thereof to find the best fitted mimetic of said recombinant interferon, said atomic coordinates optionally have a variability of root mean square deviation from the conserved backbone atoms (preferably Cα) of less than about 0.65 Å, preferably about 0.5 Å, and more preferably about 0.35 Å.
Rational drug design
Computational techniques can be used to screen, identify, select and/or design chemical entities or ligands capable of associating with interferons or structurally homologous molecules. Knowledge of the structural coordinates of the interferon disclosed herein permits the design and/or identification of synthetic compounds and/or other molecules which have a shape complementary to the conformation of the interferon disclosed herein. In particular, computational techniques can be used to identify or design chemical entities or ligands, such as receptors, modifiers, agonists and antagonists, that associate with the interferon or a portion thereof (e.g. the AB or the BC loop). Potential modifiers may bind to or interfere with all or a portion of an active site of interferon, and can be competitive, non-competitive, or uncompetitive inhibitors; or interfere with dimerization by binding at the interface between the two monomers. Once identified or screened for biological activity, these inhibitors/agonists/antagonists may be used therapeutically or prophylactically to block or enhance interferon activity. Structure-activity data for analogues of ligands that bind to or interfere with interferon can also be obtained computationally.
The term “chemical entity”, as used herein, refers to chemical compounds, complexes of two or more chemical compounds, and fragments of such compounds or complexes. Chemical entities that are determined to associate with the interferon of the present invention are potential drug candidates. A graphical three-dimensional representation of the structure of the present interferon or a structurally homologous molecule, as identified herein, or portions thereof may thus be advantageously used for drug discovery. The structural coordinates of the chemical entity are used to generate a three-dimensional image that can be computationally fitted to the three-dimensional image of an interferon or a structurally homologous molecule by one of many computation methods and techniques available in the art.
One embodiment of the method of drug design involves evaluating the potential association of a known chemical entity or ligand with the interferon or a structurally homologous molecule. The method of drug design thus includes computationally evaluating the potential of a selected chemical entity or ligand to associate with any of the molecules or molecular complexes set forth herein. In another embodiment, the method of drug design involves computer-assisted design of chemical entities or ligands that associate with the present interferon, its homologs, or portions thereof. Chemical entities or ligands can be designed in a stepwise fashion, one fragment at a time, or may be designed as a whole or “de novo”.
Thus, in one embodiment, the present invention provides a computer-based method of rational drug design, comprising the steps of: (a) providing the three-dimensional structure comprising atomic coordinates of the recombinant interferon as shown in table 7, said atomic coordinates optionally have a variability of root mean square deviation from the conserved backbone atoms (preferably Cα) of less than about 0.65 Å, preferably about 0.5 Å, and more preferably about 0.35 Å; (b) providing a plurality of molecular fragments, and generating three-dimensional structures thereof; (c) fitting each of the three-dimensional structures of step (b) against the three-dimensional structure of step (a) or selected portion thereof; and (d) assembling the selected molecular fragments into a molecule to form a candidate drug. In one embodiment, said method may further comprise the steps of: (e) obtaining or synthesizing the candidate drug; and (f) contacting the candidate drug with said recombinant interferon to determine the ability of the candidate drug to interact with said recombinant interferon.
In some embodiments of this invention, the selected portion of said three-dimensional structure comprises the atomic coordinates of one or more amino acid residues from amino acid residues 25-33 (amino acid sequence as shown in SEQ ID NO: 4) and/or 45-52 (amino acid sequence as shown in SEQ ID NO: 5) in table 7. Further, the selected portion of said three-dimensional structure comprises the atomic coordinates of the amino acid residues 25-33 (amino acid sequence as shown in SEQ ID NO: 4) and/or 45-52 (amino acid sequence as shown in SEQ ID NO: 5) in table 7, said atomic coordinates optionally have a variability of root mean square deviation from the conserved backbone atoms (preferably Cα) of less than about 0.65 Å, preferably about 0.5 Å, and more preferably about 0.35 Å.
Homology Modeling
In one aspect, using homology modeling, a computer model of an interferon homolog can be built or refined without crystallizing the homolog. First, a preliminary model of an interferon homolog is created by sequence alignment, secondary structure prediction, screening of structural libraries, or any combination of these techniques. Computational software may be used to carry out the sequence alignments and secondary structure predictions. Structural incoherencies, e.g., structural fragments around insertions and deletions, can be modeled by screening a structural library for peptides of the desired length and suitable conformation. If the interferon homolog has been crystallized, the final homology model can be used to solve the crystal structure of the homolog by techniques known in the art. Next, the preliminary model is subjected to energy minimization to yield an energy minimized model. The energy minimized model may contain regions where stereochemical restraints are violated; in such cases, these regions are remodeled to obtain a final homology model using one of many techniques known in the art.
In another aspect, the present invention provides a method for obtaining structural information about a molecule or a molecular complex of unknown structure. In one embodiment, the method includes crystallizing the molecule or molecular complex; generating an x-ray diffraction pattern from the crystallized molecule or molecular complex; and applying the x-ray diffraction pattern to at least a portion of the structural coordinates of the interferon disclosed herein to generate a three-dimensional electron density map of at least a portion of said molecule or molecular complex of unknown structure.
In another aspect, the present invention provides a method for modeling an interferon homolog. In one embodiment, the method includes aligning the amino acid sequence of a putative interferon homolog with the amino acid sequence of the present interferon and incorporating the sequence of the putative homolog into a model of interferon formed from the structural coordinates disclosed herein to yield a preliminary model of interferon homolog; subjecting the preliminary model to energy minimization to yield an energy minimized model; and remodeling regions of the energy minimized model where stereochemical restraints are violated to yield a final model of the interferon homolog.
Interferon Mimetics
The present invention provides interferon mimetics.
In one aspect, the present invention provides a peptide comprising a sequence as disclosed herein, or a derivative, active portion, analogue, variant or mimetic, and uses thereof. Thus, in one embodiment, the present invention provides a mimetic of the interferon which comprises the amino acid sequence as shown in SEQ ID NO: 4 and/or SEQ ID NO: 5. In one embodiment, after superimposition of the Cα-backbone of the three-dimensional structure of said recombinant interferon and the Cα-backbone of the three-dimensional structure of IFN-α2b protein using least squares method, the location root-mean-square deviation of Cα at residues 25-33 of said recombinant interferon and Cα in the corresponding residues of IFN-α2b protein is 3.63 Å±5%. In some embodiments, in comparison with the corresponding residues of IFN-α2b, the deviations of α carbons of residues 25-33 of said recombinant interferon are 3.291 Å±5%, 4.779 Å±5%, 5.090 Å±5%, 3.588 Å±5%, 2.567 Å±5%, 2.437 Å±5%, 3.526 Å±5%, 4.820 Å±5% and 2.756 Å±5% respectively. In some embodiments, after superimposition of the Cα-backbone of the three-dimensional structure of said recombinant interferon and the Cα-backbone of the three-dimensional structure of IFN-α2b protein using least squares method, the location root-mean-square deviation of Cα at residues 44-52 of said recombinant interferon and Cα in the corresponding residues of IFN-α2b protein is 2.90 Å±5%. In some embodiments, in comparison with the corresponding residues of IFN-α2b, the deviations of α carbons of residues 44-52 of said recombinant interferon are 1.614 Å±5%, 1.383 Å±5%, 2.735 Å±5%, 2.709 Å±5%, 5.018 Å±5%, 4.140 Å±5%, 3.809 Å±5%, 2.970 Å±5%, and 0.881 Å±5% respectively. In some embodiments, the mimetic is a functional mimetic or a structural mimetic. In some embodiments, the mimetic is a mimetic of the present recombinant interferon (rSIFN-co (SEQ ID NO: 1)). Further, the mimetics do not comprise INFERGEN® (SEQ ID NO: 1). In some embodiments, the three-dimensional structure of said interferon mimetic is similar to that of the present recombinant interferon (rSIFN-co (SEQ ID NO: 1)). In particular, both three-dimensional structures can be the same or essentially the same at the AB and BC loops. Further, the three-dimensional structure of said interferon mimetic comprises the atomic coordinates of amino acid residues 25-33 (AB loop) and/or 44-52 (BC loop) in table 7, said atomic coordinates optionally have a variability of root mean square deviation from the conserved backbone atoms, preferably Cα, of less than about 0.65 Å, preferably about 0.5 Å, and more preferably about 0.35 Å.
The present invention comprises variant peptides in which individual amino acids can be replaced by other closely related amino acids as is understood in the art. For example, individual amino acid may be replaced as follows: any hydrophobic aliphatic amino acid may be replaced by any other hydrophobic aliphatic amino acids; any hydrophobic aromatic amino acid may be replaced by any other hydrophobic aromatic amino acids; any neutral amino acid with a polar side chain may be replaced by any other neutral amino acids with a polar side chain; an acidic amino acid may be replaced by any other acidic amino acids; and a basic amino acid may be replaced by any other basic amino acids. As used herein, “mimetic”, “functional/structural mimetic” relate to peptide variants or organic compounds having the same functional/structural activity as the polypeptide disclosed herein. Examples of such mimetic or analogues include chemical compounds or peptides which are modeled to resemble the three-dimensional structure of the interferon disclosed herein (the three-dimensional structure comprise the atomic coordinates of recombinant interferon as shown in table 7), particularly compounds and peptides having the above arrangement of amino acid residues. Thus, as used herein, “mimetic of the present recombinant interferon” refers to a peptide variant or organic compound which has the same function/structure-activity as the present recombinant interferon (rSIFN-co (SEQ ID NO: 1)), especially those having the same AB loop and/or BC loop spatial structure as the present recombinant interferon, but is not the present recombinant interferon When the “mimetic” is a peptide variant, the length of its amino acid sequence is generally similar to that of the present recombinant interferon. For example, said amino acid sequence of the mimetic can comprise about 120-200 amino acid residues, preferably about 140-180 amino acid residues, more preferably about 150-175 amino acid residues, still more preferably about 160-170 amino acid residues; for example, about 164, 165, 166 or 167 amino acid residues. Alternatively, such a “mimetic” can be a peptide variant having a shorter amino acid sequence than the present recombinant interferon but comprising the AB loop and/or BC loop. For example, it can comprise about 10-100 amino acid residues, preferably about 15-80 amino acid residues.
Suitable mimetics or analogues can be generated by modeling techniques generally known in the art. This includes the design of “mimetics” which involves the study of the functional interactions and the design of compounds which contain functional groups arranged in such a manner that they could reproduce those interactions.
The design of mimetics of compounds with known pharmaceutical activity is a known approach based on lead compounds for drug development. This might be desirable where the active compound is difficult or expensive to synthesize or where it is unsuitable for common methods of administration; e.g. polypeptides are not well suited as active agents for oral compositions as they tend to be quickly degraded by proteases in the alimentary canal Mimetic design, synthesis and testing may be used to avoid randomly screening a large number of molecules for a target property.
There are several steps commonly taken in the design of a mimetic from a compound/peptide having a given target property. Firstly, determine the particular parts of the compound/peptide that are critical and/or important in determining the target property. In the case of a peptide, this can be done by systematically varying the amino acid residues in the peptide, e.g. by replacing each residue in turn. These parts or residues constituting the active region of the compound are known as its “pharmacophore”.
Once the pharmacophore has been identified, its structure can be modeled according to its physical properties, e.g. stereochemistry, bonding, size and/or charge, using data from a range of sources, e.g. spectroscopic techniques, X-ray diffraction and NMR data. Computational analysis, similarity mapping (which models the charge and/or volume of a pharmacophore, rather than the bonding between atoms) and other techniques can be used in this modeling process. In a variant of this approach, the three-dimensional structures of the ligand and its binding partner are modeled. This can be especially useful where the ligand and/or binding partner change conformation on binding, allowing further consideration of the model while designing the mimetic.
Afterwards, select a template molecule onto which chemical groups that mimic the pharmacophore can be grafted. The template molecule and the chemical groups to be grafted can be conveniently selected so that the mimetic, besides maintaining the biological activities of the lead compound, would be easy to synthesize, likely be pharmacologically acceptable, and not degrade in vivo. The mimetics found by this approach can then be screened to see whether they have the target property, or to what extent they exhibit it. Further optimization or modification can then be carried out to arrive at one or more final mimetics for in vivo or clinical testing.
In another aspect, the present invention provides an unliganded molecule including at least a portion of the interferon disclosed herein, e.g. the unliganded molecule may comprise SEQ ID NO:4 or SEQ ID NO:5 (the sequence of the AB loop and the BC loop respectively of the interferon described herein). Further, the unliganded molecule has sequence as shown in SEQ ID NO:4 or SEQ ID NO:5.
Composition and Therapeutic Application
The present invention provides a composition comprising a crystalline form of the present recombinant interferon or a mimetic of the present recombinant interferon. In one embodiment, the composition is a pharmaceutical composition. In one embodiment, said pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
Whether it is a polypeptide, antibody, peptide, nucleic acid molecule, small molecule, mimetic or other pharmaceutically useful compounds according to the present invention that is to be administered to an individual, the preferred dosage is a “prophylactically effective amount” or a “therapeutically effective amount” (although prophylaxis may be considered a therapy), this dosage being sufficient to provide its beneficial effects to the individual. The actual amount, frequency and time-course of administration will depend on the nature and severity of the disease being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of medical doctors and other medical workers. Depending on the circumstances, pharmaceutical compositions may be administered alone or in combinations.
Pharmaceutical compositions according to the present invention, and those for use with the present invention, may include, in addition to the active ingredient, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The exact nature of the carrier or other materials will depend on the route of administration, which may be oral or by injection, e.g. cutaneous, subcutaneous or intravenous. Examples of techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed.), 1980.
In some embodiments, said pharmaceutical composition can be formulated into the following dosage forms, including: tablets, capsules, oral liquids, patches, injections, sprays, suppositories, and solution preparations. The recommended dosage form is injection, such as subcutaneous or intravenous injection, and the carrier in the pharmaceutical composition may be any acceptable drug carrier, including binders, disintegrating agents, lubricants, fillers, solubilizers, buffers, preservatives, thickeners, chelating agents and other adjuvants.
On the basis of the different purposes of this invention, “pharmaceutically acceptable carriers” may be any of the standard pharmaceutical carriers. For example, known appropriate carriers include, but are not limited to, phosphate buffered saline and various wetting agents. Other carriers may include additives used for tablets, granules, and capsules. Typical carriers often contain: starch, emulsion, sugar, cellulose, certain types of clay, gelatin, stearic acid and its salts such as magnesium stearate or calcium stearate, talc, plant oils, gums, glycol or other known excipients. Such carriers may also include flavorings and color additives or other ingredients. The composition of these carriers can be formulated using known methods.
Furthermore, since the mimetics of the present recombinant interferon have the AB loop and/or BC loop structures (such as the above specific AB loop and/or BC loop space structures) of the present recombinant interferon, they are expected to be capable of treating viral diseases and/or tumor similar to the present recombinant interferon.
Therefore, in another aspect, the present invention provides a use of the crystal of the present recombinant interferon, an interferon mimetic or a composition comprising said crystal or mimetic for the preparation of medicament for treating viral diseases and/or tumors.
In another aspect, the present invention provides a method for the treatment of viral diseases and/or tumors, said method comprises administering to a subject an effective amount of the crystal of the present recombinant interferon, an interferon mimetic or a composition comprising said crystal or mimetic.
In another aspect, the present invention also provides a pharmaceutical composition for the treatment of viral diseases and/or tumors, comprising an effective amount of the crystal of the present recombinant interferon, an interferon mimetic or a composition comprising said crystal or mimetic.
In some embodiments, said viral diseases may include: hepatitis A, hepatitis B, hepatitis C, other types of hepatitis, viral infections caused by Epstein-Barr virus, human immunodeficiency virus (HIV), Ebola virus, severe acute respiratory syndrome (SARS) virus, influenza virus, cytomegalovirus, herpes simplex virus, or other type of herpes virus, papovavirus, pox virus, picornavirus, adenovirus, rhinovirus, human T-cell leukemia viruses type I, or human T-cell leukemia viruses type II, or human T-cell leukemia virus type III.
In some embodiments, said tumor is cancer or solid tumors, and said tumors may include: skin cancer, basal cell carcinoma and malignant melanoma, renal cell carcinoma, liver cancer, thyroid cancer, nasopharyngeal cancer, solid tumors, prostate cancer, stomach/abdominal cancer, esophageal cancer, rectal cancer, pancreatic cancer, breast cancer, ovarian cancer, superficial bladder cancer, hemangioma, epidermoid cancer, cervical cancer, non-small cell lung cancer, small cell lung cancer, glial stromal tumors, leukemia, acute leukemia, chronic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lymphadenoma, multiple myeloma, polycythemia, Kaposi's sarcoma.
This invention will be described in details using the following examples which are included merely for the purpose of illustrating certain aspects and embodiments of the present invention, and are not intended to limit the scope of this invention. Modifications may be made to the invention described herein without deviating from the scope of the invention.
All publications, patents and patent applications cited herein are incorporated by reference in their entireties, both individually and collectively, into this application.
EXAMPLES
Example 1
Production of Recombinant Interferon rSIFN-co (SEQ ID NO: 1)
This example describes the preparation of recombinant interferon rSIFN-co (SEQ ID NO: 1) (stock solution). (Refer to Examples 1 and 2 of U.S. Pat. No. 7,364,724, and pages 11-17 of the specification of Chinese Patent publication No. CN1740197A.)
1. Gene Cloning
Based on the published encoding DNA sequence and deduced amino acid sequence of INFERGEN® (SEQ ID NO: 1) (Klein M L, et al., Structural characterization of recombinant consensus interferon-alpha. Journal of Chromatography, 1988; 454: 205-215), the DNA encoding sequence was redesigned using E. Coli codon usage (The Wisconsin Package, by Genetics Computer Group, Inc. Copyright 1992, Medison, Wis., USA) under conditions that preserve the amino acid sequence, and then the full-length cDNA of rSIFN-co (SEQ ID NO: 1) was synthesized.
rSIFN-Co (SEQ ID NO: 1) cDNA Sequence Synthesis
Synthesis of the rSIFN-Co (SEQ ID NO: 1) cDNA 5′-Terminus and 3′-Terminus Partial Molecules
PCR was used to directly synthesize the 5′-terminus 280 bp (fragment I) and 3′-terminus 268 bp (fragment II) partial molecules of the rSIFN-co (SEQ ID NO: 1) cDNA. There was a 41-bp overlap of the complementary nucleotide sequences between the 3′ end of fragment I and the 5′ end of fragment II.







(1) Chemical synthesis of oligodeoxynucleotide


fragment


Oligomer A:


(SEQ ID NO: 6)


5′ATGTGCGACCTGCCGCAGACCCACTCCCTGGGTAACCGTCGTGCTCTG


 


ATCCTGCTGGCTCAGATGCGTCGTATCTCCCCGTTCTCCTGCCTGAAAGA


 


CCGTCACGAC3′


 


Oligomer B:


(SEQ ID NO: 7)


5′CTGAAAGACCGTCACGACTTCGGTTTCCCGCAGGAAGAATTCGACGGT


 


AACCAGTTCCAGAAAGCTCAGGCTATCTCCGTTCTGCACGAAATGATCCA


 


GCAGACCTTC3′


 


Oligomer C:


(SEQ ID NO: 8)


5′GCTGCTGGTACAGTTCGGTGTAGAATTTTTCCAGCAGGGATTCGTCCC


 


AAGCAGCGGAGGAGTCTTTGGTGGAGAACAGGTTGAAGGTCTGCTGGATC


 


ATTTC3′


 


Oligomer D:


(SEQ ID NO: 9)


5′ATCCCTGCTGGAAAAATTCTACACCGAACTGTACCAGCAGCTGAACGA


 


CCTGGAAGCTTGCGTTATCCAGGAAGTTGGTGTTGAAGAAACCCCGCTGA


 


TGAAC3′


 


Oligomer E:


(SEQ ID NO: 10)


5′GAAGAAACCCCGCTGATGAACGTTGACTCCATCCTGGCTGTTAAAAAA


 


TACTTCCAGCGTATCACCCTGTACCTGACCGAAAAAAAATACTCCCCGTG


 


CGCTTGGG3′


 


Oligomer F:


(SEQ ID NO: 11)


5′TTATTCTTTACGACGCAGACGTTCCTGCAGGTTGGTGGACAGGGAGAA


 


GGAACGCATGATTTCAGCACGAACAACTTCCCAAGCGCACGGGGAGTATT


 


TTTTTTCGGTCAGG3′






(2) PCR

PCR I for synthesizing rSIFN-co (SEQ ID NO: 1) 5′-terminus partial molecule: using oligodeoxynucleotide fragment B (SEQ ID NO: 7) as a template, oligodeoxynucleotide fragments A (SEQ ID NO: 6) and C (SEQ ID NO: 8) as primers, the rSIFN-co (SEQ ID NO: 1) 5′-terminus partial molecule with a length of 280 bp was synthesized by PCR.












(units: μl)


The PCR I reaction mixture is as follows:
(Total volume: 50 μl)
















sterilized distilled water without nuclease
39


10x Pfu buffer (Stratagene, La Jolla, CA, USA)
5


dNTP mixture (2.5 mmol/L for each dNTP)
2


Oligomer A primer (25 μmol/L) (SEQ ID NO: 6)
1


Oligomer C primer (25 μmol/L) (SEQ ID NO: 8)
1


Oligomer B template (1 μmol/L) (SEQ ID NO: 7)
1


Pfu DNA polymerase (Stratagene,
1


La Jolla, CA, USA) (25 U/μl)





PCR I reaction cycle: 95° C. 2 min→(95° C. 45 s→65° C. 1 min→72° C. 1 min) × 25 cycles→72° C. 10 min→4° C.






PCR II for synthesizing rSIFN-co (SEQ ID NO: 1) 3′-terminus partial molecule: using oligodeoxynucleotide fragment E (SEQ ID NO: 10) as a template, oligodeoxynucleotide fragments D (SEQ ID NO: 9) and F (SEQ ID NO: 11) as primers, the rSIFN-co (SEQ ID NO: 1) 3′-terminus partial molecule with a length of 268 bp was synthesized by PCR.












(units: μl)


The PCR II reaction mixture is as follows:
(Total volume: 50 μl)
















sterilized distilled water without nuclease
39


10x Pfu buffer (Stratagene, La Jolla, CA, USA)
5


dNTP mixture (2.5 mmol/L for each dNTP)
2


Oligomer D primer (25 μmol/L) (SEQ ID NO: 9)
1


Oligomer E primer (25 μmol/L) (SEQ ID NO: 10)
1


Oligomer F template (1 μmol/L)
1


(SEQ ID NO: 11)


Pfu DNA polymerase (Stratagene,
1


La Jolla, CA, USA) (25 U/μl)





PCR II reaction condition and cycle: same as PCR I






Assembling of Full-Length rSIFN-Co (SEQ ID NO: 1) cDNA

Fragments I and II were assembled together to give the complete full-length cDNA sequence of rSIFN-co (SEQ ID NO: 1) using the overlapping and extending PCR method. Restriction enzyme sites Nde I and Pst I were introduced to the 5′-terminus and 3′-terminus of the sequence respectively, so that the rSIFN-co (SEQ ID NO: 1) cDNA sequence can be cloned into the plasmid.









(1) Chemically synthesized primers



Oligomer G:



(SEQ ID NO: 12)



5′ATCGGCCATATGTGCGACCTGCCGCAGACCC3′



 



Oligomer H:



(SEQ ID NO: 13)



5′ACTGCCAGGCTGCAGTTATTCTTTACGACGCAGACGTTCC3′






(2) Overlapping and Extending PCR













(units: μl)


PCR reaction mixture
(Total volume: 50 μl)
















sterilized distilled water without nuclease
38


10x Pfu buffer (Stratagene, La Jolla, CA, USA)
5


dNTP mixture (2.5 mmol/L for each dNTP)
2


primer G (25 μmol/L) (SEQ ID NO: 12)
1


primer H (25 μmol/L) (SEQ ID NO: 13)
1


*fragment I PCR product (1 μmol/L)
1


*fragment II PCR product (1 μmol/L)
1


Pfu DNA polymerase (Stratagene, La Jolla, CA,
1


USA) (25 U/μl)





*Separating and purifying the PCR product with STRATAPREP PCR purification kit produced by Stratagene (La Jolla, CA), then dissolving the PCR product into sterilized distilled water. PCR reaction condition and cycle: same as PCR I.






rSIFN-Co (SEQ ID NO: 1) Gene Cloning and Sequence Analysis

The pLac T7 plasmid was used as vector for cloning rSIFN-co (SEQ ID NO: 1) cDNA. The pLac T7 plasmid was reconstructed from the pBLUESCRIPT II KS(+) plasmid produced by Stratagene (La Jolla, Calif., USA).
PCR product containing rSIFN-co (SEQ ID NO: 1) full-length cDNA was purified with STRATAPREP PCR purification kit produced by Stratagene (La Jolla, Calif.), followed by digestion with Nde I and Pst I. At the same time, the pLac T7 plasmid was double digested with Nde I and Pst I. These double-digested DNA fragments were separated using 1% agarose gel electrophoresis followed by recovery and purification of a 507-bp rSIFN-co (SEQ ID NO: 1) DNA fragment and a 2.9-kb plasmid DNA fragment with Wizard DNA purification kit produced by Promega (Fitchburg, Wis., USA). These fragments were ligated by T4 DNA ligase to form a recombinant plasmid. DH5α competent cells (Gibco) were transformed with the recombinant plasmid. After culturing overnight at 37° C., the positive recombinant colony, named as pHY-1, was identified.
DNA sequencing was performed with SEQUITHERMTM Cycle Sequencing Kit following instruction provided by the manufacturer (Epicentre Technologies Ltd, Madison, Wis., USA) using the universal primer T7 and T3. The DNA sequencing result showed that the sequence was consistent with the theoretical design.
The sixteen N-terminus amino acids and four C-terminus amino acids of the purified recombinant rSIFN-co (SEQ ID NO: 1) were sequenced. The results were shown below:







N-terminus:


(SEQ ID NO: 14)


Cys-Asp-Leu-Pro-Gln-Thr-His-Ser-Leu-Gly-Asn-Arg-


 


Arg-Ala-Leu-






MET at N-terminus was resected in mature protein.










C-terminus:



(SEQ ID NO: 15)



Arg-Arg-Lys-Glu-COOH






Full-length nucleotide sequence of rSIFN-co (SEQ ID NO: 1) is shown as SEQ ID NO:2 and the amino sequence is shown as SEQ ID NO:1.

Construction, Transformation, Enzyme Digestion and Identification, and Hereditary Stability of Expression Vector

Construction and Transformation of Expression Vector

E. Coli expression vector pBAD18 was digested with Nde I and linearized, then fully digested with Xba I. Electrophoresis with 1% agarose gel and purification with QIAEX II kit (QIAGEN) were performed to give a 4.8-kb fragment from pBAD18 having been digested with Nde I and Xba I.
At the same time, the pHY-1 plasmid was double digested with Ndel and Xba I and, after separation with 1% agarose gel electrophoresis, a 715-bp fragment was purified. This fragment was ligated with the above 4.8-kb fragment from pBAD18 using T4 DNA ligase to produce the recombinant plasmid. The recombinant plasmid was used to transform DH5α-competent cells. The transformed cells were spread on LB-Amp agar plate, and then cultured overnight at 37° C.
Screening for Positive Clones
E. Coli. colonies from the above LB-plate were randomly chosen, and clones containing recombinant plasmid with full length rSIFN-co (SEQ ID NO: 1) cDNA were screened using endonuclease digestion and PCR analysis. One of the PCR positive recombinant plasmid was named pHY-5, and the strain containing pHY-5 plasmid was named PVIII. PVIII was amplified and stored at −80° C. with glycerol freezing medium for future use.
High Expression of rSIFN-Co (SEQ ID NO: 1) Gene in E. Coli LMG194
In the pHY-5 plasmid, rSIFN-co (SEQ ID NO: 1) gene was under the control of the strong promoter PBAD which is regulated by the AraC protein. AraC is a protein encoded by the AraC gene located in the same plasmid. In the absence of arabinose, the dimer of AraC binds to O2 and I2 forming a 210-bp loop. This conformation leads to a complete inhibition of transcription. In the presence of arabinose, the dimer of AraC is released from O2 and binds to I1 and I2 eliminating the inhibition on transcription. Arabinose binding deactivates, represses and even activates the transcription of PBAD promoter, which stimulates PBAD to mediate high expression of rSIFN-co (SEQ ID NO: 1). rSIFN-co (SEQ ID NO: 1) expression level is more than 50% of the total bacterial protein.
2. Separation and Purification
(1) Preparation of Producing Strains
The E. coli strain LMG194 with expression vector pHY-5 was inoculated in LB culture medium, then shaken at 200 rpm overnight (about 18 h) at 37° C. To the medium was added 50% of 30% glycerine. After mixing, the medium was stored at −20° C. in 1 ml aliquots for use as the producing strain;
(2) Preparation of Grade-I Seed Strain
The producing strain was inoculated in LB culture medium (1 L containing Tryptone 10 g, Yeast extracts 5 g and NaCl 10 g) at a ratio of 1%, then shaken at 200 rpm overnight (about 18 h) at 37° C., for use as grade-I seed strain;
(3) Fermentation and Collection of the Strain
Grade-I seed strain was added to RM media (1 L containing Casein 20 g, MgCl2 1 mmol/L (0.203 g), Na2HPO4 4 g, KH2PO4 3 g, NaCl 0.5 g and NH4Cl 1 g) at a ratio of 10% and cultured at 37° C., pH 7.0. Fermentation was carried out until OD600 reached about 2.0, then arabinose (20% solution) was added until a final concentration of 0.02% as an inductor; after 4 hours, the strain was collected and centrifuged to give a pellet;
(4) Preparation of Inclusion Bodies
The strain pellet was re-suspended with an appropriate amount of buffer A (100 mmol/L Tris-HCl, pH 7.5, 10 mmol/L EDTA, 100 mmol/L NaCl), and kept at −20° C. overnight. The strain was thawed and broken by a homogenizer, then centrifuged. The pellet was washed with buffer B (50 mmol/L Tris-HCl, pH 7.5, 1 mol/L Urea, 10 mmol/L EDTA, 0.5% Triton X-100), buffer C (50 mmol/L Tris-HCl, pH 7.5, 2 mol/L Urea, 10 mmol/L EDTA, 0.5% Triton X-100) and then precipitated; this was repeated once, and the pellet was then washed once with distilled water to give inclusion bodies.
(5) Renaturation Treatment
The inclusion body was dissolved in 6 mol/L Guanidine-HCl (or urea) to obtain a slightly cloudy denaturation solution, which was then centrifuged at a speed of 10000 rpm. The supernatant was collected and used to determine the protein concentration. The denaturation solution was added in three portions into a renaturation buffer (0.5 mol/L Arg, 150 mmol/L Tris-HCl, pH 7.5, 0.2 mmol/L EDTA) and then stirred continuously at 4° C. overnight (about 18 h). The solution was dialyzed sequentially with ten times its volume of 10 mol/L phosphate buffer (PB), 5 mol/L PB buffer and distilled water; After dialysis, the pH was adjusted with 2 mol/L HAc-NaAc (pH 5.0). The solution was left to stand and then filtered.
(6) HS Cation Column Chromatography
A column was prepared with 20 mmol/L HOAc-NaOAc (pH 5.0), loaded with the renaturation product obtained from step (5) at a speed of 30 ml/min, washed with 20 column volumes (CV) of 20 mmol/L HOAc-NaOAc (pH 5.0) to remove other proteins; washed with 5 CV of 20 mmol/L HOAc-NaOAc (pH 5.0) containing 0.15 mol/L NaCl to remove other proteins; then washed with 3 CV of 20 mmol/L HOAc-NaOAc (pH 5.0) containing 0.18 mol/L NaCl to remove other proteins. Finally, 20 mmol/L HOAc-NaOAc (pH 5.0) containing 0.25 mol/L NaCl was used to elute the target protein, thereby obtaining an HS-eluted protein solution.
(7) Copper Ion Affinity Chromatography (Chelating SEPHAROSETM FAST FLOW)
The HS-eluted protein solution was added into PB buffer of 0.2 mol/L (pH 6.6). 4 mol/L NaCl was added to adjust the NaCl concentration to 1 mol/L and pH to 6.0, and the solution was ready for loading. A column was prepared with 50 mmol/L Na2HPO4 (pH 5.5) containing 1 mol/L NaCl, and loaded at a rate of 1 ml/min. The column was washed with 50 mmol/L Na2HPO4 (pH 5.0) to remove other proteins, then washed with 50 mmol/L Na2HPO4 (pH 4.0) to remove other proteins. Finally, 50 mmol/L Na2HPO4 (pH 3.6) was used to elute the target protein to obtain the chelating column-eluted target protein solution.
(8). HS Column Chromatography
The protein solution eluted from the chelating column was diluted 30 folds and its pH adjusted to 5.0, then loaded onto an HS column which was eluted with PB buffer, pH 7.0, containing 0.5 mol/L NaCl to give the recombinant interferon (Protein Stock Solution).
Example 2
Preparation of Recombinant Interferon










Lyophilized injection formula (lyophilized powder)



















rSIFN-co (SEQ ID NO: 1) stock solution of the
34.5
μg/ml



present invention



phosphate buffer, pH 7.0
10
mmol/L



glycine
0.4
mol/L










Preparation Method:

Materials were weighed according to the formula, dissolved in sterile and pyrogen-free water for injection, sterilized by filtration through a membrane with 0.22 μm pores, and then stored at 6-10° C. Samples passed the sterility test and pyrogen test, before aliquoted into vials. Every vial contained a single dose of 0.3-0.5. All the aliquoted samples were lyophilized in a lyophilization machine.










Aqueous injection formula



















rSIFN-co (SEQ ID NO: 1) stock solution of the
34.5
μg/ml



present invention



phosphate buffer, pH 7.0
25
mmol/L



NaCl
0.4
mol/L










Preparation Method:

Materials were weighed according to the formula, dissolved in sterile and pyrogen-free water for injection, sterilized by filtration through a membrane with 0.22 μm pores, and then stored at 6-10° C. Samples passed the sterility and pyrogen test before aliquoted into vials. Every vial contained a single dose of 0.3-0.5. Final products were stored in the dark at 2-10° C.
Example 3
In Vitro Study of rSIFN-Co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) Against Human Breast Cancer Cells
This example describes the in vitro study of rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) against human breast cancer cells.
The present recombinant interferon (rSIFN-co (SEQ ID NO: 1)) and INFERGEN® (SEQ ID NO: 1) produced by Amgen (U.S.) were used as test drugs to study their effects on cell proliferation, apoptosis and expression of oncogenes in MCF-7 and resistant strain MCF-7/ADR.
A. Methods
1. Cell Culture
Human breast cancer cell line MCF-7 and adriamycin resistant strain MCF-7 (MCF-7/ADR) were cultured in 25 cm2 or 75 cm2 flasks respectively. After the cells covered the bottom of the flasks, they were trypsinized with 0.25% trypsin. Cells in the logarithmic growth phase were harvested for experiments.
2. Detecting the Effects of Different Concentrations of rSIFN-Co (SEQ ID NO: 1) on Cell Proliferation with the MTT Colorimetric Assay
Experimental grouping: each cell strain was divided into 3 groups (with 11 small groups in total): rSIFN-co (SEQ ID NO: 1) group (0.02, 0.078, 0.313, 1.25, 5.0 μg/ml), INFERGEN® (SEQ ID NO: 1) group (0.02, 0.078, 0.313, 1.25, 5.0 μg/ml) and blank control group (RPMI1640 medium containing 10% fetal bovine serum (Sigma, America), also known as RPMI1640 complete medium). rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) were diluted into the desired concentrations (final ethanol concentration <1%) with the RPMI1640 complete medium, and stored at 4° C.
MCF-7 cells and MCF27/ADR cells in the logarithmic growth phase were diluted with RPMI1640 medium containing 10% fetal bovine serum to 1.25×105/ml cell suspension. Trypan blue method was used to ensure >95% cell viability. The cells were seeded in 96-well culture plates, 100 μL per well. 24 h, 48 h, 72 h after drugs were added according to the groupings mentioned above, conventional MTT assay was used to detect cell proliferation (absorbance detected with microplate reader at the wavelength of 490 nm). Each group had two wells as parallel samples. The experiment was repeated three times. The effects of different drug concentrations at different time on cell growth inhibition were calculated according to the following formula:

Cell Growth Inhibition Rate (%)=(Value of A in control group−Value of A in experimental group)/Value of A in control group×100%

3. Apoptosis Detection with Flow Cytometry (FCM)
Experimental grouping: each cell strain was divided into 3 groups: rSIFN-co (SEQ ID NO: 1) group (5 μg/mL), INFERGEN® (SEQ ID NO: 1) group (5 μg/mL), and blank control group (containing 10% calf serum RPMI1640 culture medium).
FCM detection: the cells were collected 48 h after drugs were added, then the cells were suspended as single cells and dyed with propidium iodide (PI). The apoptosis rate was assayed with the Elite Esp-based flow cytometer (Coulter, USA), and the results were analyzed with the software supplied with the equipment. These experiments were repeated 3 times.
4. Immunohistochemical Detection of Cellular Oncogene Expression
Experimental Grouping:
Each cell strain was divided into 3 groups. rSIFN-co (SEQ ID NO: 1) (5 μg/mL), INFERGEN® (SEQ ID NO: 1) (5 μg/mL), and RPMI1640 containing 10% fetal bovine serum were added to the medium of MCF-7 cell cultures. And rSIFN-co (SEQ ID NO: 1) (5 μg/mL), INFERGEN® (SEQ ID NO: 1) (5 μg/mL) and RPMI1640 containing 10% fetal bovine serum were also added to the medium of MCF-7/ADR cell cultures.
Immunohistochemical Detection of P53, Bcl-2, CerbB-2 Expression:
The coverslips were treated with acid, washed and sterilized under high pressure, and then placed in 6-well culture plates. The MCF-7 and MCF-7/ADR cells in logarithmic growth phase were digested into single cell suspensions with 0.25% trypsin. The cells were inoculated into 6-well plates, each well 1×105, and cultured at 37° C. in a CO2 incubator for 24 h. After the cells adhered to the walls, drugs were added to each group. After 48 h, the coverslips were removed. Conventional immunohistochemical SABC staining was performed, all concentrations at 1:100.
Criteria for Evaluation of Results:
Staining results were determined according to the methods of Volm (Volm M, et al., European Journal of Cancer, 1997, 33 (3), 691-693), wherein yellow or brown particles appearing in cell nucleus (P53), cytoplasm (Bcl-2) or membrane (CerbB-2) were taken as positive results. Five fields of view (FOV) on each slide under high magnification (400×) were randomly selected, counting 200 cells per field. Two factors determined if there was expression in each group of cells. Scoring was done according to the intensity of staining for each cell, 0 point for no coloring, 1 point for light yellow, 2 points for brown, 3 points for tan. The average would be the average staining intensity for a group of cells. Percentage of positive cells: no 0 point for no staining; 1 point for <25% stained cells; 2 points for 25%-50%; 3 points for >50%. Sum of the two scores: 0 means negative expression; 2-4 means positive; 4-6 means strongly positive. These experiments were double blind (stainers and observers both do not know the grouping of the slides).
B. Statistical Methods
Statistical Analysis of Experimental Data:
All the experimental data were tested with the t test, variance analysis and rank correlation analysis using the SPSS 11.5 statistical package. P value <0.05 means that the difference was statistically significant.
C. Results
1. Effects on the Proliferation of MCF-7 and MCF-7/ADR Cells
(1) MCF-7 Cells
rSIFN-co (SEQ ID NO: 1) could inhibit the proliferation of MCF-7 cells. Each cell group treated with 0.02, 0.078, 0.313, 1.25, 5.0 μg/mL of rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) showed a significant decrease in its absorbance (OA) compared with the blank control groups. The inhibitory effects of rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) showed no significant differences at the early stages (24 h, 48 h) (P>0.05). After over 72 h of treatment, the % inhibition of rSIFN-co (SEQ ID NO: 1) was higher than that of INFERGEN® (SEQ ID NO: 1) at the same concentrations except at the lowest concentration of 0.02 μg/mL, the differences were statistically significant (P<0.05) (shown in Table 1-1).







TABLE 1-1







In vitro growth inhibition of the MCF-7 cells (%, n = 6)










Dose (μg/mL)
24 h
48 h
72 h














INFERGEN ®
0.02
 8.59 ± 2.26
 8.28 ± 2.27
10.43 ± 3.59


(SEQ ID NO: 1)
0.078
13.84 ± 1.96
 7.80 ± 2.01
 9.47 ± 2.48



0.312
15.53 ± 1.51
 9.30 ± 3.28
13.39 ± 4.37



1.25
17.58 ± 0.62
12.76 ± 1.63
14.41 ± 0.83



5.0
19.98 ± 5.22
26.69 ± 3.47
24.93 ± 2.53


rSIFN-co
0.02
 7.78 ± 4.32
11.60 ± 0.77
12.53 ± 0.70


(SEQ ID NO: 1)
0.078
15.71 ± 3.68
13.03 ± 3.27
 16.77 ± 2.22*



0.312
17.49 ± 1.34
14.80 ± 2.40
 22.73 ± 6.06*



1.25
20.07 ± 1.01
24.65 ± 2.18
 27.62 ± 1.81*



5.0
24.79 ± 4.01
30.77 ± 3.09
 44.75 ± 2.32*





*P < 0.05, vs. INFERGEN ® (SEQ ID NO: 1)






(2) MCF-7/ADR Cells
rSIFN-co (SEQ ID NO: 1) could inhibit the proliferation of MCF-7/ADR cells. Each cell group treated with 0.02, 0.078, 0.313, 1.25, 5.0 μg/mL of rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) showed a significant decrease in its absorbance (OA) compared with the control groups. The inhibitory effect of rSIFN-co (SEQ ID NO: 1) was higher than that of INFERGEN® (SEQ ID NO: 1) at the same concentrations except at the lowest concentration of 0.02 μg/mL as shown by analysis of variance, the differences were statistically significant (P <0.05) (shown in Table 1-2).







TABLE 1-2







In vitro growth inhibition of MCF-7/ADR (%, n = 6)










Dose (μg/mL)
24 h
48 h
72 h














INFERGEN ®
0.02
16.36 ± 0.96
24.97 ± 0.33
28.87 ± 6.20


(SEQ ID
0.078
23.01 ± 2.11
28.04 ± 0.85
30.90 ± 3.34


NO: 1)
0.312
26.69 ± 2.49
29.64 ± 2.78
43.02 ± 2.11



1.25
31.64 ± 1.17
49.87 ± 1.74
46.68 ± 2.42



5.0
37.61 ± 0.96
57.24 ± 0.80
62.52 ± 4.01


rSIFN-co
0.02
16.24 ± 2.30
34.20 ± 1.80
34.80 ± 1.38


(SEQ ID
0.078
 29.70 ± 1.40*
 33.92 ± 1.35*
 48.71 ± 1.04*


NO: 1)
0.312
 33.46 ± 1.04*
 41.52 ± 5.27*
 47.71 ± 0.40*



1.25
 38.80 ± 2.16*
 52.50 ± 0.73*
 52.70 ± 1.01*



5.0
 48.36 ± 6.52*
 67.65 ± 4.40*
 69.44 ± 0.95*





*P < 0.05, vs. INFERGEN ® (SEQ ID NO: 1)






2. Effect on Apoptosis of MCF-7 and MCF-7/ADR Cells
Compared with the control group, 5 μg/mL of rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) induced apoptosis of MCF-7 and MCF-7/ADR cells after treatment for 48 h, the differences were statistically significant (P<0.01). rSIFN-co (SEQ ID NO: 1) showed stronger apoptosis-inducing activities on MCF-7 and MCF-7/ADR than INFERGEN® (SEQ ID NO: 1) at the same concentrations, the differences were statistically significant (P<0.01) (shown in Table 1-3).







TABLE 1-3







The % apoptosis of MCF-7 after 48 h treatment (%, n = 6)












INFERGEN ®
rSIFN-co



Blank control
(SEQ ID NO: 1)
(SEQ ID NO: 1)














MCF-7
7.27 ± 1.19
19.67 ± 0.95*
23.10 ± 0.80*▴


MCF-7/ADR
8.40 ± 0.70
34.80 ± 3.20*
65.63 ± 4.60*▴





*P < 0.01, vs. control;


▴P < 0.01, vs. INFERGEN ® (SEQ ID NO: 1)






3. Effect on Expression of P53, CerbB-2 and Bcl-2 in Each Cell Group
rSIFN-co (SEQ ID NO: 1) down-regulated the expression of P53 in MCF-7 cells compared with the control group, the difference was statistically significant (P<0.05). Although INFERGEN® (SEQ ID NO: 1) decreased the expression of P53, the decrease was not significantly different (P >0.05) compared with the control group. Both rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) down-regulated the expression of P53 in MCF-7/ADR compared with the control group, the difference was statistically significant (P<0.05), but rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) at the same concentration showed no significant difference between them (P >0.05).
rSIFN-co (SEQ ID NO: 1) down-regulated the expression of CerbB-2 in both MCF-7 and MCF-7/ADR as compared with the control group, the difference was statistically significant (P<0.01). CerbB-2 expression was decreased after INFERGEN (SEQ ID NO: 1) treatment; however, the decrease was not significantly different (P >0.05) compared with the control group.
rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) both up-regulated the expression of Bcl-2 in MCF-7 compared with the control group, the difference was statistically significant (P<0.01), but rSIFN-co (SEQ ID NO: 1) showed stronger activities than INFERGEN® (SEQ ID NO: 1) at the same concentration, the difference was statistically significant (P=0.001). rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) both up-regulated the expression of Bcl-2 in MCF-7/ADR compared with the control group, the difference was statistically significant (P<0.01). Results are shown in Table 1-4.







TABLE 1-4







Effect on the expression of P53, CerbB-2 and Bcl-2 in MCF-7 48 h after treatment


(n = 5).












INFERGEN ®
rSIFN-co


Groups
Blank control
(SEQ ID NO: 1)
(SEQ ID NO: 1)














P53
MCF-7
4.17 ± 0.0120
3.78 ± 0.0851
 2.62 ± 0.0208★



MCF-7/ADR
4.09 ± 0.0361
  2.68 ± 0.0100★
 2.60 ± 0.0089★


CerbB-2
MCF-7
4.08 ± 0.0322
3.15 ± 0.3469
2.61 ± 0.0120*



MCF-7/ADR
4.06 ± 0.0030
3.82 ± 0.0404
3.70 ± 0.0291*


Bcl-2
MCF-7
2.59 ± 0.0153
 3.93 ± 0.0306*
4.02 ± 0.0252*



MCF-7/ADR
3.64 ± 0.0252
 3.93 ± 0.0176*
4.02 ± 0.0145*





★P < 0.05,


*P < 0.01, vs. control.






Example 4
In Vitro Study of rSIFN-Co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) Against Cervical Cancer Cell
This example describes the in vitro study of rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) in inhibiting the growth and inducing apoptosis of cervical cancer cell.
The present recombinant interferon (rSIFN-co (SEQ ID NO: 1)) and INFERGEN® (SEQ ID NO: 1) produced by Amgen (U.S.) were used as test drugs to study their effects on growth inhibition and apoptosis induction of cervical cancer Caski cells (HPV16+).
A. Methods
1. Caski Cells Growth Inhibition Test
1.1 Cell Culture and Grouping
Drug samples were diluted with RPMI-1640 culture medium containing 10% fetal bovine serum. Cervical cancer Caski cells were cultured in a 96-well plate. Cells were prepared as single cell suspension using culture medium with a cell concentration of 1×105/ml. To each well was added 100 μl of cell suspension. rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) were added to the plate at a concentration gradient of 0.156 μg/ml, 0.625 μg/ml, 2.5 μg/ml and 10 μg/ml. RPMI-1640 medium containing 10% fetal bovine serum was used as control group. Each concentration was triplicated. The cells were cultured at 37° C. with 5% CO2 in an incubator for 72 h.
1.2 Cell Growth Inhibition Test by MTT Method
MTT reagent (Sigma Company, U.S.) was prepared at 5 mg/ml, and 10 μl MTT reagent was added to each well. The plate was shaken gently to homogenize the reagent, incubated at 37° C. with 5% CO2 for 4 h, whereupon blue crystals could be seen at the bottom of the wells. The supernatant was removed, and 100 μl of DMSO were added to each well, then the absorbance at 570 nm was measured with a microplate reader after the blue crystals dissolved at room temperature.
1.3 Calculation of Cell Growth Inhibition




  
    Cell
    ⁢
    
      
    
    ⁢
    growth
    ⁢
    
      
    
    ⁢
    inhibition
  
  =
  
    
      (
      
        1
        -
        
          
            OD
            ⁢
            
              
            
            ⁢
            value
            ⁢
            
              
            
            ⁢
            of
            ⁢
            
              
            
            ⁢
            sample
            ⁢
            
              
            
            ⁢
            well
          
          
            OD
            ⁢
            
              
            
            ⁢
            value
            ⁢
            
              
            
            ⁢
            of
            ⁢
            
              
            
            ⁢
            control
            ⁢
            
              
            
            ⁢
            well
          
        
      
      )
    
    ×
    100
    ⁢
    %
  




2. Apoptosis Test on Caski Cells
2.1 Cell Culture and Grouping
The Caski cells were divided into 7 groups and cultured in RPMI-1640 medium containing 10% inactivated fetal bovine serum in a 96-well plate. Group 1 was cultured for 72 h as control group. Groups 2-4 were cultured with different concentrations of rSIFN-co (SEQ ID NO: 1): 0.156 μg/ml, 0.625 μg/ml, 2.5 μg/ml. Groups 5-7 were cultured with different concentrations of INFERGEN® (SEQ ID NO: 1): 0.156 μg/ml, 0.625 μg/ml, 2.5 μg/ml.
2.2 Apoptosis Rate of Caski Cells Determined by Flow Cytometry (FCM)
Each group of cells were centrifuged at 1000 r/min for 5 min. The supernatant was removed, and the cells were tested for apoptosis with Annexin V/PI double dying method. Each specimen containing 1×106 viable cells was washed once with incubation buffer and centrifuged at 1000 r/min for 5 min. The cells were re-suspended with 100 μl marker solution, incubated at room temperature for 15 min in the dark, and centrifuged at 1000 r/min for 5 min to precipitate the cells. The cells were washed once with an incubation buffer, triturated with a fluorescent solution, then incubated at 4° C. for 20 min. in the dark, while shaken frequently, before being tested with FCM.
B. Statistical Analysis
All quantitative analysis data were expressed as x±s. Variance analysis was used to analyze the variance between different drugs and different concentrations, and the statistical analysis was performed with the SPSS 14.0 software package.
C. Results
1. Caski Cells Growth Inhibition Test
Both rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) inhibited the growth of Caski cells, and this effect increased with increasing concentrations of interferons. The effect of rSIFN-co (SEQ ID NO: 1) was greater than that of INFERGEN® (SEQ ID NO: 1) in groups of 0.625, 2.5 and 10 μg/ml. The differences displayed in Table 2-1 showed statistical significance (P<0.01):







TABLE 2-1







Inhibitory effect on Caski cells ( x± s)










Cell growth inhibition rate










Drug concentration
rSIFN-co
INFERGEN ®


(μg/ml)
(SEQ ID NO: 1)
(SEQ ID NO: 1)












0.156
 8.6 ± 2.1
7.3 ± 2.2


0.625
17.6 ± 3.3{circle around (1)}
7.4 ± 4.0


2.5
42.7 ± 1.5{circle around (1)}
9.7 ± 1.6


10
67.3 ± 4.4{circle around (1)}
53.0 ± 5.8 





{circle around (1)}Compared with INFERGEN ® (SEQ ID NO: 1) at the same concentration, P < 0.01






2. Inducing Apoptosis in Caski Cells
Both rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) induced apoptosis in Caski cells, and the effect was positively correlated with increasing concentrations of interferons. The effect of rSIFN-co (SEQ ID NO: 1) at low concentration (0.156 μg/ml) was higher than that of INFERGEN® (SEQ ID NO: 1). The difference displayed in Table 2-2, showed statistical significance (P<0.01):







TABLE 2-2







Apoptotic effect on Caski cells ( x± s)










Cell growth inhibition rate










Drug concentration
rSIFN-co
INFERGEN ®


μg/ml)
(SEQ ID NO: 1)
(SEQ ID NO: 1)












0
21.3 ± 3.9 
21.3 ± 3.9 


0.156
  53.5 ± 4.61,2
47.6 ± 3.11


0.625
64.9 ± 3.31
67.1 ± 3.61


2.5
74.4 ± 1.31
72.0 ± 2.61





1Compared with controls, P < 0.01.


2Compared with INFERGEN ® (SEQ ID NO: 1) at the same concentration, P < 0.01.






Example 5
Study of the Pharmacokinetics and Bioequivalence of rSIFN-Co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1)
This example describes the research work on the pharmacokinetics and bioequivalence between rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1). The present recombinant interferon rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) produced by Amgen (U.S.) were taken as test drugs to compare their pharmacokinetics and bioequivalence.
It is difficult to undertake pharmacokinetics study of interferon in healthy people. As the level of medicinal interferon in blood plasma is very low after injection, enzyme-linked immunosorbent assay (ELISA) or virus cytopathic inhibition assay can hardly measure it directly in the serum of healthy adults. Currently, the detection marker for pharmacokinetics study of interferon is generally 2′,5′-OAS (2-5A oligonucleotidase), which is a product induced by interferon, and also an indicator of its efficacy.
A. Subject and Method
1. Subject
There were 18 healthy male volunteers with an average age of 22.8±1.4, height of 170±5.0 cm, BMI of 20.5±2.4, and body weight of 59.4±7.2 kg. Subjects were determined to be normal by a comprehensive physical examination, laboratory tests (including hematology, urine, liver and kidney functions) and electrocardiogram. The subjects did not use any drugs within 4 weeks prior to the test, and did not use any drugs known to damage the organs within 3 months prior to the test. They had no history of allergy to the test drugs; and they volunteered for the test and signed an informed agreement.
2. Method
The experimental scheme was approved by the Medical Ethics Committee of West China Hospital, Sichuan University, operated in accordance with relevant guidelines of GCP of the PRC.
2.1 Materials
Reagents:
Lyophilized powder of recombinant interferon for injection (Test preparations, i.e. the recombinant interferon rSIFN-co (SEQ ID NO: 1) of the present invention, 9 μg/vial). Comparison preparation: INFERGEN® (SEQ ID NO: 1) injection (compare reagent, 9 μg/vial) produced by Amgen (U.S.).
2-5A Kit: Eiken′ Radioimmunoassay Kit was supplied by Eiken Chemical Co., LTD. The Kit includes: (1) I125-labelled 2′,5′-OAS, (2) Anti-2′,5′-OAS serum, (3) 2′,5′-OAS Standard vial (each contains 0, 10, 30, 90, 270 or 810 pmol/dL 2′,5′-OAS), (4) Buffer, (5) Blank serum, (6) Poly(I)-poly(C) agarose gel, (7) ATP, (8) Mercaptoethanol, and (9) Quality control serum.
2.2 Experimental Design and Dosing Methods
Using the randomized controlled crossover trial, 18 subjects were randomly divided into A and B groups, nine in each group, separate subcutaneous injections of 9 μg rSIFN-co (SEQ ID NO: 1) and 9 μg INFERGEN® (SEQ ID NO: 1) was made alternately in two cycles, one week of wash period.
Fast from 8 pm the day before the test until 2 h after dose the next morning, subcutaneous injection was taken in brachial deltoid muscle at 7:00 am. All the subjects were required to have standard meals (food without high fat), and forbidden to smoke, drink alcohol, tea, coffee beverages, and refrain from strenuous exercises. All other drugs were banned during the tests.
2.3 Collecting and Testing of Blood Samples
4 ml of blood samples were drawn before dosing, while 3.5 ml of blood samples were drawn from the elbow vein opposite the injection site at 2, 6, 12, 18, 22, 24, 26, 30, 34, 38, 42 and 48 hours after the injection; the samples were centrifuged immediately, and the resulting serum preserved at −20° C. until they were tested for the 2′,5′-OAS concentration.
3. Statistical Methods
Using the DAS ver1.0 statistical software, test Test preparation and compare preparation were compared by the paired t test using the statistical software DAS ver1.0.
B. Results
According toBased on the measured serum 2′,5′-OAS concentration of the blood samples, the mean enzyme concentration-time curves were plotted in FIG. 16.
As shown in FIG. 16, after subcutaneous injection with 9 μg of rSIFN-co (SEQ ID NO: 1) or 9 μg of INFERGEN® (SEQ ID NO: 1), the two enzyme concentration-time curves had basically the same trend; but after subcutaneous injection of rSIFN-co (SEQ ID NO: 1), the concentration at the peak of the enzyme concentration-time curve was significantly higher than that of INFERGEN® (SEQ ID NO: 1).
The relative bioavailability (F) of test preparation (rSIFN-co (SEQ ID NO: 1)) compared to the compare preparation (INFERGEN® (SEQ ID NO: 1)) was calculated by the following formula:




  F
  =
  
    
      (
      
        
          AUC
          
            test
            ⁢
            
              
            
            ⁢
            preparation
          
        
        
          AUC
          
            compare
            ⁢
            
              
            
            ⁢
            preparation
          
        
      
      )
    
    ×
    
      (
      
        
          compare
          ⁢
          
            
          
          ⁢
          preparation
          ⁢
          
            
          
          ⁢
          dosage
        
        
          test
          ⁢
          
            
          
          ⁢
          preparation
          ⁢
          
            
          
          ⁢
          dosage
        
      
      )
    
    ×
    100
    ⁢
    %
  




The results showed that the relative bioavailability of rSIFN-co (SEQ ID NO: 1) (F0 ̃48) was 125.4%. The Tmax difference between test preparation and compare preparation was not statistically significant (t=1.458, P=0.163). The difference between AUC0-48 and Cmax was statistically significant (t=2.730, P=0.014; t=2.347, P=0.031), and test preparation was higher than the compare preparation.
In addition, the INFERGEN® (SEQ ID NO: 1) group was more severe than the rSIFN-co (SEQ ID NO: 1) group in terms of the incidence, extent and duration of the adverse reactions that were compared.
C. Conclusion
(1) After subcutaneous injection, both rSIFN-co (SEQ ID NO: 1) and INFERGEN® (SEQ ID NO: 1) induced the production of 2′,5′-OAS. The pharmacokinetics curves of the two drugs were of the same trend, and the main pharmacokinetics parameters showed no statistical difference.
(2) Both the Cmax and AUC0-48 of 2′,5′-OAS induced by rSIFN-co (SEQ ID NO: 1) were higher than that of INFERGEN® (SEQ ID NO: 1), indicating that the efficacy of rSIFN-co (SEQ ID NO: 1) might be better than INFERGEN® (SEQ ID NO: 1) under the same dosage.
(3) The INFERGEN® (SEQ ID NO: 1) group was more severe than the rSIFN-co (SEQ ID NO: 1) group in the incidence, extent and duration of the adverse reactions that were compared.
(4) It was discovered, after plotting the mean enzyme concentration-time curves based on the the serum 2′,5′ oligoadenylate synthase (2′,5′-OAS) concentration measured at different times, the 2′,5′-OAS concentration induced by rSIFN-co (SEQ ID NO: 1) generally had double peaks and the area under the curve was significantly greater than that obtained by INFERGEN® (SEQ ID NO: 1) when each was separately injected under the same conditions. An increment in the area under the curve was not correlated to an increase in the incidence and/or the occurrence degree of the adverse reactions.
Example 6
Crystallization of Recombinant Interferon
The preparation of high-quality rSIFN-co (SEQ ID NO: 1) protein monocrystal is a prerequisite for determining its crystal structure. The rSIFN-co (SEQ ID NO: 1) used for crystal growth was derived from the said rSIFN-co (SEQ ID NO: 1) of the present invention. The preparation method, technical process, crystallization conditions and crystallographic parameters of the rSIFN-co (SEQ ID NO: 1) monocrystal were as follow.
lyophilized powder of the rSIFN-co (SEQ ID NO: 1) in the present invention was dissolved in pure water and stored under −20° C. at an initial protein concentration of 0.42 mg/ml. Prior to crystallization, the rSIFN-co (SEQ ID NO: 1) protein samples were concentrated to 3-3.5 mg/ml and immediately used for the crystal growth experiments. The hanging drop vapor diffusion method was used for the crystallization process held at room temperature (293K).
In the initial crystallization studies, microcrystalline rSIFN-co (SEQ ID NO: 1) appeared under different sets of conditions, but it was difficult to obtain high-quality monocrystal that could be used for X-ray diffraction analysis of sufficient resolution. After optimization of a large number of crystallization conditions, it was found that the best quality crystals were obtained using the crystallization solution made up of the following: 1.2 M LiSO4, 0.1 M CAPS (3-(cyclohexylamino)-1-propanesulfonic acid), pH 11.1 and 0.02 M MgCl2. A good monocrystal of rSIFN-co (SEQ ID NO: 1) protein was obtained after the crystallization solution prepared with this formula was left standing for 3 days to 1 week. The monocrystal was of the tripartite crystal type, and had a size of 0.42×0.08×0.08 mm. The rSIFN-co (SEQ ID NO: 1) protein crystal used in the X-ray diffraction analysis of the crystal structure is shown in FIG. 1.
Example 7
Analysis of the Crystal X-Ray Diffraction Data
Collection of Crystal Diffraction Data:
Data collection was conducted under low temperature condition (100K) using the synchrotron radiation from beamline BL5A at a photon factory in Tsukuba, Japan. The crystal diffraction data was collected using the following steps:
(1) Under a microscope, a crystal placement tool was carefully used for transferring a crystal from the mother liquor to a loop at the top part of the tool;
(2) Employing the Flash-Cooling technique, the loop containing the crystal was quickly soaked in paraffin oil (Hampton Research, U.S.), which acted as an antifreeze reagent, for several seconds and quickly transferred to the goniometer head of the diffraction apparatus. At this time, the crystal will be instantaneously in a low-temperature nitrogen stream (100K) such that data collection was conducted under the low temperature of 100K;
(3) Data collection was started after setting the required parameters; the light source wavelength was 1.0 Å, the detector was a ADSC Quantum 315 CCD (charge-coupled device) and the crystal-to-detector distance was 310 mm. The data was collected using the oscillation method, and for every image the oscillation angle was 1°, the exposure time was 12 seconds, and a total of 110 images were collected (FIG. 2).
Processing and Analysis of the Diffraction Data:
The complete set of diffraction data collected had to be processed and analyzed using the CCP4 program package before the set of intuitional diffraction images (FIG. 2) originally obtained in the diffraction experiment could be used for quality assessment of the diffraction data and structural analysis of the crystal. This process consisted of: 1) indexing: transforming the diffraction data to crystallography index (h, k, l), and calculating unit cell parameters and space group; 2) parameter modification: refining parameters such as the unit cell parameters, crystal-to-detector distance and angle, and degree of mosaicity etc; 3) integration: obtaining the intensity information from the diffraction spots; 4) merging data: merging all the diffraction spots that arose due to symmetry or are duplicated to generate a complete set of data with only independent diffraction spots; 5) transforming the intensity data into structure amplitudes. The details on the collection of rSIFN-co (SEQ ID NO: 1) crystal diffraction data and results of the analysis are shown in Table 3.







TABLE 3





RDetails on the collection of rSIFN-co (SEQ ID NO: 1) crystal diffraction


data and results of the analysis
















Data acquisition conditions



X-ray source
PF, BL-5A


Wavelength (Å)
1.0


Detector
ADSC Quantum 315 CCD


Distance (mm)
310


Temperature (K)
100


Data acquisition statistics


Space group (number of molecules/
P3121(2)


asymmetric unit)


Cell parameters


a = b (Å)
77.920


c (Å)
125.935


a = β = 90°, γ = 120°


Solvent content (%)
56.7


Resolution coverage (Å)
67.58-2.60 


Diffraction spots (I/σ (I) > 0)
86556


Unique diffraction spot (I/σ (I) > 0)
14052


Outermost shell
2.74-2.60


Symmetry related diffraction spot quality


factor R (%):


Overall, (Outermost shell)
7.1 (25.8)


Signal to noise ratio
21.2 (4.5) 


Intigrity(%): overall, (Outermost shell)
99.5 (100.0)


Redundancy: overall, (Outermost shell)
6.2 (6.5) 









Example 8
Analysis of the Crystal Structure
Determination of the Crystal Diffraction Phase and Construction of the rSIFN-Co (SEQ ID NO: 1) Initial Molecular Structural Model
The molecular replacement method was adopted to solve for the rSIFN-co (SEQ ID NO: 1) crystal structure; the crystal structure (PDB number 1B5L) of sheep INF-τ (54% sequence homology to rSIFN-co (SEQ ID NO: 1)) was selected as the homologous structural model. The software program PHASER was used for computing its rotation function and translation function which was then used to presume the location and orientation of the rSIFN-co (SEQ ID NO: 1) molecule in a unit cell. Based on the Laue groups and the systematic absence law, its space group was determined to be P3121 and the molecular model was correspondingly modified (viz. preserving residues 13-25, 37-69, 79-101, 114-151 in the 1B5L structure); results calculated from this model were as follow: Z-score was 15.71, IL-gain was 307.79, Clash was 0. The molecules heaped up reasonably in a unit cell, and IL-gain gradually rose during the process of molecular replacement. This indicated that an exact solution was obtained and the initial phase of each diffraction point had been determined. In turn, the mtz generated by PHASER, possessing the initial phases, was used for building the electron density map using FFT. The initial molecular structural model obtained was well-matched to the electron density map, demonstrating that the exact phase solution of all the diffraction points of rSIFN-co (SEQ ID NO: 1) had been obtained. Based on the results above, the rSIFN-co (SEQ ID NO: 1) initial molecular structural model was built.
Rectification of the rSIFN-Co (SEQ ID NO: 1) Structural Model
With the aim of obtaining an accurate rSIFN-co (SEQ ID NO: 1) molecular structural model, the coordinates and temperature factors of all the non-hydrogen atoms in the rSIFN-co (SEQ ID NO: 1) initial molecular structural model underwent iterative refinement by using molecular modeling techniques and a computerized optimization program.
program CNS1.1 was used for structural refinement using phaseless population data; 10% of these data was randomly extracted for use as the testing set, and the same randomly extracted testing set was kept throughout. All the atoms in the structural model participated in the refinement, and each atom possessed 4 refining parameters, including coordinates (x, y, z) and isotropic temperature factor B. Computerized automatic refinement and manual adjustment or building of the model (using software O) took place alternately during the entire refinement process. Restrictive NCS was used at the beginning of the refinement, and was disused once the structural adjustment was basically accomplished. When Rwork factor (<0.30) and Rfree factor practically stopped descending, water and solvent molecules were added to the structure to complete the structure rectification. The major indices for the rectification were a Rwork value of 0.250 and a Rfree value of 0.286. The major indices of the final rSIFN-co (SEQ ID NO: 1) structure rectification are listed in Table 4. The resulting atomic coordinates of rSIFN-co (SEQ ID NO: 1) are shown in Table 7.







TABLE 4





Major parameter indices and qualitative statistical results of rSIFN-co


(SEQ ID NO: 1) molecular structure
















Resolution ratio range(outermost shell) (Å)
20.0-2.6


Cutoff point of signal-to-noise
0.0


Crystallographic incongruent indexes (outermost shell) (%)
25.0 (36.3)


Free incongruent indexes1 (outermost shell) (%)
28.6 (40.5)


Component of asymmetric unit


Number of all the residues
293


Number of A chain residues (unbuilt residues)
146 (20) 


Number of B chain residues (unbuilt residues)
147 (19) 


Molecular number of water and solvent
123


Root mean square deviation2


Bond length (Å)
0.007


Bond angle (°)
1.379


Dihedral angle (°)
19.234


Unfit angle (°)
0.844


Wilson temperature factor (Å2)
70.7


Average temperature factor (Å2)


Number of all the atoms (2403)
61.76


Atomic number of protein (2254)
61.11


A chain of protein (1120)
58.39


B chain of protein (1134)
63.79


water and solvent (149)
68.21


Statistics of Ramachandran plot (%)3


Optimal regions
90.6


Additionally allowed regions
9.1


common allowed regions
0.4


Disallowed regions
0.0





1Free incongruent indices were calculated using 10% of the total diffraction points unmodified;


2Root mean square deviation was calculated using relative standard bond length/bond angle;


3Statistics of Ramachandran plot used software PROCHECK.






Example 9
Quality Characterization of the Quality of the rSIFN-Co (SEQ ID NO: 1) Molecular Structural Model
Quality Characterization of the Quality of the rSIFN-Co (SEQ ID NO: 1) Molecular Structural Model
The model: rSIFN-co (SEQ ID NO: 1) was displayed intuitively, clearly and accurately. FIG. 3 is a typical electron density map matching to the structure of the amino acid residues in a rSIFN-co (SEQ ID NO: 1) molecule; the spatial location and orientation of each amino acid residue could be clearly identified.
(2) Distribution map of the average temperature factors associated with the amino acid residues. (FIG. 4)
(3) Stereochemical rationality of the rSIFN-co (SEQ ID NO: 1) molecule was characterized in the Ramachandran conformational plot (FIG. 5), and showed that 90.6% of its amino acid residues were located in the optimal allowed regions, 9.1% were in the allowed regions, 0.4% were in the common allowed regions. This demonstrated that the rSIFN-co (SEQ ID NO: 1) molecular structural model was stereochemically rational.
Example 10
Crystal Structure Characteristics of the Crystal Structure of the rSIFN-Co (SEQ ID NO: 1) Molecule
Stacking and Global Assignment of the rSIFN-Co (SEQ ID NO: 1) Molecule in a Crystal
FIG. 6 shows the stacking manner of the rSIFN-co (SEQ ID NO: 1) molecule in an unit cell. An asymmetric unit in the rSIFN-co (SEQ ID NO: 1) crystal structure was made of two protein molecules (called crystallographic dimers) (FIG. 7). The embedding area between the dimers was 1033.3 Å2 with each monomer contributing 516.6 Å2. This only accounted for 6.4% of the total area in the monomer. The A, B, F sides of the A chain in the dimer corresponded to the C, D, E sides of the B chain (see FIG. 9). Using the software VADAR, the folding free energies of the monomer and dimer were calculated as −126.9 and −257.1 respectively, which meant that the folding free energy of the dimer was quite close to the free energy of the two isolated monomers (−126.9×2). This demonstrated that the interaction between the dimers was relatively weak and there were only two weak hydrogen bonds between them A12(ARG) NH2 . . . NH2 B71(Arg), 3.05 Å; A145(Arg) NH1 . . . OH B90 (Tyr), 3.14 Å.
The purification process showed that rSIFN-co (SEQ ID NO: 1) existed as monomers in solution; the current biochemical function experiments showed that the functional unit of the likes of IFN-α should be monomeric. Therefore, this dimer might be formed from the stacking of crystals.
Dimer Structure of the Dimers
Two single rSIFN-co (SEQ ID NO: 1) molecules in an asymmetric unit form one dimer. FIG. 8 shows the crystallographic dimeric organization of rSIFN-co (SEQ ID NO: 1). Chain A consisted of residues 11-103 and 111-163 (residues 1-10, 104-110 and 164-166, were not involved in building of this crystal structure since they were not shown in the electron density map); chain B consisted of residues 11-103 and 110-163 (residues 1-10, 104-109, and 164-166, were not involved in building of this crystal structure since they were not shown in the electron density map). In the crystal structure of each monomer, it was observed that the Cys29 and Cys139 formed an intramolecular disulfide bond; the intramolecular disulfide bond from Cys1 and Cys99 was not shown because Cys1 was not involved in building of this crystal structure. Besides, since the density of the side chains were not shown, residues 30-33, 47-49 of chain A and residues 30-33, 48-50 of chain B were mainly constructed as Ala or Gly. The structures of the two monomers were roughly the same and were linked by non-crystallographic symmetry (from B to A, polar angles Omega, Phi, Kappa were 170.64, 94.56, 118.35, respectively; tx, ty, tz were −1.061, −0.225, 0.155 respectively.). The two monomers were superimposed and compared; apart from the regional flexibility of a few loops on the molecular surface, most of the residues superimposed completely. The distribution of the RMSD of all the Cα associated with the amino acid residues are shown in FIG. 8c; 127 residues (13-30, 34-44, 53-101, 115-163) had a RMSD of 0.64 Å for all Cα. The difference in the local structure might be a result of the comparatively large flexibility of this protein and the differences in the environment where the crystal stacked.
Structure of a Single Molecule
Each monomer was made up of six α-helices (A, C, C′, D, E, F) and one 310 helix (B), which were connected to each other by the connecting peptides between them; the fold of the monomer structure belonged to the helical cytokines (FIG. 9). The amino-acid residues which corresponded to the six α-helices (A, C, C′, D, E, F) were 13-20, 50-68, 70-76, 79-100, 114-133, and 138-160, respectively. Residues 40-43 corresponded to the 310 helix (B). The distribution and organization of these secondary structures are shown clearly in FIG. 9. The corresponding relationship between the secondary structures and the amino acid sequence is shown in FIG. 10.
Example 11
The Three Dimensional Structure of rSIFN-Co (SEQ ID NO: 1) and IFN-α2b
Based on their receptors, IFN can broadly be divided into two types: type I and type II. Type I can further be sub-divided into α, β, ω, etc. IFN-α, in turn, contains approximately fifteen different sub-types; the different IFN-α subtypes have sequence homologies of above 80% yet they exhibit diversity in their functions. rSIFN-co (SEQ ID NO: 1) is considered to be an unnatural and artificially designed protein. To date, there are only six 3-D structures of type I IFNs (Table 5) and their sequence homology can be seen in the aligned sequences shown in FIG. 11.
From the comparative analysis shown in Table 5 and FIG. 11, the crystal structure of IFN-α2b showed the highest similarity to that of rSIFN-co (SEQ ID NO: 1) (FIG. 12). It was found, by comparing their sequences, that rSIFN-co (SEQ ID NO: 1) had one more Asp (D) than IFN-α2b at residue 45; and, by comparing their 3D structures, rSIFN-co (SEQ ID NO: 1) differed markedly from IFN-α2b with respect to the conformation of the AB loop (residues 25-33) and the BC loop (residues 44-52). The crystal structure of IFN-α2b had been determined at a resolution of 2.9 Å; however, except for the Cα, the coordinates of all other atoms were absent in the Protein Data Bank (PDB code: 1RH2) such that structural comparison between rSIFN-co (SEQ ID NO: 1) and IFN-α2b was carried out only at the Cα level. The overall RMSD of all the Cα of the two molecules was 1.577 Å; but in the AB loop and BC loop, the RMSD was 3.63 Å and 2.9 Å, which were 2.5 times and 2 times that of the total average, respectively. Besides, rSIFN-co (SEQ ID NO: 1) contained two molecules in the asymmetric unit of its crystal structure while IFN-α2b had six protein molecules, composed of 3 dimers, in its asymmetric unit. Obviously, the dimeric organization of rSIFN-co (SEQ ID NO: 1) was distinctly different from IFN-α2b (FIG. 13).







TABLE 5







The determined structures of IFNs

















Identify of





Resolution

rSIFN-co


Protein name
Source
Method
(Å)
PDB code
(SEQ ID NO: 1)





rSIFN-co
Synthesis
X-ray
2.6
This invention



(SEQ ID NO: 1)


IFN-α 2b
Human
X-ray
2.9
1RH2 (Only
89%






Cα)


IFN-α 2a
Human
NMR

1ITF
88%


IFN-τ
Human
X-ray
2.1
1B5L
54%


IFN-β
Human
X-ray
2.2
1AU1
30%


IFN-β
Mouse
X-ray
2.2
1RMI
23%









It is known that IFN, as a cytokine, first binds with specific receptors on the cell membrane to activate several signal transduction pathways that will generate biological effects in the body, such as antivirus and antitumor effects. rSIFN-co (SEQ ID NO: 1) is a type of IFN-α. Since its receptor on the cell membrane is made up of IFNAR1 and IFNAR2, a 3D model of receptor binding with IFN-α was constructed (FIG. 15a). A series of molecular biology experiments were conducted based on this model and the results suggested that IFN-α-like proteins interacted with IFNAR1 and IFNAR2 in a sandwich structure (FIG. 15a), i.e., sides A, B and F interacted with IFNAR2, and the opposite sides C, D, and E interacted with IFNAR1. Meanwhile, site-directed mutagenesis revealed that the AB loop, which interacted with IFNAR2, was the main constituent of the active site of IFN-α-like proteins (FIG. 15). Structural comparison showed that the structure of this important region was distinctly different between rSIFN-co (SEQ ID NO: 1) and IFN-α2b (FIG. 12, Table 6). Structural differences in this important region may trigger different physiological or pharmacological effects as a result of changes in the binding characteristics with receptors.
Apparently, although the molecular skeleton of rSIFN-co (SEQ ID NO: 1) was similar to that of IFN-α2b, they differed markedly in the structure of their active sites. Therefore, judging from the local structure closely related to the pharmacological activities of the molecules, it was found that rSIFN-co (SEQ ID NO: 1) was a new type of IFN different from IFN-α2b, and their structural differences had led to distinctly different biological and pharmacological characteristics. Based on the differences in the specific key region of its three dimension structure, rSIFN-co (SEQ ID NO: 1) might produce unique physiological and pharmacological effects.







TABLE 6







Root-Mean-Square Deviation (RMSD) of Cα between AB Loop and BC Loop of rSIFN-co


(SEQ ID NO: 1) and IFN-α2b (unit: Å)










Residue number of AB Loop
RMSD (Å)
Residue number of BC Loop
RMSD (Å)













25
3.291
44
1.164


26
4.779
45
1.383


27
5.090
46
2.735


28
3.588
47
2.709


29
2.567
48
5.018


30
2.437
49
4.140


31
3.526
50
3.809


32
4.820
51
2.970


33
2.756
52
0.881


Average RMSD of AB Loop
3.63
Average RMSD of BC Loop
2.90








RMSD of all Cα atoms
1.60
















TABLE 7





Atomic coordinates of rSIFN-co (SEQ ID NO: 1)















CRYST1 77.920 77.920 125.935 90.00 90.00 120.00 P 31 2 1


















ATOM
1
CB
ASN
A
11
−36.673
14.399
−31.951
1.00
79.36
A


ATOM
2
CG
ASN
A
11
−37.660
14.647
−33.090
1.00
81.91
A


ATOM
3
OD1
ASN
A
11
−37.274
14.829
−34.245
1.00
85.24
A


ATOM
4
ND2
ASN
A
11
−38.947
14.622
−32.764
1.00
82.54
A


ATOM
5
C
ASN
A
11
−34.980
16.273
−31.802
1.00
76.68
A


ATOM
6
O
ASN
A
11
−34.061
16.507
−31.007
1.00
76.57
A


ATOM
7
N
ASN
A
11
−34.283
13.985
−31.533
1.00
78.32
A


ATOM
8
CA
ASN
A
11
−35.239
14.843
−32.283
1.00
77.86
A


ATOM
9
N
ARG
A
12
−35.760
17.226
−32.307
1.00
74.41
A


ATOM
10
CA
ARG
A
12
−35.635
18.622
−31.899
1.00
69.90
A


ATOM
11
CB
ARG
A
12
−35.404
19.525
−33.115
1.00
72.01
A


ATOM
12
CG
ARG
A
12
−34.052
19.300
−33.792
1.00
77.29
A


ATOM
13
CD
ARG
A
12
−33.757
20.318
−34.894
1.00
79.77
A


ATOM
14
NE
ARG
A
12
−32.967
21.461
−34.430
1.00
83.05
A


ATOM
15
CZ
ARG
A
12
−31.669
21.635
−34.679
1.00
84.53
A


ATOM
16
NH1
ARG
A
12
−30.994
20.740
−35.390
1.00
85.41
A


ATOM
17
NH2
ARG
A
12
−31.049
22.721
−34.235
1.00
84.48
A


ATOM
18
C
ARG
A
12
−36.917
19.021
−31.174
1.00
65.99
A


ATOM
19
O
ARG
A
12
−37.334
20.177
−31.210
1.00
65.41
A


ATOM
20
N
ARG
A
13
−37.530
18.037
−30.521
1.00
61.78
A


ATOM
21
CA
ARG
A
13
−38.757
18.209
−29.750
1.00
58.49
A


ATOM
22
CB
ARG
A
13
−39.049
16.937
−28.963
1.00
61.57
A


ATOM
23
CG
ARG
A
13
−40.120
16.061
−29.535
1.00
66.89
A


ATOM
24
CD
ARG
A
13
−40.996
15.577
−28.414
1.00
69.61
A


ATOM
25
NE
ARG
A
13
−42.336
16.134
−28.518
1.00
72.80
A


ATOM
26
CZ
ARG
A
13
−43.253
16.035
−27.562
1.00
75.39
A


ATOM
27
NH1
ARG
A
13
−42.964
15.403
−26.425
1.00
74.38
A


ATOM
28
NH2
ARG
A
13
−44.462
16.555
−27.748
1.00
76.67
A


ATOM
29
C
ARG
A
13
−38.720
19.378
−28.767
1.00
54.28
A


ATOM
30
O
ARG
A
13
−39.709
20.098
−28.625
1.00
54.11
A


ATOM
31
N
ALA
A
14
−37.597
19.555
−28.075
1.00
48.77
A


ATOM
32
CA
ALA
A
14
−37.481
20.645
−27.116
1.00
45.39
A


ATOM
33
CB
ALA
A
14
−36.082
20.689
−26.526
1.00
44.44
A


ATOM
34
C
ALA
A
14
−37.816
21.984
−27.762
1.00
43.36
A


ATOM
35
O
ALA
A
14
−38.656
22.723
−27.262
1.00
42.76
A


ATOM
36
N
LEU
A
15
−37.169
22.287
−28.879
1.00
40.93
A


ATOM
37
CA
LEU
A
15
−37.402
23.542
−29.568
1.00
39.71
A


ATOM
38
CB
LEU
A
15
−36.364
23.730
−30.669
1.00
39.82
A


ATOM
39
CG
LEU
A
15
−34.952
23.714
−30.072
1.00
40.23
A


ATOM
40
CD1
LEU
A
15
−33.913
23.928
−31.151
1.00
39.64
A


ATOM
41
CD2
LEU
A
15
−34.850
24.800
−29.005
1.00
40.94
A


ATOM
42
C
LEU
A
15
−38.802
23.667
−30.130
1.00
40.00
A


ATOM
43
O
LEU
A
15
−39.372
24.751
−30.100
1.00
39.95
A


ATOM
44
N
ILE
A
16
−39.364
22.572
−30.638
1.00
40.32
A


ATOM
45
CA
ILE
A
16
−40.730
22.601
−31.179
1.00
40.64
A


ATOM
46
CB
ILE
A
16
−41.213
21.189
−31.637
1.00
43.33
A


ATOM
47
CG2
ILE
A
16
−42.605
21.283
−32.231
1.00
41.37
A


ATOM
48
CG1
ILE
A
16
−40.257
20.590
−32.673
1.00
44.72
A


ATOM
49
CD1
ILE
A
16
−40.190
21.342
−33.941
1.00
46.03
A


ATOM
50
C
ILE
A
16
−41.682
23.087
−30.080
1.00
41.12
A


ATOM
51
O
ILE
A
16
−42.425
24.051
−30.271
1.00
41.43
A


ATOM
52
N
LEU
A
17
−41.662
22.411
−28.930
1.00
40.37
A


ATOM
53
CA
LEU
A
17
−42.516
22.794
−27.812
1.00
41.00
A


ATOM
54
CB
LEU
A
17
−42.303
21.837
−26.640
1.00
42.66
A


ATOM
55
CG
LEU
A
17
−42.835
20.411
−26.850
1.00
43.03
A


ATOM
56
CD1
LEU
A
17
−42.045
19.434
−25.983
1.00
39.82
A


ATOM
57
CD2
LEU
A
17
−44.328
20.368
−26.526
1.00
40.26
A


ATOM
58
C
LEU
A
17
−42.257
24.233
−27.359
1.00
40.48
A


ATOM
59
O
LEU
A
17
−43.187
25.022
−27.212
1.00
39.35
A


ATOM
60
N
LEU
A
18
−40.986
24.574
−27.161
1.00
40.86
A


ATOM
61
CA
LEU
A
18
−40.594
25.909
−26.718
1.00
40.17
A


ATOM
62
CB
LEU
A
18
−39.073
25.973
−26.597
1.00
40.05
A


ATOM
63
CG
LEU
A
18
−38.378
26.953
−25.641
1.00
42.40
A


ATOM
64
CD1
LEU
A
18
−37.548
27.948
−26.430
1.00
42.15
A


ATOM
65
CD2
LEU
A
18
−39.393
27.657
−24.767
1.00
43.03
A


ATOM
66
C
LEU
A
18
−41.094
26.966
−27.698
1.00
40.88
A


ATOM
67
O
LEU
A
18
−41.230
28.137
−27.345
1.00
39.41
A


ATOM
68
N
ALA
A
19
−41.373
26.539
−28.929
1.00
41.87
A


ATOM
69
CA
ALA
A
19
−41.861
27.432
−29.975
1.00
44.08
A


ATOM
70
CB
ALA
A
19
−41.536
26.866
−31.358
1.00
42.64
A


ATOM
71
C
ALA
A
19
−43.359
27.594
−29.830
1.00
46.35
A


ATOM
72
O
ALA
A
19
−43.905
28.665
−30.090
1.00
47.47
A


ATOM
73
N
GLN
A
20
−44.017
26.517
−29.417
1.00
48.12
A


ATOM
74
CA
GLN
A
20
−45.462
26.519
−29.224
1.00
50.49
A


ATOM
75
CB
GLN
A
20
−45.986
25.075
−29.111
1.00
51.83
A


ATOM
76
CG
GLN
A
20
−45.540
24.097
−30.195
1.00
53.52
A


ATOM
77
CD
GLN
A
20
−46.151
22.712
−29.999
1.00
55.01
A


ATOM
78
OE1
GLN
A
20
−45.806
21.745
−30.693
1.00
52.54
A


ATOM
79
NE2
GLN
A
20
−47.069
22.614
−29.046
1.00
56.71
A


ATOM
80
C
GLN
A
20
−45.855
27.284
−27.941
1.00
51.19
A


ATOM
81
O
GLN
A
20
−47.024
27.634
−27.745
1.00
51.17
A


ATOM
82
N
MET
A
21
−44.874
27.541
−27.080
1.00
49.97
A


ATOM
83
CA
MET
A
21
−45.110
28.204
−25.802
1.00
48.63
A


ATOM
84
CB
MET
A
21
−44.002
27.808
−24.822
1.00
46.02
A


ATOM
85
CG
MET
A
21
−44.097
26.374
−24.330
1.00
43.96
A


ATOM
86
SD
MET
A
21
−42.595
25.764
−23.516
1.00
47.28
A


ATOM
87
CE
MET
A
21
−42.353
27.001
−22.206
1.00
42.84
A


ATOM
88
C
MET
A
21
−45.272
29.723
−25.809
1.00
49.74
A


ATOM
89
O
MET
A
21
−45.696
30.303
−24.807
1.00
49.63
A


ATOM
90
N
ALA
A
22
−44.950
30.375
−26.922
1.00
51.41
A


ATOM
91
CA
ALA
A
22
−45.075
31.828
−26.978
1.00
53.11
A


ATOM
92
CB
ALA
A
22
−44.641
32.362
−28.341
1.00
52.27
A


ATOM
93
C
ALA
A
22
−46.517
32.196
−26.716
1.00
53.84
A


ATOM
94
O
ALA
A
22
−47.428
31.552
−27.227
1.00
52.97
A


ATOM
95
N
ARG
A
23
−46.719
33.225
−25.904
1.00
56.56
A


ATOM
96
CA
ARG
A
23
−48.064
33.683
−25.581
1.00
59.73
A


ATOM
97
CB
ARG
A
23
−48.367
33.484
−24.094
1.00
60.59
A


ATOM
98
CG
ARG
A
23
−48.309
32.059
−23.604
1.00
62.22
A


ATOM
99
CD
ARG
A
23
−48.845
31.998
−22.183
1.00
66.26
A


ATOM
100
NE
ARG
A
23
−50.250
32.397
−22.143
1.00
70.17
A


ATOM
101
CZ
ARG
A
23
−50.744
33.339
−21.345
1.00
71.62
A


ATOM
102
NH1
ARG
A
23
−49.946
33.985
−20.504
1.00
71.69
A


ATOM
103
NH2
ARG
A
23
−52.035
33.652
−21.405
1.00
72.49
A


ATOM
104
C
ARG
A
23
−48.242
35.158
−25.921
1.00
61.02
A


ATOM
105
O
ARG
A
23
−49.334
35.584
−26.284
1.00
62.43
A


ATOM
106
N
ALA
A
24
−47.171
35.937
−25.799
1.00
61.98
A


ATOM
107
CA
ALA
A
24
−47.236
37.366
−26.080
1.00
63.61
A


ATOM
108
CB
ALA
A
24
−46.139
38.093
−25.319
1.00
62.75
A


ATOM
109
C
ALA
A
24
−47.139
37.676
−27.570
1.00
65.56
A


ATOM
110
O
ALA
A
24
−46.450
36.983
−28.322
1.00
65.76
A


ATOM
111
N
SER
A
25
−47.848
38.724
−27.984
1.00
67.91
A


ATOM
112
CA
SER
A
25
−47.865
39.157
−29.373
1.00
69.93
A


ATOM
113
CB
SER
A
25
−49.175
39.887
−29.698
1.00
71.12
A


ATOM
114
OG
SER
A
25
−50.227
38.952
−29.909
1.00
72.49
A


ATOM
115
C
SER
A
25
−46.663
40.064
−29.610
1.00
71.13
A


ATOM
116
O
SER
A
25
−46.236
40.806
−28.726
1.00
71.22
A


ATOM
117
N
PRO
A
26
−46.109
40.027
−30.825
1.00
71.97
A


ATOM
118
CD
PRO
A
26
−46.787
39.560
−32.046
1.00
72.50
A


ATOM
119
CA
PRO
A
26
−44.938
40.842
−31.165
1.00
73.26
A


ATOM
120
CB
PRO
A
26
−44.887
40.767
−32.702
1.00
73.01
A


ATOM
121
CG
PRO
A
26
−45.664
39.526
−33.023
1.00
72.89
A


ATOM
122
C
PRO
A
26
−45.008
42.284
−30.673
1.00
74.39
A


ATOM
123
O
PRO
A
26
−43.979
42.872
−30.322
1.00
74.28
A


ATOM
124
N
PHE
A
27
−46.212
42.856
−30.653
1.00
75.25
A


ATOM
125
CA
PHE
A
27
−46.375
44.245
−30.222
1.00
75.22
A


ATOM
126
CB
PHE
A
27
−47.502
44.910
−30.995
1.00
75.78
A


ATOM
127
CG
PHE
A
27
−47.305
44.909
−32.463
1.00
77.48
A


ATOM
128
CD1
PHE
A
27
−47.573
43.765
−33.204
1.00
79.44
A


ATOM
129
CD2
PHE
A
27
−46.788
46.029
−33.106
1.00
77.96
A


ATOM
130
CE1
PHE
A
27
−47.347
43.738
−34.579
1.00
80.53
A


ATOM
131
CE2
PHE
A
27
−46.557
46.022
−34.472
1.00
79.57
A


ATOM
132
CZ
PHE
A
27
−46.826
44.870
−35.215
1.00
80.89
A


ATOM
133
C
PHE
A
27
−46.635
44.449
−28.737
1.00
74.52
A


ATOM
134
O
PHE
A
27
−46.415
45.540
−28.218
1.00
74.03
A


ATOM
135
N
ALA
A
28
−47.097
43.411
−28.052
1.00
74.01
A


ATOM
136
CA
ALA
A
28
−47.394
43.532
−26.637
1.00
73.15
A


ATOM
137
CB
ALA
A
28
−47.812
42.175
−26.080
1.00
73.48
A


ATOM
138
C
ALA
A
28
−46.241
44.112
−25.822
1.00
73.09
A


ATOM
139
O
ALA
A
28
−46.460
44.586
−24.707
1.00
74.58
A


ATOM
140
N
CYS
A
29
−45.030
44.090
−26.383
1.00
72.82
A


ATOM
141
CA
CYS
A
29
−43.820
44.598
−25.713
1.00
73.33
A


ATOM
142
C
CYS
A
29
−42.968
45.450
−26.659
1.00
74.96
A


ATOM
143
O
CYS
A
29
−43.340
45.648
−27.812
1.00
75.82
A


ATOM
144
CB
CYS
A
29
−42.967
43.432
−25.217
1.00
71.43
A


ATOM
145
SG
CYS
A
29
−43.896
42.126
−24.366
1.00
69.57
A


ATOM
146
N
GLY
A
30
−41.814
45.931
−26.192
1.00
76.71
A


ATOM
147
CA
GLY
A
30
−40.990
46.756
−27.065
1.00
79.56
A


ATOM
148
C
GLY
A
30
−39.496
46.977
−26.848
1.00
81.04
A


ATOM
149
O
GLY
A
30
−38.987
47.036
−25.725
1.00
80.04
A


ATOM
150
N
GLY
A
31
−38.800
47.111
−27.976
1.00
83.09
A


ATOM
151
CA
GLY
A
31
−37.365
47.369
−27.994
1.00
86.03
A


ATOM
152
C
GLY
A
31
−36.448
46.384
−27.283
1.00
86.91
A


ATOM
153
O
GLY
A
31
−36.097
45.330
−27.822
1.00
87.85
A


ATOM
154
N
GLY
A
32
−36.030
46.767
−26.078
1.00
86.34
A


ATOM
155
CA
GLY
A
32
−35.161
45.949
−25.244
1.00
85.69
A


ATOM
156
C
GLY
A
32
−34.216
44.887
−25.810
1.00
84.42
A


ATOM
157
O
GLY
A
32
−34.386
43.694
−25.541
1.00
84.88
A


ATOM
158
N
GLY
A
33
−33.200
45.298
−26.562
1.00
82.49
A


ATOM
159
CA
GLY
A
33
−32.247
44.327
−27.076
1.00
81.23
A


ATOM
160
C
GLY
A
33
−31.315
43.958
−25.929
1.00
80.18
A


ATOM
161
O
GLY
A
33
−30.199
44.473
−25.846
1.00
79.67
A


ATOM
162
N
HIS
A
34
−31.768
43.066
−25.048
1.00
79.01
A


ATOM
163
CA
HIS
A
34
−30.984
42.654
−23.881
1.00
76.91
A


ATOM
164
CB
HIS
A
34
−31.932
42.245
−22.742
1.00
76.85
A


ATOM
165
CG
HIS
A
34
−31.313
42.323
−21.381
1.00
76.31
A


ATOM
166
CD2
HIS
A
34
−31.596
43.113
−20.319
1.00
76.73
A


ATOM
167
ND1
HIS
A
34
−30.249
41.534
−20.995
1.00
76.92
A


ATOM
168
CE1
HIS
A
34
−29.905
41.835
−19.756
1.00
76.89
A


ATOM
169
NE2
HIS
A
34
−30.707
42.791
−19.322
1.00
77.36
A


ATOM
170
C
HIS
A
34
−29.992
41.525
−24.168
1.00
74.89
A


ATOM
171
O
HIS
A
34
−30.383
40.450
−24.635
1.00
75.01
A


ATOM
172
N
ASP
A
35
−28.716
41.783
−23.869
1.00
71.97
A


ATOM
173
CA
ASP
A
35
−27.631
40.823
−24.089
1.00
69.11
A


ATOM
174
CB
ASP
A
35
−26.366
41.561
−24.542
1.00
71.02
A


ATOM
175
CG
ASP
A
35
−25.270
40.617
−25.018
1.00
73.48
A


ATOM
176
OD1
ASP
A
35
−25.490
39.904
−26.022
1.00
76.44
A


ATOM
177
OD2
ASP
A
35
−24.183
40.591
−24.398
1.00
74.76
A


ATOM
178
C
ASP
A
35
−27.318
40.010
−22.837
1.00
66.06
A


ATOM
179
O
ASP
A
35
−26.862
40.554
−21.830
1.00
66.03
A


ATOM
180
N
PHE
A
36
−27.558
38.705
−22.900
1.00
61.83
A


ATOM
181
CA
PHE
A
36
−27.282
37.853
−21.757
1.00
57.75
A


ATOM
182
CB
PHE
A
36
−28.283
36.698
−21.674
1.00
57.18
A


ATOM
183
CG
PHE
A
36
−29.696
37.146
−21.442
1.00
56.02
A


ATOM
184
CD1
PHE
A
36
−30.556
37.357
−22.505
1.00
55.11
A


ATOM
185
CD2
PHE
A
36
−30.148
37.415
−20.159
1.00
56.96
A


ATOM
186
CE1
PHE
A
36
−31.847
37.827
−22.296
1.00
56.30
A


ATOM
187
CE2
PHE
A
36
−31.441
37.889
−19.939
1.00
56.70
A


ATOM
188
CZ
PHE
A
36
−32.289
38.097
−21.010
1.00
56.38
A


ATOM
189
C
PHE
A
36
−25.870
37.326
−21.835
1.00
55.62
A


ATOM
190
O
PHE
A
36
−25.367
36.747
−20.882
1.00
55.22
A


ATOM
191
N
GLY
A
37
−25.233
37.534
−22.982
1.00
53.97
A


ATOM
192
CA
GLY
A
37
−23.859
37.103
−23.163
1.00
52.66
A


ATOM
193
C
GLY
A
37
−23.589
35.614
−23.171
1.00
52.31
A


ATOM
194
O
GLY
A
37
−22.627
35.140
−22.572
1.00
52.88
A


ATOM
195
N
PHE
A
38
−24.439
34.868
−23.856
1.00
52.34
A


ATOM
196
CA
PHE
A
38
−24.272
33.428
−23.960
1.00
53.26
A


ATOM
197
CB
PHE
A
38
−25.329
32.873
−24.925
1.00
50.67
A


ATOM
198
CG
PHE
A
38
−25.161
31.424
−25.244
1.00
48.53
A


ATOM
199
CD1
PHE
A
38
−25.352
30.457
−24.264
1.00
47.04
A


ATOM
200
CD2
PHE
A
38
−24.793
31.023
−26.529
1.00
47.77
A


ATOM
201
CE1
PHE
A
38
−25.177
29.110
−24.559
1.00
47.91
A


ATOM
202
CE2
PHE
A
38
−24.615
29.676
−26.834
1.00
46.88
A


ATOM
203
CZ
PHE
A
38
−24.806
28.719
−25.850
1.00
48.21
A


ATOM
204
C
PHE
A
38
−22.863
33.114
−24.478
1.00
54.82
A


ATOM
205
O
PHE
A
38
−22.481
33.579
−25.547
1.00
55.48
A


ATOM
206
N
PRO
A
39
−22.071
32.327
−23.724
1.00
56.41
A


ATOM
207
CD
PRO
A
39
−22.373
31.704
−22.422
1.00
56.33
A


ATOM
208
CA
PRO
A
39
−20.711
31.982
−24.158
1.00
57.36
A


ATOM
209
CB
PRO
A
39
−20.084
31.414
−22.889
1.00
55.84
A


ATOM
210
CG
PRO
A
39
−21.234
30.702
−22.266
1.00
56.06
A


ATOM
211
C
PRO
A
39
−20.705
30.974
−25.318
1.00
59.32
A


ATOM
212
O
PRO
A
39
−20.292
29.824
−25.153
1.00
59.38
A


ATOM
213
N
GLN
A
40
−21.159
31.428
−26.487
1.00
61.42
A


ATOM
214
CA
GLN
A
40
−21.235
30.616
−27.710
1.00
63.86
A


ATOM
215
CB
GLN
A
40
−21.539
31.520
−28.911
1.00
65.01
A


ATOM
216
CG
GLN
A
40
−21.996
30.776
−30.148
1.00
67.78
A


ATOM
217
CD
GLN
A
40
−22.372
31.713
−31.297
1.00
70.50
A


ATOM
218
OE1
GLN
A
40
−22.885
32.818
−31.079
1.00
70.05
A


ATOM
219
NE2
GLN
A
40
−22.135
31.262
−32.528
1.00
69.96
A


ATOM
220
C
GLN
A
40
−19.979
29.797
−28.011
1.00
64.05
A


ATOM
221
O
GLN
A
40
−20.064
28.709
−28.577
1.00
62.19
A


ATOM
222
N
GLU
A
41
−18.821
30.329
−27.630
1.00
66.08
A


ATOM
223
CA
GLU
A
41
−17.537
29.667
−27.854
1.00
68.16
A


ATOM
224
CB
GLU
A
41
−16.405
30.478
−27.216
1.00
68.78
A


ATOM
225
CG
GLU
A
41
−16.575
31.993
−27.302
1.00
71.65
A


ATOM
226
CD
GLU
A
41
−17.599
32.538
−26.309
1.00
71.91
A


ATOM
227
OE1
GLU
A
41
−17.436
32.289
−25.095
1.00
70.55
A


ATOM
228
OE2
GLU
A
41
−18.558
33.220
−26.742
1.00
72.43
A


ATOM
229
C
GLU
A
41
−17.514
28.249
−27.276
1.00
69.40
A


ATOM
230
O
GLU
A
41
−16.971
27.327
−27.884
1.00
70.02
A


ATOM
231
N
GLU
A
42
−18.107
28.081
−26.098
1.00
70.37
A


ATOM
232
CA
GLU
A
42
−18.134
26.784
−25.437
1.00
70.92
A


ATOM
233
CB
GLU
A
42
−18.816
26.907
−24.073
1.00
70.33
A


ATOM
234
CG
GLU
A
42
−18.096
27.839
−23.108
1.00
70.66
A


ATOM
235
CD
GLU
A
42
−16.674
27.387
−22.810
1.00
71.66
A


ATOM
236
OE1
GLU
A
42
−15.901
28.192
−22.245
1.00
71.99
A


ATOM
237
OE2
GLU
A
42
−16.329
26.228
−23.134
1.00
70.35
A


ATOM
238
C
GLU
A
42
−18.817
25.703
−26.263
1.00
72.31
A


ATOM
239
O
GLU
A
42
−18.658
24.515
−25.982
1.00
71.27
A


ATOM
240
N
PHE
A
43
−19.565
26.115
−27.285
1.00
74.43
A


ATOM
241
CA
PHE
A
43
−20.279
25.169
−28.142
1.00
77.01
A


ATOM
242
CB
PHE
A
43
−21.801
25.343
−27.982
1.00
73.77
A


ATOM
243
CG
PHE
A
43
−22.266
25.393
−26.551
1.00
70.14
A


ATOM
244
CD1
PHE
A
43
−22.212
26.580
−25.829
1.00
69.12
A


ATOM
245
CD2
PHE
A
43
−22.728
24.249
−25.916
1.00
69.47
A


ATOM
246
CE1
PHE
A
43
−22.608
26.627
−24.498
1.00
66.90
A


ATOM
247
CE2
PHE
A
43
−23.126
24.287
−24.579
1.00
68.62
A


ATOM
248
CZ
PHE
A
43
−23.065
25.480
−23.873
1.00
67.55
A


ATOM
249
C
PHE
A
43
−19.904
25.329
−29.620
1.00
80.52
A


ATOM
250
O
PHE
A
43
−19.615
24.350
−30.312
1.00
80.71
A


ATOM
251
N
GLY
A
44
−19.917
26.571
−30.093
1.00
84.43
A


ATOM
252
CA
GLY
A
44
−19.594
26.849
−31.483
1.00
87.53
A


ATOM
253
C
GLY
A
44
−18.109
26.912
−31.796
1.00
89.96
A


ATOM
254
O
GLY
A
44
−17.397
27.829
−31.367
1.00
89.88
A


ATOM
255
N
GLY
A
45
−17.642
25.933
−32.564
1.00
91.49
A


ATOM
256
CA
GLY
A
45
−16.243
25.889
−32.936
1.00
93.11
A


ATOM
257
C
GLY
A
45
−15.734
24.468
−33.038
1.00
94.05
A


ATOM
258
O
GLY
A
45
−16.213
23.577
−32.333
1.00
93.98
A


ATOM
259
N
GLY
A
46
−14.767
24.255
−33.925
1.00
94.77
A


ATOM
260
CA
GLY
A
46
−14.195
22.935
−34.098
1.00
95.42
A


ATOM
261
C
GLY
A
46
−13.231
22.606
−32.972
1.00
95.90
A


ATOM
262
O
GLY
A
46
−12.194
21.976
−33.199
1.00
96.10
A


ATOM
263
N
GLY
A
47
−13.570
23.040
−31.759
1.00
95.61
A


ATOM
264
CA
GLY
A
47
−12.726
22.778
−30.606
1.00
95.48
A


ATOM
265
C
GLY
A
47
−12.428
21.298
−30.455
1.00
95.42
A


ATOM
266
O
GLY
A
47
−11.319
20.921
−30.073
1.00
95.45
A


ATOM
267
N
GLY
A
48
−13.425
20.466
−30.760
1.00
94.95
A


ATOM
268
CA
GLY
A
48
−13.272
19.023
−30.674
1.00
93.55
A


ATOM
269
C
GLY
A
48
−12.943
18.541
−29.279
1.00
93.16
A


ATOM
270
O
GLY
A
48
−12.016
19.041
−28.649
1.00
94.44
A


ATOM
271
N
ALA
A
49
−13.705
17.566
−28.796
1.00
91.77
A


ATOM
272
CA
ALA
A
49
−13.507
17.000
−27.463
1.00
90.57
A


ATOM
273
CB
ALA
A
49
−13.219
18.103
−26.449
1.00
90.50
A


ATOM
274
C
ALA
A
49
−14.771
16.245
−27.069
1.00
89.91
A


ATOM
275
O
ALA
A
49
−15.801
16.855
−26.774
1.00
90.84
A


ATOM
276
N
GLY
A
50
−14.690
14.919
−27.068
1.00
88.13
A


ATOM
277
CA
GLY
A
50
−15.844
14.113
−26.727
1.00
86.16
A


ATOM
278
C
GLY
A
50
−16.495
14.504
−25.416
1.00
85.07
A


ATOM
279
O
GLY
A
50
−17.671
14.870
−25.387
1.00
84.82
A


ATOM
280
N
ALA
A
51
−15.721
14.442
−24.335
1.00
83.62
A


ATOM
281
CA
ALA
A
51
−16.211
14.753
−22.992
1.00
81.83
A


ATOM
282
CB
ALA
A
51
−15.276
14.138
−21.955
1.00
82.10
A


ATOM
283
C
ALA
A
51
−16.424
16.235
−22.685
1.00
79.92
A


ATOM
284
O
ALA
A
51
−17.409
16.602
−22.049
1.00
79.80
A


ATOM
285
N
ALA
A
52
−15.504
17.088
−23.115
1.00
77.79
A


ATOM
286
CA
ALA
A
52
−15.655
18.511
−22.852
1.00
76.55
A


ATOM
287
CB
ALA
A
52
−14.469
19.286
−23.424
1.00
76.24
A


ATOM
288
C
ALA
A
52
−16.965
19.027
−23.450
1.00
75.56
A


ATOM
289
O
ALA
A
52
−17.473
20.072
−23.037
1.00
76.89
A


ATOM
290
N
ALA
A
53
−17.510
18.288
−24.416
1.00
72.47
A


ATOM
291
CA
ALA
A
53
−18.756
18.677
−25.080
1.00
68.45
A


ATOM
292
CB
ALA
A
53
−18.737
18.220
−26.532
1.00
69.53
A


ATOM
293
C
ALA
A
53
−19.980
18.108
−24.374
1.00
64.99
A


ATOM
294
O
ALA
A
53
−21.033
18.738
−24.329
1.00
63.06
A


ATOM
295
N
ILE
A
54
−19.838
16.903
−23.841
1.00
62.13
A


ATOM
296
CA
ILE
A
54
−20.926
16.269
−23.119
1.00
59.68
A


ATOM
297
CB
ILE
A
54
−20.601
14.793
−22.815
1.00
59.54
A


ATOM
298
CG2
ILE
A
54
−21.606
14.224
−21.820
1.00
60.50
A


ATOM
299
CG1
ILE
A
54
−20.611
13.993
−24.117
1.00
59.64
A


ATOM
300
CD1
ILE
A
54
−20.368
12.518
−23.930
1.00
59.00
A


ATOM
301
C
ILE
A
54
−21.164
17.028
−21.813
1.00
57.90
A


ATOM
302
O
ILE
A
54
−22.290
17.095
−21.327
1.00
57.31
A


ATOM
303
N
SER
A
55
−20.097
17.601
−21.259
1.00
55.70
A


ATOM
304
CA
SER
A
55
−20.184
18.370
−20.023
1.00
54.92
A


ATOM
305
CB
SER
A
55
−18.793
18.751
−19.519
1.00
55.15
A


ATOM
306
OG
SER
A
55
−18.065
17.604
−19.145
1.00
57.20
A


ATOM
307
C
SER
A
55
−20.984
19.640
−20.247
1.00
53.44
A


ATOM
308
O
SER
A
55
−22.026
19.837
−19.627
1.00
55.68
A


ATOM
309
N
VAL
A
56
−20.494
20.502
−21.127
1.00
50.22
A


ATOM
310
CA
VAL
A
56
−21.178
21.752
−21.415
1.00
50.34
A


ATOM
311
CB
VAL
A
56
−20.418
22.574
−22.478
1.00
50.53
A


ATOM
312
CG1
VAL
A
56
−19.161
23.152
−21.878
1.00
50.53
A


ATOM
313
CG2
VAL
A
56
−20.078
21.697
−23.668
1.00
51.00
A


ATOM
314
C
VAL
A
56
−22.610
21.528
−21.894
1.00
49.62
A


ATOM
315
O
VAL
A
56
−23.516
22.293
−21.567
1.00
49.30
A


ATOM
316
N
LEU
A
57
−22.812
20.475
−22.673
1.00
49.64
A


ATOM
317
CA
LEU
A
57
−24.136
20.154
−23.190
1.00
49.65
A


ATOM
318
CB
LEU
A
57
−24.032
18.974
−24.152
1.00
51.00
A


ATOM
319
CG
LEU
A
57
−25.034
18.931
−25.301
1.00
52.21
A


ATOM
320
CD1
LEU
A
57
−25.250
20.322
−25.881
1.00
52.24
A


ATOM
321
CD2
LEU
A
57
−24.488
17.992
−26.361
1.00
54.20
A


ATOM
322
C
LEU
A
57
−25.054
19.800
−22.027
1.00
47.55
A


ATOM
323
O
LEU
A
57
−26.140
20.356
−21.870
1.00
46.60
A


ATOM
324
N
HIS
A
58
−24.592
18.862
−21.216
1.00
46.31
A


ATOM
325
CA
HIS
A
58
−25.319
18.415
−20.043
1.00
45.33
A


ATOM
326
CB
HIS
A
58
−24.482
17.375
−19.301
1.00
46.40
A


ATOM
327
CG
HIS
A
58
−25.242
16.619
−18.263
1.00
46.64
A


ATOM
328
CD2
HIS
A
58
−25.757
15.368
−18.275
1.00
46.79
A


ATOM
329
ND1
HIS
A
58
−25.582
17.164
−17.044
1.00
46.24
A


ATOM
330
CE1
HIS
A
58
−26.275
16.280
−16.352
1.00
48.22
A


ATOM
331
NE2
HIS
A
58
−26.397
15.180
−17.076
1.00
46.23
A


ATOM
332
C
HIS
A
58
−25.649
19.590
−19.118
1.00
43.94
A


ATOM
333
O
HIS
A
58
−26.783
19.724
−18.663
1.00
42.85
A


ATOM
334
N
GLU
A
59
−24.664
20.442
−18.847
1.00
41.52
A


ATOM
335
CA
GLU
A
59
−24.896
21.585
−17.979
1.00
41.77
A


ATOM
336
CB
GLU
A
59
−23.600
22.326
−17.702
1.00
43.24
A


ATOM
337
CG
GLU
A
59
−23.694
23.232
−16.489
1.00
47.79
A


ATOM
338
CD
GLU
A
59
−24.197
22.493
−15.249
1.00
49.54
A


ATOM
339
OE1
GLU
A
59
−23.853
21.304
−15.074
1.00
49.34
A


ATOM
340
OE2
GLU
A
59
−24.928
23.107
−14.442
1.00
52.72
A


ATOM
341
C
GLU
A
59
−25.882
22.536
−18.619
1.00
41.87
A


ATOM
342
O
GLU
A
59
−26.719
23.135
−17.942
1.00
41.28
A


ATOM
343
N
MET
A
60
−25.770
22.677
−19.935
1.00
42.94
A


ATOM
344
CA
MET
A
60
−26.662
23.542
−20.692
1.00
42.22
A


ATOM
345
CB
MET
A
60
−26.290
23.512
−22.165
1.00
43.31
A


ATOM
346
CG
MET
A
60
−27.230
24.305
−23.017
1.00
45.06
A


ATOM
347
SD
MET
A
60
−27.202
26.008
−22.511
1.00
51.70
A


ATOM
348
CE
MET
A
60
−27.674
26.784
−24.033
1.00
51.65
A


ATOM
349
C
MET
A
60
−28.096
23.052
−20.545
1.00
42.26
A


ATOM
350
O
MET
A
60
−29.039
23.839
−20.450
1.00
40.80
A


ATOM
351
N
ILE
A
61
−28.245
21.733
−20.534
1.00
40.98
A


ATOM
352
CA
ILE
A
61
−29.548
21.123
−20.418
1.00
40.78
A


ATOM
353
CB
ILE
A
61
−29.504
19.681
−20.995
1.00
42.85
A


ATOM
354
CG2
ILE
A
61
−30.790
18.936
−20.694
1.00
41.14
A


ATOM
355
CG1
ILE
A
61
−29.312
19.763
−22.518
1.00
42.64
A


ATOM
356
CD1
ILE
A
61
−29.143
18.421
−23.214
1.00
43.13
A


ATOM
357
C
ILE
A
61
−30.060
21.159
−18.984
1.00
39.56
A


ATOM
358
O
ILE
A
61
−31.195
21.558
−18.744
1.00
39.81
A


ATOM
359
N
GLN
A
62
−29.224
20.781
−18.026
1.00
39.29
A


ATOM
360
CA
GLN
A
62
−29.639
20.793
−16.627
1.00
38.51
A


ATOM
361
CB
GLN
A
62
−28.488
20.338
−15.726
1.00
39.26
A


ATOM
362
CG
GLN
A
62
−28.827
20.246
−14.242
1.00
39.53
A


ATOM
363
CD
GLN
A
62
−30.002
19.321
−13.941
1.00
40.52
A


ATOM
364
OE1
GLN
A
62
−31.042
19.758
−13.438
1.00
39.54
A


ATOM
365
NE2
GLN
A
62
−29.840
18.040
−14.248
1.00
39.51
A


ATOM
366
C
GLN
A
62
−30.102
22.189
−16.221
1.00
38.93
A


ATOM
367
O
GLN
A
62
−31.106
22.348
−15.522
1.00
37.04
A


ATOM
368
N
GLN
A
63
−29.383
23.204
−16.683
1.00
39.52
A


ATOM
369
CA
GLN
A
63
−29.741
24.578
−16.353
1.00
40.38
A


ATOM
370
CB
GLN
A
63
−28.644
25.543
−16.797
1.00
41.37
A


ATOM
371
CG
GLN
A
63
−27.350
25.361
−16.049
1.00
42.32
A


ATOM
372
CD
GLN
A
63
−27.523
25.576
−14.563
1.00
46.04
A


ATOM
373
OE1
GLN
A
63
−26.881
24.907
−13.753
1.00
47.35
A


ATOM
374
NE2
GLN
A
63
−28.386
26.526
−14.192
1.00
46.16
A


ATOM
375
C
GLN
A
63
−31.062
25.006
−16.957
1.00
40.51
A


ATOM
376
O
GLN
A
63
−31.837
25.685
−16.286
1.00
43.32
A


ATOM
377
N
THR
A
64
−31.313
24.625
−18.215
1.00
39.04
A


ATOM
378
CA
THR
A
64
−32.564
24.972
−18.904
1.00
37.15
A


ATOM
379
CB
THR
A
64
−32.539
24.536
−20.398
1.00
36.84
A


ATOM
380
OG1
THR
A
64
−31.493
25.233
−21.084
1.00
35.39
A


ATOM
381
CG2
THR
A
64
−33.872
24.834
−21.077
1.00
32.91
A


ATOM
382
C
THR
A
64
−33.714
24.265
−18.181
1.00
37.88
A


ATOM
383
O
THR
A
64
−34.827
24.791
−18.061
1.00
37.95
A


ATOM
384
N
PHE
A
65
−33.438
23.061
−17.700
1.00
37.24
A


ATOM
385
CA
PHE
A
65
−34.435
22.326
−16.951
1.00
37.39
A


ATOM
386
CB
PHE
A
65
−33.934
20.930
−16.625
1.00
37.39
A


ATOM
387
CG
PHE
A
65
−34.874
20.159
−15.749
1.00
40.42
A


ATOM
388
CD1
PHE
A
65
−35.967
19.503
−16.292
1.00
39.82
A


ATOM
389
CD2
PHE
A
65
−34.706
20.155
−14.370
1.00
40.52
A


ATOM
390
CE1
PHE
A
65
−36.871
18.861
−15.485
1.00
40.75
A


ATOM
391
CE2
PHE
A
65
−35.611
19.511
−13.556
1.00
40.34
A


ATOM
392
CZ
PHE
A
65
−36.697
18.867
−14.115
1.00
40.24
A


ATOM
393
C
PHE
A
65
−34.756
23.070
−15.639
1.00
36.83
A


ATOM
394
O
PHE
A
65
−35.918
23.289
−15.317
1.00
37.76
A


ATOM
395
N
ASN
A
66
−33.730
23.450
−14.880
1.00
35.91
A


ATOM
396
CA
ASN
A
66
−33.950
24.177
−13.633
1.00
34.39
A


ATOM
397
CB
ASN
A
66
−32.631
24.485
−12.935
1.00
32.13
A


ATOM
398
CG
ASN
A
66
−31.851
23.238
−12.606
1.00
34.28
A


ATOM
399
OD1
ASN
A
66
−32.418
22.153
−12.512
1.00
37.35
A


ATOM
400
ND2
ASN
A
66
−30.545
23.380
−12.424
1.00
33.10
A


ATOM
401
C
ASN
A
66
−34.678
25.481
−13.900
1.00
34.39
A


ATOM
402
O
ASN
A
66
−35.582
25.851
−13.163
1.00
35.59
A


ATOM
403
N
LEU
A
67
−34.299
26.172
−14.963
1.00
34.07
A


ATOM
404
CA
LEU
A
67
−34.937
27.440
−15.292
1.00
34.52
A


ATOM
405
CB
LEU
A
67
−34.189
28.135
−16.434
1.00
31.74
A


ATOM
406
CG
LEU
A
67
−34.902
29.382
−16.972
1.00
32.77
A


ATOM
407
CD1
LEU
A
67
−34.922
30.487
−15.907
1.00
29.39
A


ATOM
408
CD2
LEU
A
67
−34.216
29.848
−18.259
1.00
31.96
A


ATOM
409
C
LEU
A
67
−36.417
27.335
−15.655
1.00
34.13
A


ATOM
410
O
LEU
A
67
−37.185
28.238
−15.362
1.00
35.27
A


ATOM
411
N
PHE
A
68
−36.824
26.236
−16.280
1.00
36.35
A


ATOM
412
CA
PHE
A
68
−38.218
26.081
−16.690
1.00
37.11
A


ATOM
413
CB
PHE
A
68
−38.284
25.620
−18.150
1.00
33.91
A


ATOM
414
CG
PHE
A
68
−38.023
26.708
−19.133
1.00
31.92
A


ATOM
415
CD1
PHE
A
68
−36.724
26.985
−19.563
1.00
33.37
A


ATOM
416
CD2
PHE
A
68
−39.071
27.494
−19.607
1.00
30.01
A


ATOM
417
CE1
PHE
A
68
−36.469
28.045
−20.466
1.00
31.57
A


ATOM
418
CE2
PHE
A
68
−38.835
28.553
−20.504
1.00
30.12
A


ATOM
419
CZ
PHE
A
68
−37.534
28.830
−20.932
1.00
28.79
A


ATOM
420
C
PHE
A
68
−39.128
25.186
−15.845
1.00
39.17
A


ATOM
421
O
PHE
A
68
−40.318
25.067
−16.131
1.00
39.72
A


ATOM
422
N
SER
A
69
−38.592
24.558
−14.806
1.00
41.24
A


ATOM
423
CA
SER
A
69
−39.424
23.709
−13.969
1.00
41.35
A


ATOM
424
CB
SER
A
69
−38.721
22.398
−13.704
1.00
39.74
A


ATOM
425
OG
SER
A
69
−37.509
22.664
−13.042
1.00
40.54
A


ATOM
426
C
SER
A
69
−39.790
24.355
−12.635
1.00
42.76
A


ATOM
427
O
SER
A
69
−40.328
23.687
−11.772
1.00
45.46
A


ATOM
428
N
THR
A
70
−39.508
25.642
−12.459
1.00
44.33
A


ATOM
429
CA
THR
A
70
−39.839
26.316
−11.201
1.00
47.21
A


ATOM
430
CB
THR
A
70
−39.038
27.630
−10.990
1.00
47.32
A


ATOM
431
OG1
THR
A
70
−39.366
28.565
−12.031
1.00
49.98
A


ATOM
432
CG2
THR
A
70
−37.547
27.364
−10.977
1.00
45.16
A


ATOM
433
C
THR
A
70
−41.307
26.709
−11.179
1.00
50.70
A


ATOM
434
O
THR
A
70
−42.001
26.617
−12.195
1.00
50.43
A


ATOM
435
N
ARG
A
71
−41.777
27.164
−10.018
1.00
53.44
A


ATOM
436
CA
ARG
A
71
−43.164
27.594
−9.908
1.00
55.27
A


ATOM
437
CB
ARG
A
71
−43.576
27.847
−8.449
1.00
57.92
A


ATOM
438
CG
ARG
A
71
−43.186
26.760
−7.454
1.00
61.59
A


ATOM
439
CD
ARG
A
71
−41.834
27.104
−6.805
1.00
64.19
A


ATOM
440
NE
ARG
A
71
−40.663
26.474
−7.420
1.00
58.72
A


ATOM
441
CZ
ARG
A
71
−39.469
27.046
−7.453
1.00
55.24
A


ATOM
442
NH1
ARG
A
71
−39.304
28.250
−6.929
1.00
52.89
A


ATOM
443
NH2
ARG
A
71
−38.435
26.399
−7.964
1.00
55.93
A


ATOM
444
C
ARG
A
71
−43.298
28.891
−10.697
1.00
53.94
A


ATOM
445
O
ARG
A
71
−44.382
29.232
−11.171
1.00
53.96
A


ATOM
446
N
ASP
A
72
−42.196
29.619
−10.832
1.00
52.47
A


ATOM
447
CA
ASP
A
72
−42.232
30.857
−11.588
1.00
53.16
A


ATOM
448
CB
ASP
A
72
−40.896
31.592
−11.491
1.00
55.60
A


ATOM
449
CG
ASP
A
72
−40.517
31.929
−10.069
1.00
56.39
A


ATOM
450
OD1
ASP
A
72
−39.627
31.244
−9.517
1.00
57.77
A


ATOM
451
OD2
ASP
A
72
−41.114
32.874
−9.510
1.00
56.32
A


ATOM
452
C
ASP
A
72
−42.524
30.523
−13.050
1.00
52.84
A


ATOM
453
O
ASP
A
72
−43.402
31.114
−13.672
1.00
51.84
A


ATOM
454
N
SER
A
73
−41.780
29.569
−13.592
1.00
51.97
A


ATOM
455
CA
SER
A
73
−41.980
29.169
−14.971
1.00
52.26
A


ATOM
456
CB
SER
A
73
−40.981
28.062
−15.347
1.00
51.52
A


ATOM
457
OG
SER
A
73
−41.246
27.525
−16.629
1.00
48.35
A


ATOM
458
C
SER
A
73
−43.416
28.674
−15.134
1.00
53.10
A


ATOM
459
O
SER
A
73
−44.097
29.008
−16.107
1.00
54.40
A


ATOM
460
N
SER
A
74
−43.882
27.893
−14.165
1.00
53.63
A


ATOM
461
CA
SER
A
74
−45.231
27.342
−14.222
1.00
53.33
A


ATOM
462
CB
SER
A
74
−45.484
26.414
−13.041
1.00
51.87
A


ATOM
463
OG
SER
A
74
−45.620
25.076
−13.494
1.00
53.40
A


ATOM
464
C
SER
A
74
−46.320
28.389
−14.274
1.00
52.78
A


ATOM
465
O
SER
A
74
−47.411
28.125
−14.771
1.00
54.19
A


ATOM
466
N
ALA
A
75
−46.021
29.579
−13.770
1.00
51.42
A


ATOM
467
CA
ALA
A
75
−46.990
30.662
−13.755
1.00
50.95
A


ATOM
468
CB
ALA
A
75
−46.727
31.573
−12.556
1.00
48.85
A


ATOM
469
C
ALA
A
75
−46.927
31.473
−15.041
1.00
50.90
A


ATOM
470
O
ALA
A
75
−47.774
32.319
−15.292
1.00
52.54
A


ATOM
471
N
ALA
A
76
−45.923
31.213
−15.860
1.00
49.86
A


ATOM
472
CA
ALA
A
76
−45.769
31.969
−17.080
1.00
49.41
A


ATOM
473
CB
ALA
A
76
−44.334
32.491
−17.168
1.00
50.92
A


ATOM
474
C
ALA
A
76
−46.122
31.192
−18.341
1.00
49.59
A


ATOM
475
O
ALA
A
76
−46.417
31.794
−19.378
1.00
50.18
A


ATOM
476
N
TRP
A
77
−46.111
29.866
−18.259
1.00
47.56
A


ATOM
477
CA
TRP
A
77
−46.387
29.063
−19.438
1.00
46.48
A


ATOM
478
CB
TRP
A
77
−45.110
28.355
−19.877
1.00
44.34
A


ATOM
479
CG
TRP
A
77
−43.913
29.259
−19.895
1.00
42.62
A


ATOM
480
CD2
TRP
A
77
−43.655
30.325
−20.813
1.00
40.67
A


ATOM
481
CE2
TRP
A
77
−42.422
30.902
−20.448
1.00
40.13
A


ATOM
482
CE3
TRP
A
77
−44.344
30.847
−21.914
1.00
42.24
A


ATOM
483
CD1
TRP
A
77
−42.860
29.232
−19.036
1.00
40.98
A


ATOM
484
NE1
TRP
A
77
−41.958
30.213
−19.360
1.00
41.31
A


ATOM
485
CZ2
TRP
A
77
−41.857
31.981
−21.140
1.00
41.93
A


ATOM
486
CZ3
TRP
A
77
−43.780
31.927
−22.612
1.00
42.72
A


ATOM
487
CH2
TRP
A
77
−42.548
32.479
−22.218
1.00
40.65
A


ATOM
488
C
TRP
A
77
−47.499
28.044
−19.317
1.00
47.54
A


ATOM
489
O
TRP
A
77
−47.927
27.687
−18.228
1.00
47.95
A


ATOM
490
N
ASP
A
78
−47.964
27.578
−20.467
1.00
50.28
A


ATOM
491
CA
ASP
A
78
−49.024
26.590
−20.526
1.00
52.24
A


ATOM
492
CB
ASP
A
78
−49.376
26.310
−21.986
1.00
53.78
A


ATOM
493
CG
ASP
A
78
−50.539
25.368
−22.128
1.00
55.91
A


ATOM
494
OD1
ASP
A
78
−50.307
24.144
−22.238
1.00
57.57
A


ATOM
495
OD2
ASP
A
78
−51.689
25.857
−22.115
1.00
57.70
A


ATOM
496
C
ASP
A
78
−48.591
25.309
−19.815
1.00
53.52
A


ATOM
497
O
ASP
A
78
−47.633
24.638
−20.217
1.00
53.27
A


ATOM
498
N
ALA
A
79
−49.304
24.978
−18.746
1.00
54.38
A


ATOM
499
CA
ALA
A
79
−48.983
23.797
−17.961
1.00
54.80
A


ATOM
500
CB
ALA
A
79
−50.123
23.488
−16.991
1.00
54.45
A


ATOM
501
C
ALA
A
79
−48.692
22.594
−18.843
1.00
54.31
A


ATOM
502
O
ALA
A
79
−47.633
21.994
−18.747
1.00
55.97
A


ATOM
503
N
SER
A
80
−49.619
22.255
−19.722
1.00
54.29
A


ATOM
504
CA
SER
A
80
−49.438
21.096
−20.588
1.00
54.78
A


ATOM
505
CB
SER
A
80
−50.677
20.900
−21.471
1.00
56.80
A


ATOM
506
OG
SER
A
80
−50.573
19.708
−22.235
1.00
60.99
A


ATOM
507
C
SER
A
80
−48.184
21.198
−21.453
1.00
53.08
A


ATOM
508
O
SER
A
80
−47.441
20.225
−21.602
1.00
52.66
A


ATOM
509
N
LEU
A
81
−47.956
22.372
−22.030
1.00
51.48
A


ATOM
510
CA
LEU
A
81
−46.781
22.579
−22.858
1.00
50.28
A


ATOM
511
CB
LEU
A
81
−46.848
23.939
−23.567
1.00
50.13
A


ATOM
512
CG
LEU
A
81
−47.794
24.078
−24.770
1.00
52.07
A


ATOM
513
CD1
LEU
A
81
−47.823
25.523
−25.274
1.00
50.96
A


ATOM
514
CD2
LEU
A
81
−47.338
23.143
−25.881
1.00
51.96
A


ATOM
515
C
LEU
A
81
−45.533
22.495
−21.981
1.00
49.31
A


ATOM
516
O
LEU
A
81
−44.655
21.673
−22.231
1.00
49.33
A


ATOM
517
N
LEU
A
82
−45.473
23.319
−20.936
1.00
47.57
A


ATOM
518
CA
LEU
A
82
−44.323
23.330
−20.033
1.00
45.33
A


ATOM
519
CB
LEU
A
82
−44.636
24.117
−18.770
1.00
46.40
A


ATOM
520
CG
LEU
A
82
−43.611
25.158
−18.335
1.00
45.80
A


ATOM
521
CD1
LEU
A
82
−43.773
25.372
−16.834
1.00
43.68
A


ATOM
522
CD2
LEU
A
82
−42.207
24.705
−18.670
1.00
43.36
A


ATOM
523
C
LEU
A
82
−43.864
21.945
−19.618
1.00
43.50
A


ATOM
524
O
LEU
A
82
−42.689
21.626
−19.728
1.00
43.15
A


ATOM
525
N
ALA
A
83
−44.785
21.114
−19.146
1.00
43.10
A


ATOM
526
CA
ALA
A
83
−44.405
19.775
−18.706
1.00
43.00
A


ATOM
527
CB
ALA
A
83
−45.606
19.052
−18.090
1.00
43.77
A


ATOM
528
C
ALA
A
83
−43.791
18.937
−19.826
1.00
42.10
A


ATOM
529
O
ALA
A
83
−42.857
18.179
−19.591
1.00
41.05
A


ATOM
530
N
LYS
A
84
−44.295
19.052
−21.049
1.00
42.19
A


ATOM
531
CA
LYS
A
84
−43.688
18.251
−22.101
1.00
42.91
A


ATOM
532
CB
LYS
A
84
−44.509
18.300
−23.373
1.00
44.87
A


ATOM
533
CG
LYS
A
84
−45.866
17.660
−23.231
1.00
48.00
A


ATOM
534
CD
LYS
A
84
−46.263
16.952
−24.500
1.00
49.01
A


ATOM
535
CE
LYS
A
84
−47.734
17.105
−24.720
1.00
51.13
A


ATOM
536
NZ
LYS
A
84
−48.023
18.541
−24.942
1.00
52.74
A


ATOM
537
C
LYS
A
84
−42.285
18.763
−22.359
1.00
43.12
A


ATOM
538
O
LYS
A
84
−41.347
17.987
−22.527
1.00
44.29
A


ATOM
539
N
PHE
A
85
−42.144
20.081
−22.363
1.00
42.32
A


ATOM
540
CA
PHE
A
85
−40.852
20.704
−22.571
1.00
42.58
A


ATOM
541
CB
PHE
A
85
−40.964
22.222
−22.450
1.00
43.25
A


ATOM
542
CG
PHE
A
85
−39.681
22.944
−22.734
1.00
42.84
A


ATOM
543
CD1
PHE
A
85
−39.076
22.847
−23.982
1.00
43.39
A


ATOM
544
CD2
PHE
A
85
−39.084
23.734
−21.768
1.00
42.83
A


ATOM
545
CE1
PHE
A
85
−37.897
23.528
−24.265
1.00
42.40
A


ATOM
546
CE2
PHE
A
85
−37.904
24.417
−22.043
1.00
43.37
A


ATOM
547
CZ
PHE
A
85
−37.312
24.313
−23.295
1.00
42.70
A


ATOM
548
C
PHE
A
85
−39.813
20.206
−21.572
1.00
44.30
A


ATOM
549
O
PHE
A
85
−38.835
19.562
−21.964
1.00
45.07
A


ATOM
550
N
TYR
A
86
−40.014
20.482
−20.282
1.00
43.21
A


ATOM
551
CA
TYR
A
86
−39.018
20.055
−19.319
1.00
44.18
A


ATOM
552
CB
TYR
A
86
−39.208
20.748
−17.948
1.00
45.30
A


ATOM
553
CG
TYR
A
86
−40.455
20.448
−17.144
1.00
44.10
A


ATOM
554
CD1
TYR
A
86
−41.328
21.474
−16.797
1.00
43.43
A


ATOM
555
CE1
TYR
A
86
−42.432
21.239
−15.988
1.00
45.72
A


ATOM
556
CD2
TYR
A
86
−40.720
19.163
−16.662
1.00
43.84
A


ATOM
557
CE2
TYR
A
86
−41.828
18.915
−15.846
1.00
46.21
A


ATOM
558
CZ
TYR
A
86
−42.678
19.963
−15.513
1.00
47.37
A


ATOM
559
OH
TYR
A
86
−43.764
19.756
−14.691
1.00
49.38
A


ATOM
560
C
TYR
A
86
−38.862
18.549
−19.164
1.00
44.37
A


ATOM
561
O
TYR
A
86
−37.848
18.080
−18.656
1.00
44.46
A


ATOM
562
N
THR
A
87
−39.846
17.785
−19.621
1.00
44.44
A


ATOM
563
CA
THR
A
87
−39.752
16.330
−19.537
1.00
43.78
A


ATOM
564
CB
THR
A
87
−41.129
15.644
−19.751
1.00
43.93
A


ATOM
565
OG1
THR
A
87
−42.035
16.055
−18.722
1.00
42.91
A


ATOM
566
CG2
THR
A
87
−40.986
14.130
−19.712
1.00
40.48
A


ATOM
567
C
THR
A
87
−38.813
15.905
−20.654
1.00
43.41
A


ATOM
568
O
THR
A
87
−38.040
14.962
−20.509
1.00
42.95
A


ATOM
569
N
GLU
A
88
−38.898
16.620
−21.774
1.00
43.70
A


ATOM
570
CA
GLU
A
88
−38.057
16.359
−22.932
1.00
42.33
A


ATOM
571
CB
GLU
A
88
−38.503
17.245
−24.098
1.00
43.68
A


ATOM
572
CG
GLU
A
88
−37.754
17.014
−25.394
1.00
48.37
A


ATOM
573
CD
GLU
A
88
−37.718
15.546
−25.822
1.00
51.49
A


ATOM
574
OE1
GLU
A
88
−38.767
14.864
−25.751
1.00
51.50
A


ATOM
575
OE2
GLU
A
88
−36.634
15.083
−26.242
1.00
52.60
A


ATOM
576
C
GLU
A
88
−36.616
16.664
−22.541
1.00
40.76
A


ATOM
577
O
GLU
A
88
−35.695
15.921
−22.878
1.00
40.05
A


ATOM
578
N
LEU
A
89
−36.428
17.756
−21.809
1.00
39.65
A


ATOM
579
CA
LEU
A
89
−35.096
18.127
−21.373
1.00
40.05
A


ATOM
580
CB
LEU
A
89
−35.128
19.464
−20.619
1.00
39.26
A


ATOM
581
CG
LEU
A
89
−35.580
20.688
−21.432
1.00
39.90
A


ATOM
582
CD1
LEU
A
89
−35.594
21.916
−20.546
1.00
41.45
A


ATOM
583
CD2
LEU
A
89
−34.647
20.917
−22.599
1.00
37.56
A


ATOM
584
C
LEU
A
89
−34.555
17.030
−20.481
1.00
40.50
A


ATOM
585
O
LEU
A
89
−33.394
16.638
−20.598
1.00
39.83
A


ATOM
586
N
TYR
A
90
−35.412
16.520
−19.598
1.00
42.46
A


ATOM
587
CA
TYR
A
90
−35.020
15.465
−18.674
1.00
43.11
A


ATOM
588
CB
TYR
A
90
−36.154
15.134
−17.711
1.00
45.71
A


ATOM
589
CG
TYR
A
90
−35.682
14.361
−16.502
1.00
49.69
A


ATOM
590
CD1
TYR
A
90
−35.034
15.013
−15.447
1.00
50.12
A


ATOM
591
CE1
TYR
A
90
−34.535
14.307
−14.365
1.00
52.01
A


ATOM
592
CD2
TYR
A
90
−35.820
12.974
−16.435
1.00
50.69
A


ATOM
593
CE2
TYR
A
90
−35.326
12.256
−15.349
1.00
53.04
A


ATOM
594
CZ
TYR
A
90
−34.680
12.929
−14.321
1.00
53.92
A


ATOM
595
OH
TYR
A
90
−34.161
12.227
−13.256
1.00
56.71
A


ATOM
596
C
TYR
A
90
−34.643
14.217
−19.446
1.00
43.97
A


ATOM
597
O
TYR
A
90
−33.682
13.534
−19.106
1.00
44.98
A


ATOM
598
N
GLN
A
91
−35.406
13.915
−20.489
1.00
45.76
A


ATOM
599
CA
GLN
A
91
−35.116
12.748
−21.300
1.00
48.45
A


ATOM
600
CB
GLN
A
91
−36.126
12.616
−22.440
1.00
51.91
A


ATOM
601
CG
GLN
A
91
−36.964
11.363
−22.371
1.00
56.69
A


ATOM
602
CD
GLN
A
91
−36.141
10.178
−21.917
1.00
61.59
A


ATOM
603
OE1
GLN
A
91
−36.223
9.756
−20.760
1.00
63.01
A


ATOM
604
NE2
GLN
A
91
−35.322
9.648
−22.816
1.00
61.97
A


ATOM
605
C
GLN
A
91
−33.719
12.909
−21.880
1.00
48.95
A


ATOM
606
O
GLN
A
91
−32.906
11.984
−21.826
1.00
48.74
A


ATOM
607
N
GLN
A
92
−33.451
14.098
−22.419
1.00
48.30
A


ATOM
608
CA
GLN
A
92
−32.166
14.403
−23.030
1.00
49.20
A


ATOM
609
CB
GLN
A
92
−32.204
15.800
−23.666
1.00
49.21
A


ATOM
610
CG
GLN
A
92
−32.906
15.825
−25.020
1.00
50.13
A


ATOM
611
CD
GLN
A
92
−33.021
17.215
−25.621
1.00
51.05
A


ATOM
612
OE1
GLN
A
92
−32.087
18.010
−25.566
1.00
53.57
A


ATOM
613
NE2
GLN
A
92
−34.166
17.505
−26.214
1.00
52.77
A


ATOM
614
C
GLN
A
92
−30.998
14.279
−22.061
1.00
49.71
A


ATOM
615
O
GLN
A
92
−29.895
13.902
−22.462
1.00
50.06
A


ATOM
616
N
LEU
A
93
−31.223
14.602
−20.790
1.00
48.85
A


ATOM
617
CA
LEU
A
93
−30.148
14.463
−19.820
1.00
49.45
A


ATOM
618
CB
LEU
A
93
−30.545
15.025
−18.454
1.00
47.86
A


ATOM
619
CG
LEU
A
93
−30.469
16.530
−18.237
1.00
45.97
A


ATOM
620
CD1
LEU
A
93
−30.980
16.854
−16.851
1.00
45.24
A


ATOM
621
CD2
LEU
A
93
−29.042
16.997
−18.410
1.00
45.80
A


ATOM
622
C
LEU
A
93
−29.883
12.974
−19.679
1.00
51.53
A


ATOM
623
O
LEU
A
93
−28.730
12.531
−19.661
1.00
49.61
A


ATOM
624
N
ALA
A
94
−30.974
12.212
−19.585
1.00
54.03
A


ATOM
625
CA
ALA
A
94
−30.902
10.766
−19.439
1.00
56.50
A


ATOM
626
CB
ALA
A
94
−32.306
10.177
−19.305
1.00
55.64
A


ATOM
627
C
ALA
A
94
−30.161
10.139
−20.618
1.00
58.27
A


ATOM
628
O
ALA
A
94
−29.383
9.208
−20.431
1.00
60.16
A


ATOM
629
N
ASP
A
95
−30.382
10.654
−21.826
1.00
59.89
A


ATOM
630
CA
ASP
A
95
−29.696
10.115
−22.998
1.00
60.86
A


ATOM
631
CB
ASP
A
95
−30.293
10.665
−24.295
1.00
61.06
A


ATOM
632
CG
ASP
A
95
−31.745
10.259
−24.489
1.00
64.37
A


ATOM
633
OD1
ASP
A
95
−32.123
9.156
−24.038
1.00
65.54
A


ATOM
634
OD2
ASP
A
95
−32.513
11.034
−25.101
1.00
65.80
A


ATOM
635
C
ASP
A
95
−28.208
10.424
−22.960
1.00
62.01
A


ATOM
636
O
ASP
A
95
−27.396
9.594
−23.349
1.00
62.85
A


ATOM
637
N
LEU
A
96
−27.840
11.612
−22.492
1.00
63.44
A


ATOM
638
CA
LEU
A
96
−26.429
11.968
−22.434
1.00
65.26
A


ATOM
639
CB
LEU
A
96
−26.250
13.437
−22.063
1.00
64.67
A


ATOM
640
CG
LEU
A
96
−26.228
14.431
−23.223
1.00
64.38
A


ATOM
641
CD1
LEU
A
96
−25.876
15.815
−22.699
1.00
63.39
A


ATOM
642
CD2
LEU
A
96
−25.213
13.978
−24.256
1.00
62.74
A


ATOM
643
C
LEU
A
96
−25.665
11.115
−21.444
1.00
67.97
A


ATOM
644
O
LEU
A
96
−24.520
10.735
−21.693
1.00
68.62
A


ATOM
645
N
GLU
A
97
−26.300
10.811
−20.321
1.00
70.13
A


ATOM
646
CA
GLU
A
97
−25.657
10.017
−19.291
1.00
72.55
A


ATOM
647
CB
GLU
A
97
−26.488
10.075
−18.019
1.00
71.72
A


ATOM
648
CG
GLU
A
97
−26.985
11.485
−17.769
1.00
74.81
A


ATOM
649
CD
GLU
A
97
−27.241
11.799
−16.314
1.00
75.51
A


ATOM
650
OE1
GLU
A
97
−27.747
12.905
−16.036
1.00
74.77
A


ATOM
651
OE2
GLU
A
97
−26.931
10.953
−15.451
1.00
77.73
A


ATOM
652
C
GLU
A
97
−25.450
8.588
−19.762
1.00
74.96
A


ATOM
653
O
GLU
A
97
−24.468
7.943
−19.390
1.00
76.46
A


ATOM
654
N
ALA
A
98
−26.366
8.089
−20.586
1.00
76.86
A


ATOM
655
CA
ALA
A
98
−26.223
6.737
−21.115
1.00
78.82
A


ATOM
656
CB
ALA
A
98
−27.433
6.366
−21.954
1.00
77.13
A


ATOM
657
C
ALA
A
98
−24.965
6.775
−21.980
1.00
81.25
A


ATOM
658
O
ALA
A
98
−24.070
5.941
−21.838
1.00
81.55
A


ATOM
659
N
CYS
A
99
−24.907
7.778
−22.854
1.00
83.47
A


ATOM
660
CA
CYS
A
99
−23.786
7.987
−23.759
1.00
85.46
A


ATOM
661
CB
CYS
A
99
−23.981
9.310
−24.517
1.00
86.41
A


ATOM
662
SG
CYS
A
99
−22.959
9.545
−26.007
1.00
89.76
A


ATOM
663
C
CYS
A
99
−22.462
8.000
−22.988
1.00
86.47
A


ATOM
664
O
CYS
A
99
−21.478
7.415
−23.436
1.00
87.19
A


ATOM
665
N
VAL
A
100
−22.438
8.659
−21.832
1.00
87.06
A


ATOM
666
CA
VAL
A
100
−21.221
8.718
−21.018
1.00
88.28
A


ATOM
667
CB
VAL
A
100
−21.364
9.721
−19.840
1.00
87.74
A


ATOM
668
CG1
VAL
A
100
−20.109
9.704
−18.980
1.00
87.01
A


ATOM
669
CG2
VAL
A
100
−21.603
11.118
−20.371
1.00
87.68
A


ATOM
670
C
VAL
A
100
−20.878
7.339
−20.442
1.00
89.50
A


ATOM
671
O
VAL
A
100
−19.728
6.899
−20.506
1.00
89.46
A


ATOM
672
N
ALA
A
101
−21.881
6.666
−19.880
1.00
90.52
A


ATOM
673
CA
ALA
A
101
−21.696
5.340
−19.294
1.00
91.37
A


ATOM
674
CB
ALA
A
101
−22.924
4.958
−18.477
1.00
90.68
A


ATOM
675
C
ALA
A
101
−21.448
4.305
−20.390
1.00
92.11
A


ATOM
676
O
ALA
A
101
−22.144
3.290
−20.483
1.00
92.02
A


ATOM
677
N
GLY
A
102
−20.445
4.572
−21.218
1.00
92.66
A


ATOM
678
CA
GLY
A
102
−20.117
3.672
−22.303
1.00
93.77
A


ATOM
679
C
GLY
A
102
−19.599
4.456
−23.490
1.00
94.37
A


ATOM
680
O
GLY
A
102
−20.320
4.666
−24.467
1.00
94.30
A


ATOM
681
N
GLY
A
103
−18.345
4.893
−23.399
1.00
94.78
A


ATOM
682
CA
GLY
A
103
−17.741
5.662
−24.472
1.00
94.59
A


ATOM
683
C
GLY
A
103
−17.097
6.930
−23.948
1.00
94.45
A


ATOM
684
O
GLY
A
103
−17.324
7.326
−22.804
1.00
94.32
A


ATOM
685
N
ALA
A
111
−11.108
13.549
−17.360
1.00
90.11
A


ATOM
686
CA
ALA
A
111
−11.032
14.851
−16.699
1.00
90.12
A


ATOM
687
CB
ALA
A
111
−9.569
15.220
−16.438
1.00
89.81
A


ATOM
688
C
ALA
A
111
−11.713
15.942
−17.530
1.00
89.66
A


ATOM
689
O
ALA
A
111
−12.411
15.650
−18.506
1.00
90.16
A


ATOM
690
N
GLY
A
112
−11.509
17.197
−17.136
1.00
88.41
A


ATOM
691
CA
GLY
A
112
−12.108
18.312
−17.853
1.00
86.60
A


ATOM
692
C
GLY
A
112
−11.712
19.656
−17.267
1.00
85.50
A


ATOM
693
O
GLY
A
112
−10.617
19.797
−16.709
1.00
86.67
A


ATOM
694
N
ASN
A
113
−12.590
20.650
−17.400
1.00
82.82
A


ATOM
695
CA
ASN
A
113
−12.309
21.975
−16.860
1.00
79.24
A


ATOM
696
CB
ASN
A
113
−11.567
22.843
−17.893
1.00
81.82
A


ATOM
697
CG
ASN
A
113
−12.359
23.059
−19.177
1.00
83.86
A


ATOM
698
OD1
ASN
A
113
−12.808
22.103
−19.818
1.00
85.28
A


ATOM
699
ND2
ASN
A
113
−12.518
24.324
−19.569
1.00
83.13
A


ATOM
700
C
ASN
A
113
−13.551
22.693
−16.339
1.00
75.65
A


ATOM
701
O
ASN
A
113
−14.603
22.722
−16.985
1.00
74.61
A


ATOM
702
N
ALA
A
114
−13.397
23.272
−15.152
1.00
71.33
A


ATOM
703
CA
ALA
A
114
−14.456
23.986
−14.447
1.00
66.25
A


ATOM
704
CB
ALA
A
114
−14.016
24.237
−13.002
1.00
65.33
A


ATOM
705
C
ALA
A
114
−14.901
25.299
−15.078
1.00
61.91
A


ATOM
706
O
ALA
A
114
−16.020
25.746
−14.859
1.00
60.64
A


ATOM
707
N
ASP
A
115
−14.037
25.924
−15.858
1.00
58.78
A


ATOM
708
CA
ASP
A
115
−14.404
27.197
−16.444
1.00
57.63
A


ATOM
709
CB
ASP
A
115
−13.170
27.864
−17.050
1.00
58.76
A


ATOM
710
CG
ASP
A
115
−12.240
28.440
−15.977
1.00
60.80
A


ATOM
711
OD1
ASP
A
115
−12.644
29.410
−15.283
1.00
58.59
A


ATOM
712
OD2
ASP
A
115
−11.114
27.911
−15.822
1.00
60.92
A


ATOM
713
C
ASP
A
115
−15.553
27.143
−17.441
1.00
56.69
A


ATOM
714
O
ASP
A
115
−16.446
27.994
−17.395
1.00
55.98
A


ATOM
715
N
SER
A
116
−15.547
26.154
−18.332
1.00
54.36
A


ATOM
716
CA
SER
A
116
−16.629
26.025
−19.305
1.00
51.56
A


ATOM
717
CB
SER
A
116
−16.464
24.749
−20.132
1.00
51.85
A


ATOM
718
OG
SER
A
116
−15.262
24.765
−20.875
1.00
52.43
A


ATOM
719
C
SER
A
116
−17.957
25.964
−18.549
1.00
50.12
A


ATOM
720
O
SER
A
116
−18.876
26.747
−18.798
1.00
48.52
A


ATOM
721
N
ILE
A
117
−18.035
25.028
−17.612
1.00
48.20
A


ATOM
722
CA
ILE
A
117
−19.234
24.839
−16.809
1.00
47.04
A


ATOM
723
CB
ILE
A
117
−19.056
23.654
−15.843
1.00
45.89
A


ATOM
724
CG2
ILE
A
117
−20.128
23.680
−14.771
1.00
41.04
A


ATOM
725
CG1
ILE
A
117
−19.086
22.351
−16.645
1.00
44.74
A


ATOM
726
CD1
ILE
A
117
−18.727
21.139
−15.847
1.00
47.83
A


ATOM
727
C
ILE
A
117
−19.577
26.093
−16.029
1.00
47.34
A


ATOM
728
O
ILE
A
117
−20.747
26.363
−15.755
1.00
47.25
A


ATOM
729
N
LEU
A
118
−18.549
26.857
−15.676
1.00
47.11
A


ATOM
730
CA
LEU
A
118
−18.743
28.095
−14.941
1.00
46.33
A


ATOM
731
CB
LEU
A
118
−17.391
28.640
−14.481
1.00
46.21
A


ATOM
732
CG
LEU
A
118
−17.207
29.082
−13.023
1.00
47.56
A


ATOM
733
CD1
LEU
A
118
−17.864
28.110
−12.045
1.00
45.29
A


ATOM
734
CD2
LEU
A
118
−15.717
29.169
−12.742
1.00
46.63
A


ATOM
735
C
LEU
A
118
−19.419
29.071
−15.894
1.00
45.37
A


ATOM
736
O
LEU
A
118
−20.361
29.770
−15.522
1.00
45.75
A


ATOM
737
N
ALA
A
119
−18.947
29.095
−17.135
1.00
43.53
A


ATOM
738
CA
ALA
A
119
−19.515
29.980
−18.145
1.00
44.02
A


ATOM
739
CB
ALA
A
119
−18.835
29.746
−19.483
1.00
43.57
A


ATOM
740
C
ALA
A
119
−21.022
29.760
−18.282
1.00
44.16
A


ATOM
741
O
ALA
A
119
−21.802
30.707
−18.185
1.00
43.43
A


ATOM
742
N
VAL
A
120
−21.420
28.506
−18.504
1.00
43.64
A


ATOM
743
CA
VAL
A
120
−22.826
28.157
−18.653
1.00
41.82
A


ATOM
744
CB
VAL
A
120
−23.023
26.629
−18.940
1.00
41.05
A


ATOM
745
CG1
VAL
A
120
−24.488
26.335
−19.229
1.00
38.92
A


ATOM
746
CG2
VAL
A
120
−22.176
26.185
−20.109
1.00
35.59
A


ATOM
747
C
VAL
A
120
−23.582
28.530
−17.378
1.00
42.89
A


ATOM
748
O
VAL
A
120
−24.632
29.168
−17.443
1.00
43.59
A


ATOM
749
N
LYS
A
121
−23.050
28.148
−16.218
1.00
43.62
A


ATOM
750
CA
LYS
A
121
−23.713
28.470
−14.950
1.00
43.47
A


ATOM
751
CB
LYS
A
121
−22.938
27.909
−13.757
1.00
42.82
A


ATOM
752
CG
LYS
A
121
−23.098
26.405
−13.565
1.00
42.66
A


ATOM
753
CD
LYS
A
121
−22.183
25.886
−12.463
1.00
44.00
A


ATOM
754
CE
LYS
A
121
−22.464
24.418
−12.136
1.00
45.31
A


ATOM
755
NZ
LYS
A
121
−23.826
24.200
−11.551
1.00
43.66
A


ATOM
756
C
LYS
A
121
−23.892
29.963
−14.773
1.00
43.91
A


ATOM
757
O
LYS
A
121
−24.932
30.404
−14.305
1.00
45.66
A


ATOM
758
N
LYS
A
122
−22.889
30.746
−15.156
1.00
45.29
A


ATOM
759
CA
LYS
A
122
−22.979
32.200
−15.028
1.00
45.49
A


ATOM
760
CB
LYS
A
122
−21.584
32.824
−15.117
1.00
46.13
A


ATOM
761
CG
LYS
A
122
−20.822
32.741
−13.784
1.00
49.15
A


ATOM
762
CD
LYS
A
122
−19.309
32.760
−13.945
1.00
52.08
A


ATOM
763
CE
LYS
A
122
−18.822
33.994
−14.692
1.00
54.97
A


ATOM
764
NZ
LYS
A
122
−17.332
33.997
−14.825
1.00
58.31
A


ATOM
765
C
LYS
A
122
−23.930
32.815
−16.051
1.00
44.74
A


ATOM
766
O
LYS
A
122
−24.576
33.819
−15.774
1.00
44.79
A


ATOM
767
N
TYR
A
123
−24.035
32.201
−17.226
1.00
43.85
A


ATOM
768
CA
TYR
A
123
−24.959
32.687
−18.249
1.00
41.73
A


ATOM
769
CB
TYR
A
123
−24.823
31.864
−19.534
1.00
43.00
A


ATOM
770
CG
TYR
A
123
−26.012
31.914
−20.483
1.00
43.26
A


ATOM
771
CD1
TYR
A
123
−26.334
33.079
−21.181
1.00
42.96
A


ATOM
772
CE1
TYR
A
123
−27.375
33.096
−22.120
1.00
43.17
A


ATOM
773
CD2
TYR
A
123
−26.768
30.761
−20.739
1.00
44.34
A


ATOM
774
CE2
TYR
A
123
−27.808
30.764
−21.676
1.00
43.97
A


ATOM
775
CZ
TYR
A
123
−28.100
31.934
−22.361
1.00
43.84
A


ATOM
776
OH
TYR
A
123
−29.106
31.942
−23.289
1.00
43.65
A


ATOM
777
C
TYR
A
123
−26.374
32.558
−17.718
1.00
40.54
A


ATOM
778
O
TYR
A
123
−27.180
33.464
−17.886
1.00
40.80
A


ATOM
779
N
PHE
A
124
−26.667
31.429
−17.076
1.00
40.17
A


ATOM
780
CA
PHE
A
124
−27.993
31.187
−16.520
1.00
42.42
A


ATOM
781
CB
PHE
A
124
−28.188
29.688
−16.247
1.00
41.69
A


ATOM
782
CG
PHE
A
124
−28.617
28.909
−17.462
1.00
42.10
A


ATOM
783
CD1
PHE
A
124
−29.922
29.007
−17.939
1.00
42.51
A


ATOM
784
CD2
PHE
A
124
−27.708
28.120
−18.165
1.00
40.74
A


ATOM
785
CE1
PHE
A
124
−30.317
28.332
−19.106
1.00
41.41
A


ATOM
786
CE2
PHE
A
124
−28.095
27.445
−19.329
1.00
41.37
A


ATOM
787
CZ
PHE
A
124
−29.400
27.554
−19.797
1.00
39.97
A


ATOM
788
C
PHE
A
124
−28.242
32.023
−15.264
1.00
43.39
A


ATOM
789
O
PHE
A
124
−29.378
32.322
−14.922
1.00
42.59
A


ATOM
790
N
GLN
A
125
−27.179
32.421
−14.587
1.00
45.23
A


ATOM
791
CA
GLN
A
125
−27.343
33.251
−13.415
1.00
48.87
A


ATOM
792
CB
GLN
A
125
−25.980
33.479
−12.749
1.00
52.70
A


ATOM
793
CG
GLN
A
125
−26.006
34.131
−11.371
1.00
53.89
A


ATOM
794
CD
GLN
A
125
−26.959
33.442
−10.402
1.00
58.25
A


ATOM
795
OE1
GLN
A
125
−27.117
32.216
−10.422
1.00
58.23
A


ATOM
796
NE2
GLN
A
125
−27.590
34.233
−9.534
1.00
58.44
A


ATOM
797
C
GLN
A
125
−27.942
34.565
−13.920
1.00
49.60
A


ATOM
798
O
GLN
A
125
−28.921
35.070
−13.366
1.00
50.24
A


ATOM
799
N
ARG
A
126
−27.361
35.119
−14.979
1.00
50.02
A


ATOM
800
CA
ARG
A
126
−27.883
36.362
−15.537
1.00
51.12
A


ATOM
801
CB
ARG
A
126
−27.070
36.766
−16.753
1.00
50.74
A


ATOM
802
CG
ARG
A
126
−25.703
37.248
−16.397
1.00
51.91
A


ATOM
803
CD
ARG
A
126
−24.873
37.578
−17.655
1.00
53.15
A


ATOM
804
NE
ARG
A
126
−23.567
36.942
−17.591
1.00
56.26
A


ATOM
805
CZ
ARG
A
126
−23.143
36.070
−18.500
1.00
56.88
A


ATOM
806
NH1
ARG
A
126
−21.926
35.525
−18.418
1.00
61.63
A


ATOM
807
NH2
ARG
A
126
−23.950
35.718
−19.488
1.00
57.30
A


ATOM
808
C
ARG
A
126
−29.365
36.270
−15.891
1.00
51.99
A


ATOM
809
O
ARG
A
126
−30.141
37.168
−15.542
1.00
53.15
A


ATOM
810
N
ILE
A
127
−29.758
35.181
−16.554
1.00
51.87
A


ATOM
811
CA
ILE
A
127
−31.152
34.972
−16.914
1.00
50.67
A


ATOM
812
CB
ILE
A
127
−31.403
33.556
−17.498
1.00
49.15
A


ATOM
813
CG2
ILE
A
127
−32.888
33.373
−17.759
1.00
45.24
A


ATOM
814
CG1
ILE
A
127
−30.611
33.343
−18.790
1.00
49.62
A


ATOM
815
CD1
ILE
A
127
−31.121
34.119
−19.945
1.00
50.32
A


ATOM
816
C
ILE
A
127
−31.992
35.089
−15.644
1.00
51.30
A


ATOM
817
O
ILE
A
127
−32.917
35.891
−15.579
1.00
50.89
A


ATOM
818
N
THR
A
128
−31.669
34.274
−14.644
1.00
52.07
A


ATOM
819
CA
THR
A
128
−32.412
34.277
−13.391
1.00
55.06
A


ATOM
820
CB
THR
A
128
−31.762
33.325
−12.358
1.00
54.18
A


ATOM
821
OG1
THR
A
128
−32.194
31.987
−12.618
1.00
55.56
A


ATOM
822
CG2
THR
A
128
−32.163
33.691
−10.943
1.00
56.16
A


ATOM
823
C
THR
A
128
−32.517
35.679
−12.811
1.00
56.81
A


ATOM
824
O
THR
A
128
−33.602
36.128
−12.445
1.00
56.02
A


ATOM
825
N
LEU
A
129
−31.383
36.370
−12.754
1.00
59.30
A


ATOM
826
CA
LEU
A
129
−31.321
37.718
−12.212
1.00
60.85
A


ATOM
827
CB
LEU
A
129
−29.863
38.176
−12.166
1.00
63.37
A


ATOM
828
CG
LEU
A
129
−29.428
39.036
−10.972
1.00
67.01
A


ATOM
829
CD1
LEU
A
129
−27.937
38.819
−10.757
1.00
67.40
A


ATOM
830
CD2
LEU
A
129
−29.758
40.522
−11.184
1.00
65.11
A


ATOM
831
C
LEU
A
129
−32.158
38.693
−13.037
1.00
61.24
A


ATOM
832
O
LEU
A
129
−32.768
39.610
−12.491
1.00
62.01
A


ATOM
833
N
TYR
A
130
−32.181
38.497
−14.351
1.00
60.00
A


ATOM
834
CA
TYR
A
130
−32.953
39.357
−15.243
1.00
58.99
A


ATOM
835
CB
TYR
A
130
−32.663
38.993
−16.701
1.00
58.50
A


ATOM
836
CG
TYR
A
130
−33.584
39.637
−17.715
1.00
57.74
A


ATOM
837
CD1
TYR
A
130
−33.439
40.974
−18.074
1.00
58.05
A


ATOM
838
CE1
TYR
A
130
−34.279
41.560
−19.020
1.00
58.22
A


ATOM
839
CD2
TYR
A
130
−34.594
38.901
−18.327
1.00
58.06
A


ATOM
840
CE2
TYR
A
130
−35.437
39.478
−19.272
1.00
57.76
A


ATOM
841
CZ
TYR
A
130
−35.274
40.805
−19.613
1.00
58.23
A


ATOM
842
OH
TYR
A
130
−36.113
41.378
−20.540
1.00
58.83
A


ATOM
843
C
TYR
A
130
−34.434
39.166
−14.957
1.00
59.31
A


ATOM
844
O
TYR
A
130
−35.183
40.134
−14.814
1.00
59.29
A


ATOM
845
N
LEU
A
131
−34.844
37.904
−14.875
1.00
58.83
A


ATOM
846
CA
LEU
A
131
−36.233
37.558
−14.617
1.00
58.58
A


ATOM
847
CB
LEU
A
131
−36.390
36.037
−14.555
1.00
55.68
A


ATOM
848
CG
LEU
A
131
−36.422
35.361
−15.922
1.00
53.74
A


ATOM
849
CD1
LEU
A
131
−36.318
33.863
−15.755
1.00
54.07
A


ATOM
850
CD2
LEU
A
131
−37.699
35.742
−16.649
1.00
52.53
A


ATOM
851
C
LEU
A
131
−36.740
38.193
−13.330
1.00
59.15
A


ATOM
852
O
LEU
A
131
−37.811
38.807
−13.304
1.00
57.39
A


ATOM
853
N
THR
A
132
−35.966
38.041
−12.262
1.00
60.31
A


ATOM
854
CA
THR
A
132
−36.342
38.608
−10.982
1.00
61.04
A


ATOM
855
CB
THR
A
132
−35.474
38.034
−9.826
1.00
61.40
A


ATOM
856
OG1
THR
A
132
−35.587
38.887
−8.680
1.00
64.65
A


ATOM
857
CG2
THR
A
132
−34.026
37.929
−10.227
1.00
59.77
A


ATOM
858
C
THR
A
132
−36.212
40.125
−11.044
1.00
61.41
A


ATOM
859
O
THR
A
132
−37.112
40.853
−10.624
1.00
61.07
A


ATOM
860
N
GLY
A
133
−35.102
40.598
−11.597
1.00
62.03
A


ATOM
861
CA
GLY
A
133
−34.891
42.029
−11.705
1.00
62.46
A


ATOM
862
C
GLY
A
133
−35.929
42.684
−12.592
1.00
62.83
A


ATOM
863
O
GLY
A
133
−36.032
43.905
−12.634
1.00
63.96
A


ATOM
864
N
LYS
A
134
−36.708
41.869
−13.295
1.00
62.98
A


ATOM
865
CA
LYS
A
134
−37.729
42.375
−14.205
1.00
62.76
A


ATOM
866
CB
LYS
A
134
−37.523
41.775
−15.595
1.00
63.31
A


ATOM
867
CG
LYS
A
134
−37.830
42.712
−16.742
1.00
63.91
A


ATOM
868
CD
LYS
A
134
−36.734
43.744
−16.932
1.00
64.03
A


ATOM
869
CE
LYS
A
134
−37.008
44.589
−18.172
1.00
65.71
A


ATOM
870
NZ
LYS
A
134
−35.986
45.656
−18.394
1.00
66.60
A


ATOM
871
C
LYS
A
134
−39.122
42.026
−13.694
1.00
62.52
A


ATOM
872
O
LYS
A
134
−40.118
42.159
−14.408
1.00
61.64
A


ATOM
873
N
ALA
A
135
−39.175
41.558
−12.454
1.00
62.91
A


ATOM
874
CA
ALA
A
135
−40.433
41.207
−11.809
1.00
62.68
A


ATOM
875
CB
ALA
A
135
−41.307
42.469
−11.671
1.00
63.48
A


ATOM
876
C
ALA
A
135
−41.221
40.096
−12.501
1.00
61.65
A


ATOM
877
O
ALA
A
135
−42.444
40.041
−12.385
1.00
61.18
A


ATOM
878
N
TYR
A
136
−40.525
39.215
−13.213
1.00
60.39
A


ATOM
879
CA
TYR
A
136
−41.166
38.091
−13.908
1.00
60.51
A


ATOM
880
CB
TYR
A
136
−41.622
37.024
−12.899
1.00
60.08
A


ATOM
881
CG
TYR
A
136
−40.547
36.596
−11.924
1.00
62.10
A


ATOM
882
CD1
TYR
A
136
−40.241
37.378
−10.807
1.00
62.66
A


ATOM
883
CE1
TYR
A
136
−39.227
37.007
−9.919
1.00
63.23
A


ATOM
884
CD2
TYR
A
136
−39.811
35.424
−12.131
1.00
62.49
A


ATOM
885
CE2
TYR
A
136
−38.792
35.044
−11.249
1.00
64.05
A


ATOM
886
CZ
TYR
A
136
−38.507
35.844
−10.146
1.00
63.71
A


ATOM
887
OH
TYR
A
136
−37.495
35.495
−9.280
1.00
63.34
A


ATOM
888
C
TYR
A
136
−42.359
38.479
−14.785
1.00
60.49
A


ATOM
889
O
TYR
A
136
−43.334
37.731
−14.882
1.00
60.06
A


ATOM
890
N
SER
A
137
−42.289
39.641
−15.425
1.00
61.06
A


ATOM
891
CA
SER
A
137
−43.383
40.088
−16.284
1.00
61.14
A


ATOM
892
CB
SER
A
137
−43.205
41.557
−16.650
1.00
60.90
A


ATOM
893
OG
SER
A
137
−42.133
41.713
−17.559
1.00
63.48
A


ATOM
894
C
SER
A
137
−43.432
39.257
−17.563
1.00
61.21
A


ATOM
895
O
SER
A
137
−42.414
38.718
−18.004
1.00
59.84
A


ATOM
896
N
PRO
A
138
−44.624
39.150
−18.178
1.00
61.71
A


ATOM
897
CD
PRO
A
138
−45.906
39.727
−17.725
1.00
60.80
A


ATOM
898
CA
PRO
A
138
−44.819
38.384
−19.414
1.00
60.13
A


ATOM
899
CB
PRO
A
138
−46.238
38.773
−19.831
1.00
59.80
A


ATOM
900
CG
PRO
A
138
−46.929
38.932
−18.523
1.00
58.23
A


ATOM
901
C
PRO
A
138
−43.783
38.661
−20.506
1.00
59.03
A


ATOM
902
O
PRO
A
138
−43.361
37.737
−21.199
1.00
59.70
A


ATOM
903
N
CYS
A
139
−43.382
39.922
−20.659
1.00
57.95
A


ATOM
904
CA
CYS
A
139
−42.392
40.296
−21.666
1.00
58.35
A


ATOM
905
C
CYS
A
139
−41.024
39.758
−21.311
1.00
57.19
A


ATOM
906
O
CYS
A
139
−40.267
39.329
−22.185
1.00
57.07
A


ATOM
907
CB
CYS
A
139
−42.280
41.813
−21.798
1.00
60.88
A


ATOM
908
SG
CYS
A
139
−43.778
42.639
−22.404
1.00
68.54
A


ATOM
909
N
ALA
A
140
−40.701
39.807
−20.022
1.00
55.95
A


ATOM
910
CA
ALA
A
140
−39.420
39.318
−19.537
1.00
53.50
A


ATOM
911
CB
ALA
A
140
−39.307
39.547
−18.039
1.00
51.95
A


ATOM
912
C
ALA
A
140
−39.311
37.831
−19.857
1.00
52.02
A


ATOM
913
O
ALA
A
140
−38.249
37.350
−20.237
1.00
52.56
A


ATOM
914
N
TRP
A
141
−40.418
37.111
−19.714
1.00
50.19
A


ATOM
915
CA
TRP
A
141
−40.429
35.685
−19.990
1.00
49.75
A


ATOM
916
CB
TRP
A
141
−41.662
35.034
−19.365
1.00
48.78
A


ATOM
917
CG
TRP
A
141
−41.411
34.516
−17.981
1.00
49.84
A


ATOM
918
CD2
TRP
A
141
−40.564
33.415
−17.616
1.00
48.87
A


ATOM
919
CE2
TRP
A
141
−40.649
33.274
−16.212
1.00
48.13
A


ATOM
920
CE3
TRP
A
141
−39.744
32.534
−18.340
1.00
46.28
A


ATOM
921
CD1
TRP
A
141
−41.953
34.984
−16.814
1.00
47.90
A


ATOM
922
NE1
TRP
A
141
−41.501
34.243
−15.754
1.00
47.02
A


ATOM
923
CZ2
TRP
A
141
−39.944
32.281
−15.514
1.00
46.41
A


ATOM
924
CZ3
TRP
A
141
−39.042
31.544
−17.644
1.00
44.50
A


ATOM
925
CH2
TRP
A
141
−39.150
31.428
−16.246
1.00
46.31
A


ATOM
926
C
TRP
A
141
−40.373
35.394
−21.487
1.00
49.99
A


ATOM
927
O
TRP
A
141
−39.865
34.356
−21.908
1.00
49.91
A


ATOM
928
N
GLU
A
142
−40.902
36.314
−22.285
1.00
49.68
A


ATOM
929
CA
GLU
A
142
−40.885
36.176
−23.734
1.00
49.54
A


ATOM
930
CB
GLU
A
142
−41.879
37.161
−24.359
1.00
51.93
A


ATOM
931
CG
GLU
A
142
−42.054
37.014
−25.862
1.00
55.37
A


ATOM
932
CD
GLU
A
142
−42.079
35.566
−26.315
1.00
58.44
A


ATOM
933
OE1
GLU
A
142
−42.804
34.747
−25.698
1.00
59.65
A


ATOM
934
OE2
GLU
A
142
−41.371
35.252
−27.296
1.00
58.89
A


ATOM
935
C
GLU
A
142
−39.457
36.445
−24.235
1.00
48.12
A


ATOM
936
O
GLU
A
142
−38.990
35.830
−25.195
1.00
46.88
A


ATOM
937
N
VAL
A
143
−38.766
37.363
−23.569
1.00
46.47
A


ATOM
938
CA
VAL
A
143
−37.387
37.685
−23.918
1.00
46.26
A


ATOM
939
CB
VAL
A
143
−36.925
38.990
−23.219
1.00
46.29
A


ATOM
940
CG1
VAL
A
143
−35.505
39.327
−23.605
1.00
43.99
A


ATOM
941
CG2
VAL
A
143
−37.855
40.124
−23.594
1.00
48.07
A


ATOM
942
C
VAL
A
143
−36.471
36.532
−23.490
1.00
45.08
A


ATOM
943
O
VAL
A
143
−35.421
36.312
−24.087
1.00
46.32
A


ATOM
944
N
VAL
A
144
−36.861
35.800
−22.451
1.00
42.03
A


ATOM
945
CA
VAL
A
144
−36.051
34.680
−22.010
1.00
40.59
A


ATOM
946
CB
VAL
A
144
−36.331
34.343
−20.517
1.00
39.36
A


ATOM
947
CG1
VAL
A
144
−35.716
32.999
−20.144
1.00
38.27
A


ATOM
948
CG2
VAL
A
144
−35.722
35.421
−19.626
1.00
37.69
A


ATOM
949
C
VAL
A
144
−36.328
33.472
−22.916
1.00
41.36
A


ATOM
950
O
VAL
A
144
−35.419
32.715
−23.262
1.00
39.87
A


ATOM
951
N
ARG
A
145
−37.584
33.304
−23.311
1.00
42.03
A


ATOM
952
CA
ARG
A
145
−37.954
32.200
−24.178
1.00
43.63
A


ATOM
953
CB
ARG
A
145
−39.458
32.238
−24.485
1.00
43.53
A


ATOM
954
CG
ARG
A
145
−40.010
30.975
−25.172
1.00
44.12
A


ATOM
955
CD
ARG
A
145
−41.466
31.179
−25.671
1.00
47.31
A


ATOM
956
NE
ARG
A
145
−41.546
32.147
−26.772
1.00
49.05
A


ATOM
957
CZ
ARG
A
145
−41.087
31.924
−28.005
1.00
47.86
A


ATOM
958
NH1
ARG
A
145
−40.526
30.765
−28.323
1.00
47.20
A


ATOM
959
NH2
ARG
A
145
−41.141
32.882
−28.910
1.00
48.43
A


ATOM
960
C
ARG
A
145
−37.144
32.333
−25.474
1.00
44.89
A


ATOM
961
O
ARG
A
145
−36.551
31.367
−25.952
1.00
44.68
A


ATOM
962
N
ALA
A
146
−37.098
33.542
−26.024
1.00
45.26
A


ATOM
963
CA
ALA
A
146
−36.366
33.786
−27.267
1.00
44.68
A


ATOM
964
CB
ALA
A
146
−36.639
35.199
−27.766
1.00
41.89
A


ATOM
965
C
ALA
A
146
−34.865
33.564
−27.115
1.00
44.62
A


ATOM
966
O
ALA
A
146
−34.214
33.063
−28.028
1.00
45.73
A


ATOM
967
N
GLU
A
147
−34.319
33.940
−25.963
1.00
43.92
A


ATOM
968
CA
GLU
A
147
−32.894
33.772
−25.697
1.00
42.58
A


ATOM
969
CB
GLU
A
147
−32.512
34.500
−24.403
1.00
40.40
A


ATOM
970
CG
GLU
A
147
−31.124
34.186
−23.878
1.00
40.78
A


ATOM
971
CD
GLU
A
147
−30.021
34.667
−24.802
1.00
44.78
A


ATOM
972
OE1
GLU
A
147
−30.039
35.853
−25.201
1.00
46.12
A


ATOM
973
OE2
GLU
A
147
−29.125
33.862
−25.128
1.00
46.08
A


ATOM
974
C
GLU
A
147
−32.526
32.288
−25.600
1.00
42.73
A


ATOM
975
O
GLU
A
147
−31.490
31.871
−26.130
1.00
41.47
A


ATOM
976
N
ILE
A
148
−33.367
31.497
−24.929
1.00
41.27
A


ATOM
977
CA
ILE
A
148
−33.103
30.066
−24.794
1.00
42.00
A


ATOM
978
CB
ILE
A
148
−34.031
29.409
−23.715
1.00
42.87
A


ATOM
979
CG2
ILE
A
148
−34.159
27.894
−23.939
1.00
41.81
A


ATOM
980
CG1
ILE
A
148
−33.423
29.613
−22.331
1.00
42.77
A


ATOM
981
CD1
ILE
A
148
−33.158
31.046
−21.993
1.00
47.88
A


ATOM
982
C
ILE
A
148
−33.284
29.382
−26.148
1.00
42.52
A


ATOM
983
O
ILE
A
148
−32.521
28.489
−26.510
1.00
40.95
A


ATOM
984
N
MET
A
149
−34.297
29.820
−26.890
1.00
43.15
A


ATOM
985
CA
MET
A
149
−34.594
29.288
−28.210
1.00
43.66
A


ATOM
986
CB
MET
A
149
−35.738
30.082
−28.840
1.00
45.34
A


ATOM
987
CG
MET
A
149
−36.136
29.660
−30.241
1.00
47.78
A


ATOM
988
SD
MET
A
149
−37.331
28.311
−30.248
1.00
53.42
A


ATOM
989
CE
MET
A
149
−36.351
27.036
−30.894
1.00
52.10
A


ATOM
990
C
MET
A
149
−33.342
29.456
−29.052
1.00
45.41
A


ATOM
991
O
MET
A
149
−32.924
28.543
−29.776
1.00
46.37
A


ATOM
992
N
ARG
A
150
−32.733
30.629
−28.945
1.00
45.61
A


ATOM
993
CA
ARG
A
150
−31.540
30.895
−29.709
1.00
47.17
A


ATOM
994
CB
ARG
A
150
−31.254
32.389
−29.720
1.00
48.49
A


ATOM
995
CG
ARG
A
150
−30.191
32.777
−30.712
1.00
53.95
A


ATOM
996
CD
ARG
A
150
−29.717
34.199
−30.516
1.00
59.85
A


ATOM
997
NE
ARG
A
150
−28.745
34.560
−31.546
1.00
66.19
A


ATOM
998
CZ
ARG
A
150
−27.975
35.644
−31.513
1.00
69.41
A


ATOM
999
NH1
ARG
A
150
−28.053
36.493
−30.488
1.00
70.95
A


ATOM
1000
NH2
ARG
A
150
−27.129
35.882
−32.510
1.00
69.33
A


ATOM
1001
C
ARG
A
150
−30.334
30.126
−29.161
1.00
48.23
A


ATOM
1002
O
ARG
A
150
−29.612
29.473
−29.923
1.00
48.56
A


ATOM
1003
N
SER
A
151
−30.122
30.177
−27.847
1.00
47.72
A


ATOM
1004
CA
SER
A
151
−28.973
29.492
−27.258
1.00
48.57
A


ATOM
1005
CB
SER
A
151
−28.714
29.993
−25.837
1.00
48.92
A


ATOM
1006
OG
SER
A
151
−29.880
29.900
−25.045
1.00
54.27
A


ATOM
1007
C
SER
A
151
−29.090
27.979
−27.253
1.00
48.50
A


ATOM
1008
O
SER
A
151
−28.113
27.278
−27.517
1.00
46.55
A


ATOM
1009
N
PHE
A
152
−30.277
27.468
−26.953
1.00
49.05
A


ATOM
1010
CA
PHE
A
152
−30.463
26.024
−26.938
1.00
50.72
A


ATOM
1011
CB
PHE
A
152
−31.808
25.667
−26.301
1.00
48.90
A


ATOM
1012
CG
PHE
A
152
−31.872
24.270
−25.772
1.00
47.92
A


ATOM
1013
CD1
PHE
A
152
−31.364
23.970
−24.514
1.00
48.09
A


ATOM
1014
CD2
PHE
A
152
−32.430
23.246
−26.535
1.00
48.59
A


ATOM
1015
CE1
PHE
A
152
−31.406
22.667
−24.010
1.00
47.02
A


ATOM
1016
CE2
PHE
A
152
−32.480
21.938
−26.047
1.00
49.53
A


ATOM
1017
CZ
PHE
A
152
−31.964
21.649
−24.775
1.00
48.38
A


ATOM
1018
C
PHE
A
152
−30.376
25.492
−28.387
1.00
52.04
A


ATOM
1019
O
PHE
A
152
−30.086
24.319
−28.612
1.00
51.28
A


ATOM
1020
N
ALA
A
153
−30.628
26.359
−29.366
1.00
53.53
A


ATOM
1021
CA
ALA
A
153
−30.521
25.960
−30.771
1.00
55.59
A


ATOM
1022
CB
ALA
A
153
−31.077
27.049
−31.698
1.00
53.76
A


ATOM
1023
C
ALA
A
153
−29.040
25.729
−31.060
1.00
55.66
A


ATOM
1024
O
ALA
A
153
−28.665
24.692
−31.599
1.00
55.80
A


ATOM
1025
N
LEU
A
154
−28.205
26.699
−30.696
1.00
57.44
A


ATOM
1026
CA
LEU
A
154
−26.756
26.584
−30.891
1.00
60.09
A


ATOM
1027
CB
LEU
A
154
−26.045
27.854
−30.407
1.00
57.36
A


ATOM
1028
CG
LEU
A
154
−26.306
29.106
−31.239
1.00
56.81
A


ATOM
1029
CD1
LEU
A
154
−25.681
30.305
−30.566
1.00
54.66
A


ATOM
1030
CD2
LEU
A
154
−25.746
28.915
−32.642
1.00
54.86
A


ATOM
1031
C
LEU
A
154
−26.212
25.376
−30.122
1.00
61.78
A


ATOM
1032
O
LEU
A
154
−25.251
24.730
−30.550
1.00
62.63
A


ATOM
1033
N
SER
A
155
−26.840
25.084
−28.986
1.00
62.76
A


ATOM
1034
CA
SER
A
155
−26.446
23.966
−28.146
1.00
63.82
A


ATOM
1035
CB
SER
A
155
−27.144
24.065
−26.797
1.00
63.60
A


ATOM
1036
OG
SER
A
155
−26.966
22.869
−26.066
1.00
65.69
A


ATOM
1037
C
SER
A
155
−26.779
22.627
−28.798
1.00
65.21
A


ATOM
1038
O
SER
A
155
−25.974
21.697
−28.767
1.00
65.58
A


ATOM
1039
N
THR
A
156
−27.976
22.531
−29.371
1.00
66.30
A


ATOM
1040
CA
THR
A
156
−28.422
21.319
−30.050
1.00
67.72
A


ATOM
1041
CB
THR
A
156
−29.893
21.452
−30.519
1.00
67.52
A


ATOM
1042
OG1
THR
A
156
−30.765
21.393
−29.386
1.00
69.40
A


ATOM
1043
CG2
THR
A
156
−30.262
20.339
−31.479
1.00
68.25
A


ATOM
1044
C
THR
A
156
−27.535
21.032
−31.267
1.00
69.26
A


ATOM
1045
O
THR
A
156
−27.422
19.885
−31.693
1.00
69.59
A


ATOM
1046
N
ASN
A
157
−26.915
22.076
−31.822
1.00
70.20
A


ATOM
1047
CA
ASN
A
157
−26.031
21.928
−32.979
1.00
70.93
A


ATOM
1048
CB
ASN
A
157
−25.561
23.295
−33.490
1.00
71.29
A


ATOM
1049
CG
ASN
A
157
−26.661
24.082
−34.186
1.00
71.77
A


ATOM
1050
OD1
ASN
A
157
−27.846
23.776
−34.054
1.00
71.35
A


ATOM
1051
ND2
ASN
A
157
−26.268
25.116
−34.924
1.00
72.68
A


ATOM
1052
C
ASN
A
157
−24.818
21.117
−32.560
1.00
72.23
A


ATOM
1053
O
ASN
A
157
−24.347
20.254
−33.302
1.00
73.06
A


ATOM
1054
N
LEU
A
158
−24.309
21.409
−31.367
1.00
73.17
A


ATOM
1055
CA
LEU
A
158
−23.152
20.701
−30.836
1.00
73.49
A


ATOM
1056
CB
LEU
A
158
−22.680
21.363
−29.539
1.00
73.26
A


ATOM
1057
CG
LEU
A
158
−21.264
21.080
−29.018
1.00
74.00
A


ATOM
1058
CD1
LEU
A
158
−21.085
21.764
−27.673
1.00
73.67
A


ATOM
1059
CD2
LEU
A
158
−21.025
19.591
−28.866
1.00
74.47
A


ATOM
1060
C
LEU
A
158
−23.601
19.270
−30.561
1.00
73.89
A


ATOM
1061
O
LEU
A
158
−22.823
18.328
−30.663
1.00
72.76
A


ATOM
1062
N
GLN
A
159
−24.875
19.120
−30.220
1.00
75.65
A


ATOM
1063
CA
GLN
A
159
−25.439
17.811
−29.926
1.00
78.32
A


ATOM
1064
CB
GLN
A
159
−26.861
17.972
−29.374
1.00
79.21
A


ATOM
1065
CG
GLN
A
159
−27.392
16.753
−28.635
1.00
80.98
A


ATOM
1066
CD
GLN
A
159
−28.629
17.063
−27.811
1.00
81.67
A


ATOM
1067
OE1
GLN
A
159
−29.666
17.463
−28.347
1.00
82.31
A


ATOM
1068
NE2
GLN
A
159
−28.522
16.883
−26.499
1.00
80.98
A


ATOM
1069
C
GLN
A
159
−25.446
16.967
−31.198
1.00
79.66
A


ATOM
1070
O
GLN
A
159
−25.157
15.769
−31.165
1.00
79.48
A


ATOM
1071
N
GLY
A
160
−25.776
17.605
−32.320
1.00
81.34
A


ATOM
1072
CA
GLY
A
160
−25.793
16.909
−33.592
1.00
81.32
A


ATOM
1073
C
GLY
A
160
−24.383
16.471
−33.944
1.00
82.28
A


ATOM
1074
O
GLY
A
160
−24.160
15.338
−34.363
1.00
82.91
A


ATOM
1075
N
ALA
A
161
−23.420
17.369
−33.756
1.00
82.27
A


ATOM
1076
CA
ALA
A
161
−22.023
17.071
−34.057
1.00
82.68
A


ATOM
1077
CB
ALA
A
161
−21.197
18.371
−34.048
1.00
82.24
A


ATOM
1078
C
ALA
A
161
−21.435
16.061
−33.067
1.00
82.41
A


ATOM
1079
O
ALA
A
161
−20.248
15.738
−33.117
1.00
82.19
A


ATOM
1080
N
LEU
A
162
−22.274
15.560
−32.171
1.00
82.59
A


ATOM
1081
CA
LEU
A
162
−21.833
14.600
−31.169
1.00
82.81
A


ATOM
1082
CB
LEU
A
162
−22.266
15.075
−29.776
1.00
81.71
A


ATOM
1083
CG
LEU
A
162
−22.133
14.141
−28.573
1.00
80.63
A


ATOM
1084
CD1
LEU
A
162
−21.690
14.939
−27.359
1.00
80.31
A


ATOM
1085
CD2
LEU
A
162
−23.463
13.447
−28.309
1.00
79.59
A


ATOM
1086
C
LEU
A
162
−22.379
13.206
−31.450
1.00
83.84
A


ATOM
1087
O
LEU
A
162
−21.694
12.207
−31.222
1.00
83.86
A


ATOM
1088
N
GLY
A
163
−23.606
13.142
−31.958
1.00
84.78
A


ATOM
1089
CA
GLY
A
163
−24.212
11.855
−32.255
1.00
85.12
A


ATOM
1090
C
GLY
A
163
−23.963
11.378
−33.671
1.00
85.32
A


ATOM
1091
O
GLY
A
163
−24.939
10.958
−34.330
1.00
85.87
A


ATOM
1092
OXT
GLY
A
163
−22.795
11.408
−34.121
1.00
84.75
A


ATOM
1093
CB
ASN
B
11
−36.003
31.054
−49.710
1.00
85.15
B


ATOM
1094
CG
ASN
B
11
−35.553
29.922
−50.640
1.00
85.60
B


ATOM
1095
OD1
ASN
B
11
−34.661
29.139
−50.297
1.00
84.41
B


ATOM
1096
ND2
ASN
B
11
−36.172
29.834
−51.818
1.00
84.86
B


ATOM
1097
C
ASN
B
11
−38.419
31.748
−49.975
1.00
83.40
B


ATOM
1098
O
ASN
B
11
−38.848
32.106
−48.869
1.00
83.24
B


ATOM
1099
N
ASN
B
11
−36.612
33.443
−50.017
1.00
85.25
B


ATOM
1100
CA
ASN
B
11
−36.970
32.041
−50.393
1.00
84.75
B


ATOM
1101
N
ARG
B
12
−39.176
31.116
−50.871
1.00
80.64
B


ATOM
1102
CA
ARG
B
12
−40.566
30.781
−50.583
1.00
75.89
B


ATOM
1103
CB
ARG
B
12
−41.494
31.295
−51.681
1.00
76.32
B


ATOM
1104
CG
ARG
B
12
−42.957
31.189
−51.303
1.00
77.28
B


ATOM
1105
CD
ARG
B
12
−43.165
31.751
−49.908
1.00
77.55
B


ATOM
1106
NE
ARG
B
12
−44.512
32.270
−49.718
1.00
78.19
B


ATOM
1107
CZ
ARG
B
12
−44.864
33.064
−48.715
1.00
77.18
B


ATOM
1108
NH1
ARG
B
12
−43.962
33.426
−47.813
1.00
76.35
B


ATOM
1109
NH2
ARG
B
12
−46.113
33.503
−48.622
1.00
76.77
B


ATOM
1110
C
ARG
B
12
−40.747
29.286
−50.453
1.00
72.00
B


ATOM
1111
O
ARG
B
12
−41.679
28.718
−51.024
1.00
69.87
B


ATOM
1112
N
ARG
B
13
−39.860
28.652
−49.694
1.00
68.53
B


ATOM
1113
CA
ARG
B
13
−39.940
27.215
−49.514
1.00
66.86
B


ATOM
1114
CB
ARG
B
13
−38.635
26.669
−48.944
1.00
69.00
B


ATOM
1115
CG
ARG
B
13
−38.279
27.157
−47.572
1.00
72.00
B


ATOM
1116
CD
ARG
B
13
−37.016
26.456
−47.145
1.00
75.81
B


ATOM
1117
NE
ARG
B
13
−37.112
25.019
−47.396
1.00
78.98
B


ATOM
1118
CZ
ARG
B
13
−36.088
24.176
−47.307
1.00
80.56
B


ATOM
1119
NH1
ARG
B
13
−34.886
24.632
−46.971
1.00
82.00
B


ATOM
1120
NH2
ARG
B
13
−36.263
22.882
−47.557
1.00
78.63
B


ATOM
1121
C
ARG
B
13
−41.110
26.828
−48.628
1.00
63.21
B


ATOM
1122
O
ARG
B
13
−41.297
25.660
−48.296
1.00
63.10
B


ATOM
1123
N
ALA
B
14
−41.906
27.819
−48.256
1.00
58.81
B


ATOM
1124
CA
ALA
B
14
−43.068
27.565
−47.439
1.00
56.19
B


ATOM
1125
CB
ALA
B
14
−43.667
28.874
−46.988
1.00
57.98
B


ATOM
1126
C
ALA
B
14
−44.066
26.779
−48.288
1.00
54.53
B


ATOM
1127
O
ALA
B
14
−44.438
25.651
−47.958
1.00
53.40
B


ATOM
1128
N
LEU
B
15
−44.490
27.379
−49.393
1.00
53.25
B


ATOM
1129
CA
LEU
B
15
−45.437
26.730
−50.287
1.00
51.60
B


ATOM
1130
CB
LEU
B
15
−45.868
27.717
−51.376
1.00
53.42
B


ATOM
1131
CG
LEU
B
15
−46.780
28.860
−50.918
1.00
54.05
B


ATOM
1132
CD1
LEU
B
15
−46.739
30.011
−51.905
1.00
53.59
B


ATOM
1133
CD2
LEU
B
15
−48.192
28.335
−50.780
1.00
55.07
B


ATOM
1134
C
LEU
B
15
−44.836
25.465
−50.911
1.00
49.98
B


ATOM
1135
O
LEU
B
15
−45.538
24.473
−51.136
1.00
49.36
B


ATOM
1136
N
ILE
B
16
−43.535
25.491
−51.178
1.00
46.77
B


ATOM
1137
CA
ILE
B
16
−42.883
24.334
−51.765
1.00
45.58
B


ATOM
1138
CB
ILE
B
16
−41.435
24.679
−52.164
1.00
45.17
B


ATOM
1139
CG2
ILE
B
16
−40.607
23.420
−52.375
1.00
42.57
B


ATOM
1140
CG1
ILE
B
16
−41.466
25.512
−53.448
1.00
44.62
B


ATOM
1141
CD1
ILE
B
16
−40.094
25.930
−53.945
1.00
47.42
B


ATOM
1142
C
ILE
B
16
−42.926
23.097
−50.863
1.00
46.11
B


ATOM
1143
O
ILE
B
16
−43.308
22.013
−51.309
1.00
45.20
B


ATOM
1144
N
LEU
B
17
−42.548
23.246
−49.596
1.00
46.19
B


ATOM
1145
CA
LEU
B
17
−42.584
22.105
−48.676
1.00
45.40
B


ATOM
1146
CB
LEU
B
17
−42.067
22.519
−47.303
1.00
43.77
B


ATOM
1147
CG
LEU
B
17
−40.618
22.983
−47.397
1.00
43.17
B


ATOM
1148
CD1
LEU
B
17
−40.256
23.847
−46.210
1.00
42.11
B


ATOM
1149
CD2
LEU
B
17
−39.723
21.774
−47.522
1.00
42.21
B


ATOM
1150
C
LEU
B
17
−44.007
21.566
−48.567
1.00
45.21
B


ATOM
1151
O
LEU
B
17
−44.219
20.354
−48.575
1.00
45.78
B


ATOM
1152
N
LEU
B
18
−44.983
22.464
−48.466
1.00
44.38
B


ATOM
1153
CA
LEU
B
18
−46.373
22.046
−48.391
1.00
44.44
B


ATOM
1154
CB
LEU
B
18
−47.291
23.257
−48.262
1.00
43.44
B


ATOM
1155
CG
LEU
B
18
−47.574
23.721
−46.831
1.00
43.94
B


ATOM
1156
CD1
LEU
B
18
−48.104
25.149
−46.842
1.00
42.55
B


ATOM
1157
CD2
LEU
B
18
−48.565
22.761
−46.172
1.00
40.40
B


ATOM
1158
C
LEU
B
18
−46.713
21.278
−49.654
1.00
46.61
B


ATOM
1159
O
LEU
B
18
−47.504
20.332
−49.628
1.00
47.62
B


ATOM
1160
N
ALA
B
19
−46.107
21.692
−50.764
1.00
47.27
B


ATOM
1161
CA
ALA
B
19
−46.326
21.043
−52.053
1.00
47.65
B


ATOM
1162
CB
ALA
B
19
−45.762
21.912
−53.174
1.00
47.43
B


ATOM
1163
C
ALA
B
19
−45.679
19.659
−52.087
1.00
48.06
B


ATOM
1164
O
ALA
B
19
−46.257
18.715
−52.620
1.00
47.48
B


ATOM
1165
N
GLN
B
20
−44.474
19.553
−51.526
1.00
49.52
B


ATOM
1166
CA
GLN
B
20
−43.742
18.286
−51.482
1.00
50.43
B


ATOM
1167
CB
GLN
B
20
−42.266
18.521
−51.141
1.00
50.28
B


ATOM
1168
CG
GLN
B
20
−41.409
19.164
−52.227
1.00
48.64
B


ATOM
1169
CD
GLN
B
20
−40.000
19.484
−51.738
1.00
49.87
B


ATOM
1170
OE1
GLN
B
20
−39.518
18.888
−50.778
1.00
51.73
B


ATOM
1171
NE2
GLN
B
20
−39.333
20.418
−52.403
1.00
49.40
B


ATOM
1172
C
GLN
B
20
−44.352
17.371
−50.428
1.00
51.95
B


ATOM
1173
O
GLN
B
20
−44.020
16.199
−50.350
1.00
52.62
B


ATOM
1174
N
MET
B
21
−45.249
17.915
−49.618
1.00
54.15
B


ATOM
1175
CA
MET
B
21
−45.892
17.138
−48.568
1.00
56.60
B


ATOM
1176
CB
MET
B
21
−46.325
18.064
−47.420
1.00
56.38
B


ATOM
1177
CG
MET
B
21
−45.231
18.357
−46.394
1.00
57.01
B


ATOM
1178
SD
MET
B
21
−45.690
19.612
−45.174
1.00
57.20
B


ATOM
1179
CE
MET
B
21
−47.211
18.885
−44.499
1.00
57.95
B


ATOM
1180
C
MET
B
21
−47.090
16.327
−49.056
1.00
58.24
B


ATOM
1181
O
MET
B
21
−47.551
15.424
−48.363
1.00
58.12
B


ATOM
1182
N
ALA
B
22
−47.600
16.645
−50.243
1.00
61.09
B


ATOM
1183
CA
ALA
B
22
−48.754
15.922
−50.773
1.00
62.96
B


ATOM
1184
CB
ALA
B
22
−49.151
16.468
−52.145
1.00
61.96
B


ATOM
1185
C
ALA
B
22
−48.415
14.446
−50.872
1.00
64.38
B


ATOM
1186
O
ALA
B
22
−47.323
14.086
−51.300
1.00
64.43
B


ATOM
1187
N
ARG
B
23
−49.352
13.596
−50.463
1.00
67.27
B


ATOM
1188
CA
ARG
B
23
−49.132
12.158
−50.508
1.00
70.44
B


ATOM
1189
CB
ARG
B
23
−48.613
11.669
−49.152
1.00
71.01
B


ATOM
1190
CG
ARG
B
23
−49.450
12.102
−47.968
1.00
72.18
B


ATOM
1191
CD
ARG
B
23
−48.731
11.815
−46.667
1.00
73.33
B


ATOM
1192
NE
ARG
B
23
−48.552
10.385
−46.450
1.00
76.38
B


ATOM
1193
CZ
ARG
B
23
−47.854
9.860
−45.445
1.00
78.19
B


ATOM
1194
NH1
ARG
B
23
−47.256
10.649
−44.553
1.00
77.51
B


ATOM
1195
NH2
ARG
B
23
−47.760
8.538
−45.329
1.00
77.90
B


ATOM
1196
C
ARG
B
23
−50.362
11.354
−50.923
1.00
72.04
B


ATOM
1197
O
ARG
B
23
−50.280
10.139
−51.102
1.00
73.43
B


ATOM
1198
N
ALA
B
24
−51.500
12.023
−51.077
1.00
73.32
B


ATOM
1199
CA
ALA
B
24
−52.721
11.340
−51.489
1.00
75.11
B


ATOM
1200
CB
ALA
B
24
−53.947
12.016
−50.872
1.00
72.05
B


ATOM
1201
C
ALA
B
24
−52.817
11.370
−53.011
1.00
77.82
B


ATOM
1202
O
ALA
B
24
−52.334
12.309
−53.653
1.00
78.81
B


ATOM
1203
N
SER
B
25
−53.429
10.339
−53.588
1.00
79.74
B


ATOM
1204
CA
SER
B
25
−53.599
10.261
−55.033
1.00
82.06
B


ATOM
1205
CB
SER
B
25
−53.912
8.827
−55.442
1.00
82.21
B


ATOM
1206
OG
SER
B
25
−55.044
8.348
−54.737
1.00
83.63
B


ATOM
1207
C
SER
B
25
−54.746
11.178
−55.459
1.00
84.39
B


ATOM
1208
O
SER
B
25
−55.633
11.492
−54.657
1.00
84.68
B


ATOM
1209
N
PRO
B
26
−54.749
11.614
−56.730
1.00
85.80
B


ATOM
1210
CD
PRO
B
26
−53.769
11.287
−57.779
1.00
85.92
B


ATOM
1211
CA
PRO
B
26
−55.793
12.500
−57.254
1.00
87.16
B


ATOM
1212
CB
PRO
B
26
−55.212
12.950
−58.588
1.00
86.58
B


ATOM
1213
CG
PRO
B
26
−54.482
11.736
−59.038
1.00
86.26
B


ATOM
1214
C
PRO
B
26
−57.166
11.837
−57.407
1.00
88.81
B


ATOM
1215
O
PRO
B
26
−58.139
12.487
−57.795
1.00
89.06
B


ATOM
1216
N
PHE
B
27
−57.242
10.544
−57.108
1.00
89.93
B


ATOM
1217
CA
PHE
B
27
−58.507
9.823
−57.207
1.00
91.46
B


ATOM
1218
CB
PHE
B
27
−58.359
8.550
−58.053
1.00
91.94
B


ATOM
1219
CG
PHE
B
27
−57.967
8.801
−59.482
1.00
91.42
B


ATOM
1220
CD1
PHE
B
27
−56.659
9.137
−59.811
1.00
91.14
B


ATOM
1221
CD2
PHE
B
27
−58.909
8.695
−60.498
1.00
90.75
B


ATOM
1222
CE1
PHE
B
27
−56.294
9.361
−61.131
1.00
91.14
B


ATOM
1223
CE2
PHE
B
27
−58.555
8.917
−61.820
1.00
91.00
B


ATOM
1224
CZ
PHE
B
27
−57.245
9.252
−62.139
1.00
91.47
B


ATOM
1225
C
PHE
B
27
−58.989
9.426
−55.820
1.00
92.32
B


ATOM
1226
O
PHE
B
27
−60.192
9.267
−55.599
1.00
93.11
B


ATOM
1227
N
ALA
B
28
−58.035
9.269
−54.900
1.00
92.92
B


ATOM
1228
CA
ALA
B
28
−58.295
8.864
−53.516
1.00
92.18
B


ATOM
1229
CB
ALA
B
28
−56.996
8.915
−52.706
1.00
91.40
B


ATOM
1230
C
ALA
B
28
−59.387
9.649
−52.790
1.00
91.90
B


ATOM
1231
O
ALA
B
28
−60.199
9.057
−52.074
1.00
91.57
B


ATOM
1232
N
CYS
B
29
−59.416
10.969
−52.963
1.00
91.32
B


ATOM
1233
CA
CYS
B
29
−60.433
11.772
−52.288
1.00
91.47
B


ATOM
1234
C
CYS
B
29
−61.450
12.374
−53.243
1.00
92.66
B


ATOM
1235
O
CYS
B
29
−61.088
12.992
−54.245
1.00
92.45
B


ATOM
1236
CB
CYS
B
29
−59.780
12.887
−51.463
1.00
89.53
B


ATOM
1237
SG
CYS
B
29
−58.531
12.280
−50.282
1.00
86.39
B


ATOM
1238
N
GLY
B
30
−62.727
12.178
−52.926
1.00
93.98
B


ATOM
1239
CA
GLY
B
30
−63.784
12.716
−53.758
1.00
95.70
B


ATOM
1240
C
GLY
B
30
−63.862
14.212
−53.543
1.00
96.95
B


ATOM
1241
O
GLY
B
30
−63.276
14.727
−52.592
1.00
97.62
B


ATOM
1242
N
GLY
B
31
−64.577
14.908
−54.420
1.00
97.39
B


ATOM
1243
CA
GLY
B
31
−64.707
16.349
−54.296
1.00
97.58
B


ATOM
1244
C
GLY
B
31
−65.411
16.803
−53.027
1.00
97.64
B


ATOM
1245
O
GLY
B
31
−66.503
17.375
−53.083
1.00
98.81
B


ATOM
1246
N
GLY
B
32
−64.787
16.546
−51.880
1.00
96.79
B


ATOM
1247
CA
GLY
B
32
−65.360
16.951
−50.609
1.00
94.95
B


ATOM
1248
C
GLY
B
32
−64.893
18.350
−50.254
1.00
93.64
B


ATOM
1249
O
GLY
B
32
−64.396
18.597
−49.150
1.00
93.49
B


ATOM
1250
N
GLY
B
33
−65.052
19.265
−51.207
1.00
92.18
B


ATOM
1251
CA
GLY
B
33
−64.646
20.645
−51.009
1.00
89.82
B


ATOM
1252
C
GLY
B
33
−65.345
21.318
−49.846
1.00
88.28
B


ATOM
1253
O
GLY
B
33
−66.577
21.331
−49.762
1.00
88.34
B


ATOM
1254
N
HIS
B
34
−64.544
21.878
−48.943
1.00
85.84
B


ATOM
1255
CA
HIS
B
34
−65.053
22.571
−47.762
1.00
82.36
B


ATOM
1256
CB
HIS
B
34
−64.630
21.808
−46.496
1.00
80.60
B


ATOM
1257
CG
HIS
B
34
−65.146
22.398
−45.220
1.00
78.05
B


ATOM
1258
CD2
HIS
B
34
−65.986
21.899
−44.281
1.00
76.62
B


ATOM
1259
ND1
HIS
B
34
−64.766
23.644
−44.763
1.00
77.24
B


ATOM
1260
CE1
HIS
B
34
−65.346
23.883
−43.603
1.00
75.05
B


ATOM
1261
NE2
HIS
B
34
−66.092
22.838
−43.287
1.00
75.00
B


ATOM
1262
C
HIS
B
34
−64.472
23.983
−47.764
1.00
80.50
B


ATOM
1263
O
HIS
B
34
−63.349
24.198
−48.226
1.00
81.27
B


ATOM
1264
N
ASP
B
35
−65.246
24.947
−47.278
1.00
77.74
B


ATOM
1265
CA
ASP
B
35
−64.787
26.330
−47.225
1.00
75.78
B


ATOM
1266
CB
ASP
B
35
−65.795
27.264
−47.895
1.00
76.50
B


ATOM
1267
CG
ASP
B
35
−65.703
28.687
−47.371
1.00
77.21
B


ATOM
1268
OD1
ASP
B
35
−64.578
29.227
−47.288
1.00
77.48
B


ATOM
1269
OD2
ASP
B
35
−66.759
29.266
−47.040
1.00
77.57
B


ATOM
1270
C
ASP
B
35
−64.579
26.767
−45.784
1.00
73.69
B


ATOM
1271
O
ASP
B
35
−65.486
26.653
−44.956
1.00
74.03
B


ATOM
1272
N
PHE
B
36
−63.390
27.282
−45.484
1.00
69.71
B


ATOM
1273
CA
PHE
B
36
−63.097
27.707
−44.125
1.00
65.47
B


ATOM
1274
CB
PHE
B
36
−61.694
27.260
−43.724
1.00
63.29
B


ATOM
1275
CG
PHE
B
36
−61.484
25.780
−43.842
1.00
61.40
B


ATOM
1276
CD1
PHE
B
36
−61.068
25.218
−45.040
1.00
60.82
B


ATOM
1277
CD2
PHE
B
36
−61.722
24.942
−42.762
1.00
59.30
B


ATOM
1278
CE1
PHE
B
36
−60.896
23.840
−45.157
1.00
59.96
B


ATOM
1279
CE2
PHE
B
36
−61.554
23.568
−42.873
1.00
58.76
B


ATOM
1280
CZ
PHE
B
36
−61.139
23.018
−44.071
1.00
57.07
B


ATOM
1281
C
PHE
B
36
−63.254
29.195
−43.882
1.00
63.46
B


ATOM
1282
O
PHE
B
36
−62.813
29.701
−42.860
1.00
63.36
B


ATOM
1283
N
GLY
B
37
−63.892
29.889
−44.816
1.00
61.85
B


ATOM
1284
CA
GLY
B
37
−64.105
31.317
−44.657
1.00
60.22
B


ATOM
1285
C
GLY
B
37
−62.860
32.105
−44.299
1.00
59.45
B


ATOM
1286
O
GLY
B
37
−62.897
32.984
−43.436
1.00
59.52
B


ATOM
1287
N
PHE
B
38
−61.757
31.785
−44.965
1.00
58.21
B


ATOM
1288
CA
PHE
B
38
−60.496
32.467
−44.735
1.00
57.09
B


ATOM
1289
CB
PHE
B
38
−59.465
32.035
−45.776
1.00
55.16
B


ATOM
1290
CG
PHE
B
38
−58.169
32.774
−45.684
1.00
52.52
B


ATOM
1291
CD1
PHE
B
38
−57.409
32.728
−44.523
1.00
51.16
B


ATOM
1292
CD2
PHE
B
38
−57.704
33.517
−46.760
1.00
52.45
B


ATOM
1293
CE1
PHE
B
38
−56.201
33.414
−44.433
1.00
50.89
B


ATOM
1294
CE2
PHE
B
38
−56.492
34.207
−46.681
1.00
52.43
B


ATOM
1295
CZ
PHE
B
38
−55.741
34.152
−45.511
1.00
51.93
B


ATOM
1296
C
PHE
B
38
−60.729
33.958
−44.844
1.00
57.08
B


ATOM
1297
O
PHE
B
38
−61.224
34.434
−45.853
1.00
56.69
B


ATOM
1298
N
PRO
B
39
−60.369
34.716
−43.802
1.00
58.27
B


ATOM
1299
CD
PRO
B
39
−59.687
34.259
−42.581
1.00
58.11
B


ATOM
1300
CA
PRO
B
39
−60.542
36.168
−43.776
1.00
60.08
B


ATOM
1301
CB
PRO
B
39
−60.253
36.511
−42.323
1.00
59.19
B


ATOM
1302
CG
PRO
B
39
−59.163
35.556
−41.999
1.00
58.94
B


ATOM
1303
C
PRO
B
39
−59.596
36.875
−44.742
1.00
62.95
B


ATOM
1304
O
PRO
B
39
−58.544
37.387
−44.344
1.00
63.46
B


ATOM
1305
N
GLN
B
40
−59.982
36.908
−46.014
1.00
65.02
B


ATOM
1306
CA
GLN
B
40
−59.163
37.545
−47.031
1.00
66.34
B


ATOM
1307
CB
GLN
B
40
−59.705
37.224
−48.412
1.00
66.89
B


ATOM
1308
CG
GLN
B
40
−58.720
37.527
−49.510
1.00
69.39
B


ATOM
1309
CD
GLN
B
40
−59.274
37.201
−50.872
1.00
71.14
B


ATOM
1310
OE1
GLN
B
40
−59.732
36.084
−51.121
1.00
71.05
B


ATOM
1311
NE2
GLN
B
40
−59.235
38.174
−51.769
1.00
72.52
B


ATOM
1312
C
GLN
B
40
−59.085
39.056
−46.856
1.00
67.85
B


ATOM
1313
O
GLN
B
40
−58.107
39.678
−47.260
1.00
67.07
B


ATOM
1314
N
GLU
B
41
−60.110
39.643
−46.248
1.00
70.00
B


ATOM
1315
CA
GLU
B
41
−60.135
41.085
−46.029
1.00
73.07
B


ATOM
1316
CB
GLU
B
41
−61.390
41.506
−45.255
1.00
73.73
B


ATOM
1317
CG
GLU
B
41
−62.623
40.648
−45.473
1.00
75.45
B


ATOM
1318
CD
GLU
B
41
−62.636
39.399
−44.604
1.00
76.40
B


ATOM
1319
OE1
GLU
B
41
−62.528
39.534
−43.363
1.00
75.97
B


ATOM
1320
OE2
GLU
B
41
−62.764
38.285
−45.162
1.00
76.54
B


ATOM
1321
C
GLU
B
41
−58.914
41.562
−45.241
1.00
74.88
B


ATOM
1322
O
GLU
B
41
−58.437
42.675
−45.439
1.00
75.45
B


ATOM
1323
N
GLU
B
42
−58.414
40.722
−44.342
1.00
76.27
B


ATOM
1324
CA
GLU
B
42
−57.272
41.091
−43.515
1.00
76.77
B


ATOM
1325
CB
GLU
B
42
−57.154
40.118
−42.341
1.00
77.03
B


ATOM
1326
CG
GLU
B
42
−58.484
39.812
−41.670
1.00
76.96
B


ATOM
1327
CD
GLU
B
42
−59.135
41.036
−41.062
1.00
77.01
B


ATOM
1328
OE1
GLU
B
42
−60.354
40.980
−40.783
1.00
76.54
B


ATOM
1329
OE2
GLU
B
42
−58.428
42.047
−40.855
1.00
77.00
B


ATOM
1330
C
GLU
B
42
−55.953
41.136
−44.276
1.00
77.34
B


ATOM
1331
O
GLU
B
42
−54.978
41.721
−43.797
1.00
76.70
B


ATOM
1332
N
PHE
B
43
−55.927
40.523
−45.460
1.00
78.79
B


ATOM
1333
CA
PHE
B
43
−54.716
40.481
−46.282
1.00
79.57
B


ATOM
1334
CB
PHE
B
43
−54.354
39.030
−46.614
1.00
76.30
B


ATOM
1335
CG
PHE
B
43
−54.174
38.158
−45.407
1.00
73.38
B


ATOM
1336
CD1
PHE
B
43
−55.259
37.518
−44.827
1.00
72.32
B


ATOM
1337
CD2
PHE
B
43
−52.918
37.982
−44.846
1.00
72.34
B


ATOM
1338
CE1
PHE
B
43
−55.093
36.716
−43.708
1.00
71.63
B


ATOM
1339
CE2
PHE
B
43
−52.743
37.182
−43.727
1.00
71.80
B


ATOM
1340
CZ
PHE
B
43
−53.832
36.547
−43.158
1.00
71.86
B


ATOM
1341
C
PHE
B
43
−54.830
41.274
−47.584
1.00
81.78
B


ATOM
1342
O
PHE
B
43
−54.032
42.171
−47.855
1.00
82.37
B


ATOM
1343
N
GLY
B
44
−55.825
40.932
−48.391
1.00
84.35
B


ATOM
1344
CA
GLY
B
44
−56.013
41.619
−49.654
1.00
86.86
B


ATOM
1345
C
GLY
B
44
−56.880
42.859
−49.557
1.00
88.99
B


ATOM
1346
O
GLY
B
44
−58.085
42.785
−49.304
1.00
88.66
B


ATOM
1347
N
GLY
B
45
−56.259
44.011
−49.766
1.00
90.98
B


ATOM
1348
CA
GLY
B
45
−56.995
45.256
−49.708
1.00
93.31
B


ATOM
1349
C
GLY
B
45
−56.073
46.453
−49.679
1.00
95.02
B


ATOM
1350
O
GLY
B
45
−54.874
46.323
−49.413
1.00
95.65
B


ATOM
1351
N
GLY
B
46
−56.633
47.624
−49.967
1.00
95.75
B


ATOM
1352
CA
GLY
B
46
−55.846
48.839
−49.947
1.00
96.64
B


ATOM
1353
C
GLY
B
46
−55.513
49.204
−48.513
1.00
97.19
B


ATOM
1354
O
GLY
B
46
−55.188
50.354
−48.212
1.00
97.50
B


ATOM
1355
N
GLY
B
47
−55.602
48.218
−47.623
1.00
97.06
B


ATOM
1356
CA
GLY
B
47
−55.307
48.454
−46.223
1.00
97.22
B


ATOM
1357
C
GLY
B
47
−54.088
49.337
−46.029
1.00
97.43
B


ATOM
1358
O
GLY
B
47
−54.193
50.430
−45.463
1.00
97.59
B


ATOM
1359
N
GLY
B
48
−52.935
48.868
−46.508
1.00
96.90
B


ATOM
1360
CA
GLY
B
48
−51.700
49.623
−46.371
1.00
95.31
B


ATOM
1361
C
GLY
B
48
−51.429
50.049
−44.937
1.00
94.30
B


ATOM
1362
O
GLY
B
48
−51.772
51.165
−44.541
1.00
94.67
B


ATOM
1363
N
ALA
B
49
−50.817
49.163
−44.155
1.00
92.52
B


ATOM
1364
CA
ALA
B
49
−50.508
49.455
−42.756
1.00
90.44
B


ATOM
1365
CB
ALA
B
49
−51.795
49.488
−41.929
1.00
90.39
B


ATOM
1366
C
ALA
B
49
−49.536
48.424
−42.182
1.00
88.31
B


ATOM
1367
O
ALA
B
49
−49.944
47.366
−41.697
1.00
87.77
B


ATOM
1368
N
GLY
B
50
−48.249
48.753
−42.241
1.00
85.76
B


ATOM
1369
CA
GLY
B
50
−47.214
47.865
−41.742
1.00
82.69
B


ATOM
1370
C
GLY
B
50
−47.476
47.214
−40.396
1.00
80.16
B


ATOM
1371
O
GLY
B
50
−46.976
46.125
−40.130
1.00
80.60
B


ATOM
1372
N
ALA
B
51
−48.256
47.867
−39.543
1.00
77.39
B


ATOM
1373
CA
ALA
B
51
−48.548
47.319
−38.223
1.00
74.09
B


ATOM
1374
CB
ALA
B
51
−48.967
48.433
−37.273
1.00
74.25
B


ATOM
1375
C
ALA
B
51
−49.631
46.252
−38.287
1.00
71.65
B


ATOM
1376
O
ALA
B
51
−49.622
45.307
−37.499
1.00
70.67
B


ATOM
1377
N
ALA
B
52
−50.568
46.412
−39.220
1.00
68.72
B


ATOM
1378
CA
ALA
B
52
−51.652
45.450
−39.392
1.00
65.82
B


ATOM
1379
CB
ALA
B
52
−52.784
46.066
−40.204
1.00
65.58
B


ATOM
1380
C
ALA
B
52
−51.102
44.226
−40.111
1.00
63.64
B


ATOM
1381
O
ALA
B
52
−51.346
43.086
−39.713
1.00
63.09
B


ATOM
1382
N
ALA
B
53
−50.351
44.472
−41.175
1.00
60.70
B


ATOM
1383
CA
ALA
B
53
−49.758
43.390
−41.942
1.00
58.62
B


ATOM
1384
CB
ALA
B
53
−48.812
43.959
−42.994
1.00
57.63
B


ATOM
1385
C
ALA
B
53
−49.003
42.443
−41.014
1.00
56.79
B


ATOM
1386
O
ALA
B
53
−49.350
41.271
−40.897
1.00
56.46
B


ATOM
1387
N
ILE
B
54
−47.977
42.971
−40.350
1.00
55.35
B


ATOM
1388
CA
ILE
B
54
−47.139
42.197
−39.440
1.00
53.78
B


ATOM
1389
CB
ILE
B
54
−46.178
43.100
−38.678
1.00
53.66
B


ATOM
1390
CG2
ILE
B
54
−45.360
42.267
−37.708
1.00
53.50
B


ATOM
1391
CG1
ILE
B
54
−45.275
43.848
−39.665
1.00
54.89
B


ATOM
1392
CD1
ILE
B
54
−44.430
44.947
−39.029
1.00
53.54
B


ATOM
1393
C
ILE
B
54
−47.913
41.393
−38.412
1.00
53.50
B


ATOM
1394
O
ILE
B
54
−47.529
40.280
−38.074
1.00
53.63
B


ATOM
1395
N
SER
B
55
−48.999
41.965
−37.916
1.00
53.54
B


ATOM
1396
CA
SER
B
55
−49.820
41.306
−36.922
1.00
53.69
B


ATOM
1397
CB
SER
B
55
−50.764
42.312
−36.277
1.00
55.26
B


ATOM
1398
OG
SER
B
55
−50.023
43.376
−35.708
1.00
58.90
B


ATOM
1399
C
SER
B
55
−50.615
40.161
−37.515
1.00
52.96
B


ATOM
1400
O
SER
B
55
−50.797
39.142
−36.867
1.00
54.85
B


ATOM
1401
N
VAL
B
56
−51.098
40.307
−38.738
1.00
51.44
B


ATOM
1402
CA
VAL
B
56
−51.849
39.210
−39.318
1.00
51.64
B


ATOM
1403
CB
VAL
B
56
−52.798
39.692
−40.431
1.00
51.99
B


ATOM
1404
CG1
VAL
B
56
−53.812
40.643
−39.846
1.00
50.15
B


ATOM
1405
CG2
VAL
B
56
−52.020
40.360
−41.536
1.00
51.94
B


ATOM
1406
C
VAL
B
56
−50.924
38.115
−39.849
1.00
51.00
B


ATOM
1407
O
VAL
B
56
−51.165
36.937
−39.613
1.00
50.59
B


ATOM
1408
N
LEU
B
57
−49.867
38.489
−40.560
1.00
50.84
B


ATOM
1409
CA
LEU
B
57
−48.943
37.479
−41.061
1.00
51.20
B


ATOM
1410
CB
LEU
B
57
−47.755
38.107
−41.798
1.00
51.55
B


ATOM
1411
CG
LEU
B
57
−47.820
38.373
−43.304
1.00
52.66
B


ATOM
1412
CD1
LEU
B
57
−48.796
37.400
−43.946
1.00
52.07
B


ATOM
1413
CD2
LEU
B
57
−48.221
39.805
−43.569
1.00
52.06
B


ATOM
1414
C
LEU
B
57
−48.410
36.699
−39.871
1.00
50.92
B


ATOM
1415
O
LEU
B
57
−48.392
35.462
−39.879
1.00
51.14
B


ATOM
1416
N
HIS
B
58
−47.983
37.427
−38.841
1.00
48.84
B


ATOM
1417
CA
HIS
B
58
−47.433
36.786
−37.649
1.00
48.56
B


ATOM
1418
CB
HIS
B
58
−47.033
37.837
−36.593
1.00
45.06
B


ATOM
1419
CG
HIS
B
58
−46.150
37.292
−35.510
1.00
41.60
B


ATOM
1420
CD2
HIS
B
58
−44.811
37.390
−35.322
1.00
40.97
B


ATOM
1421
ND1
HIS
B
58
−46.620
36.470
−34.511
1.00
41.10
B


ATOM
1422
CE1
HIS
B
58
−45.605
36.077
−33.754
1.00
39.76
B


ATOM
1423
NE2
HIS
B
58
−44.500
36.619
−34.225
1.00
38.18
B


ATOM
1424
C
HIS
B
58
−48.405
35.769
−37.035
1.00
47.89
B


ATOM
1425
O
HIS
B
58
−48.000
34.667
−36.652
1.00
47.61
B


ATOM
1426
N
GLU
B
59
−49.682
36.125
−36.955
1.00
44.67
B


ATOM
1427
CA
GLU
B
59
−50.649
35.215
−36.376
1.00
44.65
B


ATOM
1428
CB
GLU
B
59
−51.992
35.911
−36.156
1.00
45.09
B


ATOM
1429
CG
GLU
B
59
−52.996
35.078
−35.377
1.00
46.22
B


ATOM
1430
CD
GLU
B
59
−52.491
34.750
−33.994
1.00
48.75
B


ATOM
1431
OE1
GLU
B
59
−51.714
35.571
−33.474
1.00
50.15
B


ATOM
1432
OE2
GLU
B
59
−52.860
33.696
−33.422
1.00
48.92
B


ATOM
1433
C
GLU
B
59
−50.857
33.998
−37.257
1.00
44.41
B


ATOM
1434
O
GLU
B
59
−51.033
32.892
−36.757
1.00
44.67
B


ATOM
1435
N
MET
B
60
−50.842
34.196
−38.571
1.00
44.37
B


ATOM
1436
CA
MET
B
60
−51.055
33.079
−39.471
1.00
45.11
B


ATOM
1437
CB
MET
B
60
−51.331
33.559
−40.897
1.00
48.89
B


ATOM
1438
CG
MET
B
60
−51.721
32.415
−41.821
1.00
53.44
B


ATOM
1439
SD
MET
B
60
−51.754
32.856
−43.555
1.00
61.98
B


ATOM
1440
CE
MET
B
60
−50.021
33.361
−43.846
1.00
58.01
B


ATOM
1441
C
MET
B
60
−49.864
32.128
−39.465
1.00
43.04
B


ATOM
1442
O
MET
B
60
−50.039
30.909
−39.449
1.00
40.32
B


ATOM
1443
N
ILE
B
61
−48.655
32.671
−39.481
1.00
40.71
B


ATOM
1444
CA
ILE
B
61
−47.500
31.802
−39.457
1.00
42.41
B


ATOM
1445
CB
ILE
B
61
−46.170
32.608
−39.520
1.00
43.92
B


ATOM
1446
CG2
ILE
B
61
−44.975
31.667
−39.434
1.00
44.05
B


ATOM
1447
CG1
ILE
B
61
−46.094
33.395
−40.823
1.00
41.85
B


ATOM
1448
CD1
ILE
B
61
−46.283
32.551
−42.028
1.00
45.99
B


ATOM
1449
C
ILE
B
61
−47.557
30.991
−38.153
1.00
43.11
B


ATOM
1450
O
ILE
B
61
−47.413
29.762
−38.158
1.00
43.91
B


ATOM
1451
N
GLN
B
62
−47.795
31.690
−37.049
1.00
42.04
B


ATOM
1452
CA
GLN
B
62
−47.863
31.082
−35.726
1.00
43.22
B


ATOM
1453
CB
GLN
B
62
−48.229
32.140
−34.685
1.00
46.41
B


ATOM
1454
CG
GLN
B
62
−48.049
31.713
−33.245
1.00
46.91
B


ATOM
1455
CD
GLN
B
62
−46.596
31.663
−32.837
1.00
52.53
B


ATOM
1456
OE1
GLN
B
62
−45.904
30.665
−33.070
1.00
55.84
B


ATOM
1457
NE2
GLN
B
62
−46.113
32.748
−32.228
1.00
54.09
B


ATOM
1458
C
GLN
B
62
−48.880
29.960
−35.663
1.00
43.47
B


ATOM
1459
O
GLN
B
62
−48.587
28.870
−35.152
1.00
44.07
B


ATOM
1460
N
GLN
B
63
−50.083
30.228
−36.163
1.00
42.32
B


ATOM
1461
CA
GLN
B
63
−51.140
29.221
−36.158
1.00
43.14
B


ATOM
1462
CB
GLN
B
63
−52.456
29.812
−36.653
1.00
43.36
B


ATOM
1463
CG
GLN
B
63
−53.088
30.810
−35.702
1.00
45.90
B


ATOM
1464
CD
GLN
B
63
−53.432
30.220
−34.339
1.00
44.57
B


ATOM
1465
OE1
GLN
B
63
−53.643
30.956
−33.386
1.00
44.63
B


ATOM
1466
NE2
GLN
B
63
−53.497
28.896
−34.250
1.00
44.30
B


ATOM
1467
C
GLN
B
63
−50.796
28.018
−37.017
1.00
43.72
B


ATOM
1468
O
GLN
B
63
−51.089
26.880
−36.649
1.00
44.40
B


ATOM
1469
N
THR
B
64
−50.177
28.277
−38.164
1.00
42.86
B


ATOM
1470
CA
THR
B
64
−49.811
27.211
−39.073
1.00
42.63
B


ATOM
1471
CB
THR
B
64
−49.271
27.777
−40.409
1.00
42.59
B


ATOM
1472
OG1
THR
B
64
−50.275
28.599
−41.012
1.00
40.41
B


ATOM
1473
CG2
THR
B
64
−48.910
26.649
−41.368
1.00
39.23
B


ATOM
1474
C
THR
B
64
−48.762
26.343
−38.405
1.00
43.08
B


ATOM
1475
O
THR
B
64
−48.801
25.118
−38.509
1.00
45.34
B


ATOM
1476
N
PHE
B
65
−47.820
26.980
−37.724
1.00
41.85
B


ATOM
1477
CA
PHE
B
65
−46.781
26.245
−37.026
1.00
41.65
B


ATOM
1478
CB
PHE
B
65
−45.890
27.210
−36.231
1.00
39.65
B


ATOM
1479
CG
PHE
B
65
−44.753
26.533
−35.514
1.00
37.50
B


ATOM
1480
CD1
PHE
B
65
−43.503
26.448
−36.095
1.00
38.07
B


ATOM
1481
CD2
PHE
B
65
−44.952
25.931
−34.285
1.00
38.71
B


ATOM
1482
CE1
PHE
B
65
−42.463
25.766
−35.473
1.00
38.97
B


ATOM
1483
CE2
PHE
B
65
−43.927
25.247
−33.651
1.00
40.75
B


ATOM
1484
CZ
PHE
B
65
−42.674
25.163
−34.252
1.00
41.00
B


ATOM
1485
C
PHE
B
65
−47.459
25.268
−36.062
1.00
42.95
B


ATOM
1486
O
PHE
B
65
−47.199
24.067
−36.077
1.00
41.78
B


ATOM
1487
N
ASN
B
66
−48.346
25.797
−35.228
1.00
44.10
B


ATOM
1488
CA
ASN
B
66
−49.036
24.976
−34.244
1.00
45.15
B


ATOM
1489
CB
ASN
B
66
−50.014
25.836
−33.444
1.00
45.22
B


ATOM
1490
CG
ASN
B
66
−49.309
26.882
−32.588
1.00
45.60
B


ATOM
1491
OD1
ASN
B
66
−49.917
27.866
−32.179
1.00
47.81
B


ATOM
1492
ND2
ASN
B
66
−48.026
26.667
−32.310
1.00
45.74
B


ATOM
1493
C
ASN
B
66
−49.758
23.802
−34.874
1.00
45.93
B


ATOM
1494
O
ASN
B
66
−49.592
22.661
−34.443
1.00
46.70
B


ATOM
1495
N
LEU
B
67
−50.545
24.087
−35.906
1.00
46.78
B


ATOM
1496
CA
LEU
B
67
−51.314
23.072
−36.614
1.00
45.25
B


ATOM
1497
CB
LEU
B
67
−52.027
23.708
−37.802
1.00
44.17
B


ATOM
1498
CG
LEU
B
67
−52.943
22.848
−38.673
1.00
44.83
B


ATOM
1499
CD1
LEU
B
67
−54.221
22.524
−37.908
1.00
43.33
B


ATOM
1500
CD2
LEU
B
67
−53.269
23.609
−39.950
1.00
43.75
B


ATOM
1501
C
LEU
B
67
−50.465
21.914
−37.109
1.00
46.02
B


ATOM
1502
O
LEU
B
67
−50.888
20.763
−37.037
1.00
47.59
B


ATOM
1503
N
PHE
B
68
−49.270
22.209
−37.606
1.00
45.93
B


ATOM
1504
CA
PHE
B
68
−48.407
21.165
−38.142
1.00
48.01
B


ATOM
1505
CB
PHE
B
68
−47.690
21.674
−39.400
1.00
47.07
B


ATOM
1506
CG
PHE
B
68
−48.573
21.725
−40.623
1.00
47.28
B


ATOM
1507
CD1
PHE
B
68
−49.374
22.834
−40.879
1.00
47.40
B


ATOM
1508
CD2
PHE
B
68
−48.629
20.643
−41.497
1.00
45.54
B


ATOM
1509
CE1
PHE
B
68
−50.217
22.863
−41.985
1.00
45.20
B


ATOM
1510
CE2
PHE
B
68
−49.463
20.660
−42.598
1.00
45.58
B


ATOM
1511
CZ
PHE
B
68
−50.261
21.772
−42.843
1.00
45.21
B


ATOM
1512
C
PHE
B
68
−47.385
20.564
−37.174
1.00
50.56
B


ATOM
1513
O
PHE
B
68
−46.660
19.625
−37.519
1.00
50.22
B


ATOM
1514
N
SER
B
69
−47.333
21.093
−35.959
1.00
52.03
B


ATOM
1515
CA
SER
B
69
−46.397
20.592
−34.963
1.00
51.91
B


ATOM
1516
CB
SER
B
69
−45.844
21.762
−34.145
1.00
50.79
B


ATOM
1517
OG
SER
B
69
−46.861
22.698
−33.850
1.00
50.68
B


ATOM
1518
C
SER
B
69
−47.098
19.559
−34.071
1.00
52.49
B


ATOM
1519
O
SER
B
69
−46.471
18.877
−33.263
1.00
51.65
B


ATOM
1520
N
THR
B
70
−48.406
19.437
−34.256
1.00
53.35
B


ATOM
1521
CA
THR
B
70
−49.220
18.485
−33.519
1.00
54.95
B


ATOM
1522
CB
THR
B
70
−50.715
18.667
−33.892
1.00
54.32
B


ATOM
1523
OG1
THR
B
70
−51.292
19.672
−33.051
1.00
53.43
B


ATOM
1524
CG2
THR
B
70
−51.491
17.378
−33.749
1.00
53.28
B


ATOM
1525
C
THR
B
70
−48.816
17.024
−33.764
1.00
57.60
B


ATOM
1526
O
THR
B
70
−48.196
16.683
−34.775
1.00
56.59
B


ATOM
1527
N
ARG
B
71
−49.183
16.177
−32.806
1.00
60.45
B


ATOM
1528
CA
ARG
B
71
−48.931
14.739
−32.839
1.00
63.09
B


ATOM
1529
CB
ARG
B
71
−49.445
14.131
−31.527
1.00
66.17
B


ATOM
1530
CG
ARG
B
71
−50.748
14.806
−31.033
1.00
71.66
B


ATOM
1531
CD
ARG
B
71
−50.651
15.471
−29.626
1.00
74.28
B


ATOM
1532
NE
ARG
B
71
−49.626
16.519
−29.495
1.00
75.60
B


ATOM
1533
CZ
ARG
B
71
−48.406
16.325
−28.982
1.00
76.64
B


ATOM
1534
NH1
ARG
B
71
−48.039
15.122
−28.548
1.00
76.04
B


ATOM
1535
NH2
ARG
B
71
−47.551
17.338
−28.891
1.00
75.84
B


ATOM
1536
C
ARG
B
71
−49.654
14.119
−34.046
1.00
62.93
B


ATOM
1537
O
ARG
B
71
−49.156
13.186
−34.684
1.00
62.66
B


ATOM
1538
N
ASP
B
72
−50.834
14.654
−34.344
1.00
62.27
B


ATOM
1539
CA
ASP
B
72
−51.642
14.201
−35.465
1.00
61.32
B


ATOM
1540
CB
ASP
B
72
−53.017
14.844
−35.398
1.00
63.05
B


ATOM
1541
CG
ASP
B
72
−53.745
14.517
−34.121
1.00
65.14
B


ATOM
1542
OD1
ASP
B
72
−54.164
13.350
−33.973
1.00
66.97
B


ATOM
1543
OD2
ASP
B
72
−53.894
15.425
−33.270
1.00
65.14
B


ATOM
1544
C
ASP
B
72
−50.973
14.600
−36.768
1.00
60.42
B


ATOM
1545
O
ASP
B
72
−51.034
13.882
−37.762
1.00
61.00
B


ATOM
1546
N
SER
B
73
−50.341
15.762
−36.758
1.00
59.06
B


ATOM
1547
CA
SER
B
73
−49.657
16.238
−37.938
1.00
58.72
B


ATOM
1548
CB
SER
B
73
−49.126
17.654
−37.704
1.00
57.83
B


ATOM
1549
OG
SER
B
73
−48.578
18.194
−38.892
1.00
58.48
B


ATOM
1550
C
SER
B
73
−48.509
15.281
−38.262
1.00
58.75
B


ATOM
1551
O
SER
B
73
−48.355
14.859
−39.408
1.00
58.86
B


ATOM
1552
N
SER
B
74
−47.718
14.927
−37.250
1.00
57.50
B


ATOM
1553
CA
SER
B
74
−46.582
14.026
−37.443
1.00
56.83
B


ATOM
1554
CB
SER
B
74
−45.849
13.794
−36.127
1.00
55.68
B


ATOM
1555
OG
SER
B
74
−45.131
14.949
−35.737
1.00
59.88
B


ATOM
1556
C
SER
B
74
−47.000
12.686
−38.020
1.00
55.92
B


ATOM
1557
O
SER
B
74
−46.286
12.097
−38.837
1.00
54.81
B


ATOM
1558
N
ALA
B
75
−48.154
12.201
−37.583
1.00
54.52
B


ATOM
1559
CA
ALA
B
75
−48.658
10.929
−38.069
1.00
54.44
B


ATOM
1560
CB
ALA
B
75
−49.870
10.520
−37.268
1.00
53.67
B


ATOM
1561
C
ALA
B
75
−49.029
11.043
−39.540
1.00
54.05
B


ATOM
1562
O
ALA
B
75
−48.835
10.114
−40.323
1.00
53.83
B


ATOM
1563
N
ALA
B
76
−49.542
12.211
−39.905
1.00
53.41
B


ATOM
1564
CA
ALA
B
76
−49.996
12.477
−41.255
1.00
52.31
B


ATOM
1565
CB
ALA
B
76
−51.042
13.580
−41.208
1.00
52.11
B


ATOM
1566
C
ALA
B
76
−48.946
12.810
−42.315
1.00
52.55
B


ATOM
1567
O
ALA
B
76
−49.114
12.443
−43.477
1.00
52.41
B


ATOM
1568
N
TRP
B
77
−47.862
13.481
−41.941
1.00
51.98
B


ATOM
1569
CA
TRP
B
77
−46.879
13.868
−42.947
1.00
51.34
B


ATOM
1570
CB
TRP
B
77
−46.887
15.391
−43.126
1.00
50.88
B


ATOM
1571
CG
TRP
B
77
−48.248
15.994
−43.099
1.00
52.09
B


ATOM
1572
CD2
TRP
B
77
−49.187
16.052
−44.178
1.00
53.10
B


ATOM
1573
CE2
TRP
B
77
−50.347
16.691
−43.689
1.00
53.99
B


ATOM
1574
CE3
TRP
B
77
−49.163
15.624
−45.512
1.00
52.69
B


ATOM
1575
CD1
TRP
B
77
−48.858
16.579
−42.032
1.00
53.81
B


ATOM
1576
NE1
TRP
B
77
−50.119
17.002
−42.375
1.00
54.33
B


ATOM
1577
CZ2
TRP
B
77
−51.476
16.916
−44.490
1.00
54.45
B


ATOM
1578
CZ3
TRP
B
77
−50.287
15.845
−46.309
1.00
50.90
B


ATOM
1579
CH2
TRP
B
77
−51.427
16.486
−45.794
1.00
51.54
B


ATOM
1580
C
TRP
B
77
−45.450
13.425
−42.722
1.00
50.67
B


ATOM
1581
O
TRP
B
77
−45.053
13.094
−41.620
1.00
49.80
B


ATOM
1582
N
ASP
B
78
−44.672
13.436
−43.796
1.00
52.39
B


ATOM
1583
CA
ASP
B
78
−43.278
13.064
−43.711
1.00
53.40
B


ATOM
1584
CB
ASP
B
78
−42.578
13.257
−45.050
1.00
55.50
B


ATOM
1585
CG
ASP
B
78
−41.104
12.936
−44.966
1.00
59.62
B


ATOM
1586
OD1
ASP
B
78
−40.273
13.875
−45.018
1.00
62.42
B


ATOM
1587
OD2
ASP
B
78
−40.777
11.738
−44.820
1.00
59.99
B


ATOM
1588
C
ASP
B
78
−42.602
13.933
−42.663
1.00
53.04
B


ATOM
1589
O
ASP
B
78
−42.706
15.160
−42.700
1.00
53.12
B


ATOM
1590
N
ALA
B
79
−41.901
13.287
−41.738
1.00
52.08
B


ATOM
1591
CA
ALA
B
79
−41.220
13.983
−40.662
1.00
52.01
B


ATOM
1592
CB
ALA
B
79
−40.643
12.968
−39.675
1.00
50.85
B


ATOM
1593
C
ALA
B
79
−40.128
14.917
−41.179
1.00
51.80
B


ATOM
1594
O
ALA
B
79
−40.008
16.050
−40.723
1.00
52.56
B


ATOM
1595
N
SER
B
80
−39.341
14.453
−42.138
1.00
51.82
B


ATOM
1596
CA
SER
B
80
−38.273
15.277
−42.687
1.00
51.59
B


ATOM
1597
CB
SER
B
80
−37.511
14.507
−43.764
1.00
53.55
B


ATOM
1598
OG
SER
B
80
−36.317
15.188
−44.120
1.00
57.70
B


ATOM
1599
C
SER
B
80
−38.818
16.577
−43.280
1.00
50.52
B


ATOM
1600
O
SER
B
80
−38.223
17.649
−43.113
1.00
51.02
B


ATOM
1601
N
LEU
B
81
−39.937
16.487
−43.990
1.00
47.40
B


ATOM
1602
CA
LEU
B
81
−40.521
17.684
−44.574
1.00
46.68
B


ATOM
1603
CB
LEU
B
81
−41.665
17.327
−45.531
1.00
44.63
B


ATOM
1604
CG
LEU
B
81
−41.253
16.605
−46.824
1.00
43.12
B


ATOM
1605
CD1
LEU
B
81
−42.433
16.565
−47.792
1.00
40.61
B


ATOM
1606
CD2
LEU
B
81
−40.080
17.329
−47.467
1.00
38.50
B


ATOM
1607
C
LEU
B
81
−41.021
18.607
−43.464
1.00
47.01
B


ATOM
1608
O
LEU
B
81
−40.806
19.823
−43.507
1.00
46.43
B


ATOM
1609
N
LEU
B
82
−41.668
18.019
−42.462
1.00
45.79
B


ATOM
1610
CA
LEU
B
82
−42.184
18.790
−41.344
1.00
44.38
B


ATOM
1611
CB
LEU
B
82
−42.915
17.881
−40.355
1.00
43.65
B


ATOM
1612
CG
LEU
B
82
−44.350
17.506
−40.712
1.00
42.39
B


ATOM
1613
CD1
LEU
B
82
−44.969
16.779
−39.542
1.00
41.48
B


ATOM
1614
CD2
LEU
B
82
−45.148
18.764
−41.040
1.00
40.02
B


ATOM
1615
C
LEU
B
82
−41.106
19.579
−40.608
1.00
43.60
B


ATOM
1616
O
LEU
B
82
−41.306
20.748
−40.294
1.00
43.44
B


ATOM
1617
N
ALA
B
83
−39.968
18.958
−40.326
1.00
41.84
B


ATOM
1618
CA
ALA
B
83
−38.920
19.686
−39.617
1.00
42.47
B


ATOM
1619
CB
ALA
B
83
−37.732
18.749
−39.241
1.00
42.87
B


ATOM
1620
C
ALA
B
83
−38.442
20.857
−40.466
1.00
40.93
B


ATOM
1621
O
ALA
B
83
−38.074
21.898
−39.930
1.00
41.51
B


ATOM
1622
N
LYS
B
84
−38.458
20.693
−41.785
1.00
39.80
B


ATOM
1623
CA
LYS
B
84
−38.041
21.770
−42.680
1.00
40.20
B


ATOM
1624
CB
LYS
B
84
−37.916
21.257
−44.121
1.00
42.21
B


ATOM
1625
CG
LYS
B
84
−36.919
20.117
−44.326
1.00
44.38
B


ATOM
1626
CD
LYS
B
84
−36.542
20.019
−45.799
1.00
45.90
B


ATOM
1627
CE
LYS
B
84
−35.545
18.920
−46.068
1.00
45.47
B


ATOM
1628
NZ
LYS
B
84
−36.209
17.606
−45.922
1.00
49.90
B


ATOM
1629
C
LYS
B
84
−39.076
22.902
−42.631
1.00
39.06
B


ATOM
1630
O
LYS
B
84
−38.743
24.087
−42.678
1.00
39.36
B


ATOM
1631
N
PHE
B
85
−40.338
22.512
−42.539
1.00
37.58
B


ATOM
1632
CA
PHE
B
85
−41.449
23.442
−42.475
1.00
38.00
B


ATOM
1633
CB
PHE
B
85
−42.749
22.644
−42.492
1.00
38.99
B


ATOM
1634
CG
PHE
B
85
−43.959
23.458
−42.811
1.00
39.63
B


ATOM
1635
CD1
PHE
B
85
−43.942
24.366
−43.866
1.00
38.44
B


ATOM
1636
CD2
PHE
B
85
−45.137
23.276
−42.099
1.00
38.81
B


ATOM
1637
CE1
PHE
B
85
−45.076
25.079
−44.211
1.00
39.59
B


ATOM
1638
CE2
PHE
B
85
−46.288
23.986
−42.439
1.00
41.20
B


ATOM
1639
CZ
PHE
B
85
−46.255
24.891
−43.501
1.00
41.17
B


ATOM
1640
C
PHE
B
85
−41.387
24.331
−41.223
1.00
38.99
B


ATOM
1641
O
PHE
B
85
−41.419
25.557
−41.334
1.00
39.44
B


ATOM
1642
N
TYR
B
86
−41.299
23.709
−40.044
1.00
38.21
B


ATOM
1643
CA
TYR
B
86
−41.217
24.435
−38.769
1.00
37.40
B


ATOM
1644
CB
TYR
B
86
−40.998
23.493
−37.574
1.00
35.90
B


ATOM
1645
CG
TYR
B
86
−41.920
22.311
−37.450
1.00
33.12
B


ATOM
1646
CD1
TYR
B
86
−43.276
22.428
−37.721
1.00
32.96
B


ATOM
1647
CE1
TYR
B
86
−44.138
21.343
−37.563
1.00
35.08
B


ATOM
1648
CD2
TYR
B
86
−41.435
21.077
−37.019
1.00
30.36
B


ATOM
1649
CE2
TYR
B
86
−42.276
19.992
−36.861
1.00
30.76
B


ATOM
1650
CZ
TYR
B
86
−43.628
20.133
−37.129
1.00
34.57
B


ATOM
1651
OH
TYR
B
86
−44.491
19.085
−36.932
1.00
37.86
B


ATOM
1652
C
TYR
B
86
−40.044
25.403
−38.776
1.00
38.65
B


ATOM
1653
O
TYR
B
86
−40.156
26.527
−38.300
1.00
40.78
B


ATOM
1654
N
THR
B
87
−38.905
24.948
−39.289
1.00
38.79
B


ATOM
1655
CA
THR
B
87
−37.712
25.778
−39.347
1.00
38.38
B


ATOM
1656
CB
THR
B
87
−36.538
25.026
−39.984
1.00
35.81
B


ATOM
1657
OG1
THR
B
87
−36.316
23.803
−39.276
1.00
35.27
B


ATOM
1658
CG2
THR
B
87
−35.280
25.870
−39.946
1.00
28.02
B


ATOM
1659
C
THR
B
87
−37.976
27.029
−40.165
1.00
40.34
B


ATOM
1660
O
THR
B
87
−37.600
28.136
−39.768
1.00
42.58
B


ATOM
1661
N
GLU
B
88
−38.629
26.849
−41.308
1.00
41.62
B


ATOM
1662
CA
GLU
B
88
−38.948
27.962
−42.196
1.00
41.56
B


ATOM
1663
CB
GLU
B
88
−39.541
27.428
−43.498
1.00
41.09
B


ATOM
1664
CG
GLU
B
88
−39.850
28.487
−44.526
1.00
43.87
B


ATOM
1665
CD
GLU
B
88
−38.622
29.295
−44.906
1.00
47.13
B


ATOM
1666
OE1
GLU
B
88
−37.542
28.689
−45.046
1.00
48.15
B


ATOM
1667
OE2
GLU
B
88
−38.728
30.528
−45.078
1.00
48.87
B


ATOM
1668
C
GLU
B
88
−39.941
28.907
−41.523
1.00
41.37
B


ATOM
1669
O
GLU
B
88
−39.719
30.120
−41.441
1.00
42.84
B


ATOM
1670
N
LEU
B
89
−41.037
28.342
−41.032
1.00
39.06
B


ATOM
1671
CA
LEU
B
89
−42.049
29.144
−40.380
1.00
38.27
B


ATOM
1672
CB
LEU
B
89
−43.214
28.255
−39.938
1.00
34.88
B


ATOM
1673
CG
LEU
B
89
−43.971
27.575
−41.087
1.00
32.56
B


ATOM
1674
CD1
LEU
B
89
−45.074
26.700
−40.540
1.00
29.69
B


ATOM
1675
CD2
LEU
B
89
−44.519
28.629
−42.014
1.00
29.86
B


ATOM
1676
C
LEU
B
89
−41.475
29.923
−39.199
1.00
39.22
B


ATOM
1677
O
LEU
B
89
−41.707
31.125
−39.070
1.00
38.24
B


ATOM
1678
N
TYR
B
90
−40.703
29.257
−38.351
1.00
39.74
B


ATOM
1679
CA
TYR
B
90
−40.153
29.951
−37.214
1.00
41.05
B


ATOM
1680
CB
TYR
B
90
−39.453
28.987
−36.256
1.00
43.39
B


ATOM
1681
CG
TYR
B
90
−39.363
29.572
−34.863
1.00
45.73
B


ATOM
1682
CD1
TYR
B
90
−40.479
29.577
−34.019
1.00
44.72
B


ATOM
1683
CE1
TYR
B
90
−40.446
30.218
−32.789
1.00
46.68
B


ATOM
1684
CD2
TYR
B
90
−38.203
30.219
−34.429
1.00
45.13
B


ATOM
1685
CE2
TYR
B
90
−38.160
30.863
−33.193
1.00
46.07
B


ATOM
1686
CZ
TYR
B
90
−39.287
30.863
−32.379
1.00
46.81
B


ATOM
1687
OH
TYR
B
90
−39.272
31.538
−31.177
1.00
46.41
B


ATOM
1688
C
TYR
B
90
−39.193
31.047
−37.639
1.00
42.36
B


ATOM
1689
O
TYR
B
90
−39.092
32.086
−36.986
1.00
43.93
B


ATOM
1690
N
GLN
B
91
−38.487
30.831
−38.738
1.00
43.52
B


ATOM
1691
CA
GLN
B
91
−37.557
31.844
−39.217
1.00
45.08
B


ATOM
1692
CB
GLN
B
91
−36.684
31.262
−40.330
1.00
44.47
B


ATOM
1693
CG
GLN
B
91
−35.262
31.826
−40.377
1.00
48.72
B


ATOM
1694
CD
GLN
B
91
−34.471
31.656
−39.068
1.00
49.14
B


ATOM
1695
OE1
GLN
B
91
−34.568
30.634
−38.385
1.00
49.61
B


ATOM
1696
NE2
GLN
B
91
−33.669
32.660
−38.735
1.00
49.34
B


ATOM
1697
C
GLN
B
91
−38.382
33.040
−39.721
1.00
45.99
B


ATOM
1698
O
GLN
B
91
−38.042
34.204
−39.472
1.00
44.12
B


ATOM
1699
N
GLN
B
92
−39.482
32.753
−40.412
1.00
45.91
B


ATOM
1700
CA
GLN
B
92
−40.340
33.821
−40.904
1.00
47.21
B


ATOM
1701
CB
GLN
B
92
−41.514
33.244
−41.698
1.00
47.99
B


ATOM
1702
CG
GLN
B
92
−41.191
32.841
−43.123
1.00
51.32
B


ATOM
1703
CD
GLN
B
92
−42.447
32.523
−43.905
1.00
55.62
B


ATOM
1704
OE1
GLN
B
92
−43.411
33.290
−43.885
1.00
57.55
B


ATOM
1705
NE2
GLN
B
92
−42.448
31.390
−44.602
1.00
56.89
B


ATOM
1706
C
GLN
B
92
−40.873
34.654
−39.733
1.00
47.67
B


ATOM
1707
O
GLN
B
92
−41.157
35.838
−39.880
1.00
48.06
B


ATOM
1708
N
LEU
B
93
−41.011
34.017
−38.575
1.00
48.22
B


ATOM
1709
CA
LEU
B
93
−41.502
34.663
−37.366
1.00
46.33
B


ATOM
1710
CB
LEU
B
93
−41.793
33.606
−36.312
1.00
44.07
B


ATOM
1711
CG
LEU
B
93
−43.211
33.418
−35.790
1.00
42.19
B


ATOM
1712
CD1
LEU
B
93
−44.271
33.719
−36.855
1.00
40.20
B


ATOM
1713
CD2
LEU
B
93
−43.303
31.992
−35.296
1.00
38.45
B


ATOM
1714
C
LEU
B
93
−40.454
35.629
−36.848
1.00
47.84
B


ATOM
1715
O
LEU
B
93
−40.772
36.740
−36.439
1.00
47.68
B


ATOM
1716
N
ASN
B
94
−39.196
35.201
−36.857
1.00
49.68
B


ATOM
1717
CA
ASN
B
94
−38.118
36.067
−36.396
1.00
50.86
B


ATOM
1718
CB
ASN
B
94
−36.797
35.295
−36.302
1.00
49.93
B


ATOM
1719
CG
ASN
B
94
−36.741
34.372
−35.097
1.00
49.12
B


ATOM
1720
OD1
ASN
B
94
−37.613
34.402
−34.228
1.00
48.85
B


ATOM
1721
ND2
ASN
B
94
−35.699
33.555
−35.035
1.00
50.25
B


ATOM
1722
C
ASN
B
94
−37.957
37.256
−37.339
1.00
52.00
B


ATOM
1723
O
ASN
B
94
−37.673
38.362
−36.902
1.00
52.28
B


ATOM
1724
N
ASP
B
95
−38.144
37.038
−38.635
1.00
54.31
B


ATOM
1725
CA
ASP
B
95
−38.016
38.147
−39.574
1.00
55.94
B


ATOM
1726
CB
ASP
B
95
−38.055
37.651
−41.021
1.00
56.73
B


ATOM
1727
CG
ASP
B
95
−36.892
36.737
−41.344
1.00
59.74
B


ATOM
1728
OD1
ASP
B
95
−35.823
36.923
−40.721
1.00
60.29
B


ATOM
1729
OD2
ASP
B
95
−37.037
35.844
−42.216
1.00
60.62
B


ATOM
1730
C
ASP
B
95
−39.114
39.167
−39.340
1.00
55.97
B


ATOM
1731
O
ASP
B
95
−38.849
40.357
−39.328
1.00
55.88
B


ATOM
1732
N
LEU
B
96
−40.343
38.701
−39.145
1.00
57.37
B


ATOM
1733
CA
LEU
B
96
−41.460
39.602
−38.898
1.00
59.48
B


ATOM
1734
CB
LEU
B
96
−42.762
38.813
−38.735
1.00
57.57
B


ATOM
1735
CG
LEU
B
96
−43.302
38.114
−39.984
1.00
56.36
B


ATOM
1736
CD1
LEU
B
96
−44.553
37.313
−39.654
1.00
53.91
B


ATOM
1737
CD2
LEU
B
96
−43.607
39.163
−41.034
1.00
57.46
B


ATOM
1738
C
LEU
B
96
−41.201
40.436
−37.644
1.00
62.45
B


ATOM
1739
O
LEU
B
96
−41.511
41.628
−37.601
1.00
62.77
B


ATOM
1740
N
GLU
B
97
−40.628
39.812
−36.622
1.00
65.05
B


ATOM
1741
CA
GLU
B
97
−40.338
40.528
−35.392
1.00
68.23
B


ATOM
1742
CB
GLU
B
97
−39.952
39.540
−34.277
1.00
68.89
B


ATOM
1743
CG
GLU
B
97
−41.097
38.626
−33.830
1.00
71.87
B


ATOM
1744
CD
GLU
B
97
−40.668
37.539
−32.849
1.00
73.15
B


ATOM
1745
OE1
GLU
B
97
−40.181
37.886
−31.756
1.00
76.25
B


ATOM
1746
OE2
GLU
B
97
−40.820
36.337
−33.164
1.00
72.83
B


ATOM
1747
C
GLU
B
97
−39.214
41.532
−35.651
1.00
70.40
B


ATOM
1748
O
GLU
B
97
−39.135
42.571
−34.998
1.00
71.54
B


ATOM
1749
N
ALA
B
98
−38.349
41.229
−36.614
1.00
73.00
B


ATOM
1750
CA
ALA
B
98
−37.248
42.128
−36.952
1.00
75.20
B


ATOM
1751
CB
ALA
B
98
−36.322
41.474
−37.970
1.00
75.82
B


ATOM
1752
C
ALA
B
98
−37.808
43.423
−37.523
1.00
76.99
B


ATOM
1753
O
ALA
B
98
−37.160
44.467
−37.448
1.00
77.06
B


ATOM
1754
N
CYS
B
99
−39.015
43.337
−38.088
1.00
79.24
B


ATOM
1755
CA
CYS
B
99
−39.711
44.478
−38.691
1.00
81.14
B


ATOM
1756
CB
CYS
B
99
−40.765
44.002
−39.695
1.00
81.56
B


ATOM
1757
SG
CYS
B
99
−40.126
43.247
−41.210
1.00
84.65
B


ATOM
1758
C
CYS
B
99
−40.397
45.359
−37.658
1.00
82.14
B


ATOM
1759
O
CYS
B
99
−40.290
46.582
−37.715
1.00
82.34
B


ATOM
1760
N
VAL
B
100
−41.116
44.740
−36.725
1.00
83.70
B


ATOM
1761
CA
VAL
B
100
−41.814
45.493
−35.684
1.00
85.68
B


ATOM
1762
CB
VAL
B
100
−42.619
44.556
−34.740
1.00
85.07
B


ATOM
1763
CG1
VAL
B
100
−41.688
43.602
−34.020
1.00
84.36
B


ATOM
1764
CG2
VAL
B
100
−43.405
45.381
−33.741
1.00
85.62
B


ATOM
1765
C
VAL
B
100
−40.801
46.287
−34.863
1.00
87.06
B


ATOM
1766
O
VAL
B
100
−41.162
47.202
−34.115
1.00
87.20
B


ATOM
1767
N
ALA
B
101
−39.529
45.927
−35.023
1.00
88.22
B


ATOM
1768
CA
ALA
B
101
−38.434
46.582
−34.323
1.00
89.09
B


ATOM
1769
CB
ALA
B
101
−37.497
45.533
−33.730
1.00
88.54
B


ATOM
1770
C
ALA
B
101
−37.666
47.498
−35.276
1.00
89.84
B


ATOM
1771
O
ALA
B
101
−37.324
48.626
−34.925
1.00
90.61
B


ATOM
1772
N
GLY
B
102
−37.401
47.010
−36.484
1.00
90.46
B


ATOM
1773
CA
GLY
B
102
−36.678
47.808
−37.457
1.00
91.07
B


ATOM
1774
C
GLY
B
102
−37.577
48.761
−38.223
1.00
92.05
B


ATOM
1775
O
GLY
B
102
−37.266
49.135
−39.351
1.00
92.33
B


ATOM
1776
N
GLY
B
103
−38.692
49.157
−37.612
1.00
92.84
B


ATOM
1777
CA
GLY
B
103
−39.616
50.069
−38.266
1.00
92.74
B


ATOM
1778
C
GLY
B
103
−40.887
50.291
−37.465
1.00
92.62
B


ATOM
1779
O
GLY
B
103
−41.047
51.321
−36.807
1.00
92.47
B


ATOM
1780
N
ALA
B
111
−51.414
47.696
−31.869
1.00
93.96
B


ATOM
1781
CA
ALA
B
111
−51.666
47.368
−33.267
1.00
93.85
B


ATOM
1782
CB
ALA
B
111
−51.378
45.889
−33.516
1.00
92.71
B


ATOM
1783
C
ALA
B
111
−53.105
47.697
−33.661
1.00
93.95
B


ATOM
1784
O
ALA
B
111
−53.906
46.792
−33.916
1.00
94.29
B


ATOM
1785
N
GLY
B
112
−53.424
48.993
−33.708
1.00
92.98
B


ATOM
1786
CA
GLY
B
112
−54.760
49.429
−34.080
1.00
91.20
B


ATOM
1787
C
GLY
B
112
−55.854
48.615
−33.416
1.00
90.66
B


ATOM
1788
O
GLY
B
112
−56.271
48.924
−32.298
1.00
91.11
B


ATOM
1789
N
ASN
B
113
−56.328
47.575
−34.101
1.00
88.98
B


ATOM
1790
CA
ASN
B
113
−57.368
46.715
−33.546
1.00
86.63
B


ATOM
1791
CB
ASN
B
113
−58.702
46.922
−34.275
1.00
88.02
B


ATOM
1792
CG
ASN
B
113
−58.597
46.693
−35.770
1.00
88.87
B


ATOM
1793
OD1
ASN
B
113
−57.973
45.729
−36.226
1.00
88.93
B


ATOM
1794
ND2
ASN
B
113
−59.225
47.573
−36.545
1.00
89.31
B


ATOM
1795
C
ASN
B
113
−56.988
45.237
−33.586
1.00
84.10
B


ATOM
1796
O
ASN
B
113
−56.396
44.750
−34.559
1.00
82.68
B


ATOM
1797
N
ALA
B
114
−57.333
44.538
−32.507
1.00
80.69
B


ATOM
1798
CA
ALA
B
114
−57.053
43.117
−32.365
1.00
77.04
B


ATOM
1799
CB
ALA
B
114
−57.060
42.734
−30.885
1.00
74.97
B


ATOM
1800
C
ALA
B
114
−58.094
42.307
−33.129
1.00
75.04
B


ATOM
1801
O
ALA
B
114
−58.167
41.092
−32.987
1.00
75.09
B


ATOM
1802
N
ASP
B
115
−58.898
42.993
−33.935
1.00
73.04
B


ATOM
1803
CA
ASP
B
115
−59.940
42.354
−34.739
1.00
71.39
B


ATOM
1804
CB
ASP
B
115
−60.755
43.408
−35.493
1.00
75.02
B


ATOM
1805
CG
ASP
B
115
−61.440
44.387
−34.573
1.00
77.51
B


ATOM
1806
OD1
ASP
B
115
−61.719
45.520
−35.022
1.00
77.99
B


ATOM
1807
OD2
ASP
B
115
−61.707
44.019
−33.408
1.00
80.45
B


ATOM
1808
C
ASP
B
115
−59.318
41.429
−35.766
1.00
68.05
B


ATOM
1809
O
ASP
B
115
−59.626
40.245
−35.834
1.00
67.22
B


ATOM
1810
N
SER
B
116
−58.451
42.002
−36.585
1.00
65.47
B


ATOM
1811
CA
SER
B
116
−57.775
41.259
−37.628
1.00
62.95
B


ATOM
1812
CB
SER
B
116
−56.707
42.137
−38.277
1.00
63.58
B


ATOM
1813
OG
SER
B
116
−57.268
43.350
−38.753
1.00
63.46
B


ATOM
1814
C
SER
B
116
−57.140
39.998
−37.062
1.00
61.42
B


ATOM
1815
O
SER
B
116
−57.296
38.917
−37.626
1.00
62.05
B


ATOM
1816
N
ILE
B
117
−56.430
40.137
−35.946
1.00
58.31
B


ATOM
1817
CA
ILE
B
117
−55.772
38.999
−35.313
1.00
54.83
B


ATOM
1818
CB
ILE
B
117
−54.966
39.423
−34.076
1.00
53.03
B


ATOM
1819
CG2
ILE
B
117
−54.366
38.202
−33.414
1.00
51.47
B


ATOM
1820
CG1
ILE
B
117
−53.871
40.404
−34.477
1.00
52.17
B


ATOM
1821
CD1
ILE
B
117
−53.280
41.161
−33.307
1.00
50.94
B


ATOM
1822
C
ILE
B
117
−56.772
37.944
−34.870
1.00
54.11
B


ATOM
1823
O
ILE
B
117
−56.565
36.761
−35.091
1.00
56.60
B


ATOM
1824
N
LEU
B
118
−57.854
38.370
−34.235
1.00
52.88
B


ATOM
1825
CA
LEU
B
118
−58.862
37.430
−33.766
1.00
50.60
B


ATOM
1826
CB
LEU
B
118
−59.955
38.167
−32.984
1.00
51.65
B


ATOM
1827
CG
LEU
B
118
−61.046
37.271
−32.391
1.00
54.03
B


ATOM
1828
CD1
LEU
B
118
−60.591
36.760
−31.040
1.00
54.61
B


ATOM
1829
CD2
LEU
B
118
−62.343
38.044
−32.249
1.00
53.11
B


ATOM
1830
C
LEU
B
118
−59.470
36.716
−34.966
1.00
49.21
B


ATOM
1831
O
LEU
B
118
−59.797
35.534
−34.900
1.00
47.90
B


ATOM
1832
N
ALA
B
119
−59.611
37.436
−36.072
1.00
48.72
B


ATOM
1833
CA
ALA
B
119
−60.183
36.852
−37.278
1.00
49.24
B


ATOM
1834
CB
ALA
B
119
−60.323
37.916
−38.343
1.00
48.04
B


ATOM
1835
C
ALA
B
119
−59.339
35.674
−37.793
1.00
50.65
B


ATOM
1836
O
ALA
B
119
−59.884
34.667
−38.270
1.00
51.27
B


ATOM
1837
N
VAL
B
120
−58.016
35.795
−37.691
1.00
49.50
B


ATOM
1838
CA
VAL
B
120
−57.130
34.727
−38.130
1.00
50.37
B


ATOM
1839
CB
VAL
B
120
−55.657
35.188
−38.178
1.00
49.79
B


ATOM
1840
CG1
VAL
B
120
−54.746
33.979
−38.348
1.00
47.60
B


ATOM
1841
CG2
VAL
B
120
−55.455
36.190
−39.315
1.00
47.48
B


ATOM
1842
C
VAL
B
120
−57.235
33.546
−37.170
1.00
52.26
B


ATOM
1843
O
VAL
B
120
−57.177
32.377
−37.582
1.00
51.97
B


ATOM
1844
N
LYS
B
121
−57.382
33.855
−35.883
1.00
53.62
B


ATOM
1845
CA
LYS
B
121
−57.501
32.811
−34.875
1.00
54.59
B


ATOM
1846
CB
LYS
B
121
−57.508
33.413
−33.475
1.00
54.64
B


ATOM
1847
CG
LYS
B
121
−56.148
33.911
−33.017
1.00
58.06
B


ATOM
1848
CD
LYS
B
121
−56.232
34.584
−31.650
1.00
60.35
B


ATOM
1849
CE
LYS
B
121
−54.864
35.021
−31.140
1.00
60.35
B


ATOM
1850
NZ
LYS
B
121
−53.990
33.861
−30.842
1.00
61.51
B


ATOM
1851
C
LYS
B
121
−58.769
32.005
−35.108
1.00
55.58
B


ATOM
1852
O
LYS
B
121
−58.744
30.780
−35.065
1.00
55.57
B


ATOM
1853
N
LYS
B
122
−59.876
32.689
−35.378
1.00
56.77
B


ATOM
1854
CA
LYS
B
122
−61.140
31.997
−35.618
1.00
58.18
B


ATOM
1855
CB
LYS
B
122
−62.275
33.014
−35.811
1.00
60.88
B


ATOM
1856
CG
LYS
B
122
−62.628
33.807
−34.545
1.00
63.85
B


ATOM
1857
CD
LYS
B
122
−63.785
34.770
−34.784
1.00
67.04
B


ATOM
1858
CE
LYS
B
122
−65.079
34.020
−35.089
1.00
70.23
B


ATOM
1859
NZ
LYS
B
122
−66.260
34.925
−35.259
1.00
71.84
B


ATOM
1860
C
LYS
B
122
−61.036
31.078
−36.835
1.00
57.34
B


ATOM
1861
O
LYS
B
122
−61.588
29.975
−36.846
1.00
57.39
B


ATOM
1862
N
TYR
B
123
−60.316
31.540
−37.852
1.00
55.98
B


ATOM
1863
CA
TYR
B
123
−60.117
30.774
−39.080
1.00
54.34
B


ATOM
1864
CB
TYR
B
123
−59.252
31.593
−40.050
1.00
54.18
B


ATOM
1865
CG
TYR
B
123
−58.689
30.830
−41.226
1.00
53.30
B


ATOM
1866
CD1
TYR
B
123
−59.524
30.175
−42.130
1.00
53.39
B


ATOM
1867
CE1
TYR
B
123
−59.001
29.474
−43.217
1.00
53.48
B


ATOM
1868
CD2
TYR
B
123
−57.315
30.767
−41.436
1.00
53.09
B


ATOM
1869
CE2
TYR
B
123
−56.781
30.069
−42.518
1.00
53.78
B


ATOM
1870
CZ
TYR
B
123
−57.627
29.426
−43.404
1.00
53.93
B


ATOM
1871
OH
TYR
B
123
−57.097
28.736
−44.471
1.00
52.16
B


ATOM
1872
C
TYR
B
123
−59.458
29.430
−38.773
1.00
53.07
B


ATOM
1873
O
TYR
B
123
−59.994
28.369
−39.100
1.00
51.67
B


ATOM
1874
N
PHE
B
124
−58.296
29.487
−38.133
1.00
52.86
B


ATOM
1875
CA
PHE
B
124
−57.555
28.283
−37.775
1.00
53.45
B


ATOM
1876
CB
PHE
B
124
−56.200
28.665
−37.186
1.00
50.18
B


ATOM
1877
CG
PHE
B
124
−55.177
29.018
−38.228
1.00
48.40
B


ATOM
1878
CD1
PHE
B
124
−54.460
28.019
−38.880
1.00
43.87
B


ATOM
1879
CD2
PHE
B
124
−54.958
30.345
−38.590
1.00
46.73
B


ATOM
1880
CE1
PHE
B
124
−53.553
28.327
−39.865
1.00
41.12
B


ATOM
1881
CE2
PHE
B
124
−54.040
30.659
−39.587
1.00
44.49
B


ATOM
1882
CZ
PHE
B
124
−53.338
29.641
−40.223
1.00
41.38
B


ATOM
1883
C
PHE
B
124
−58.336
27.440
−36.796
1.00
55.05
B


ATOM
1884
O
PHE
B
124
−58.134
26.234
−36.695
1.00
54.37
B


ATOM
1885
N
GLN
B
125
−59.238
28.094
−36.076
1.00
59.25
B


ATOM
1886
CA
GLN
B
125
−60.081
27.421
−35.106
1.00
60.57
B


ATOM
1887
CB
GLN
B
125
−60.883
28.445
−34.307
1.00
64.50
B


ATOM
1888
CG
GLN
B
125
−61.759
27.839
−33.227
1.00
70.78
B


ATOM
1889
CD
GLN
B
125
−60.960
27.038
−32.212
1.00
74.51
B


ATOM
1890
OE1
GLN
B
125
−60.071
27.575
−31.540
1.00
76.71
B


ATOM
1891
NE2
GLN
B
125
−61.272
25.744
−32.095
1.00
75.37
B


ATOM
1892
C
GLN
B
125
−61.014
26.525
−35.894
1.00
59.74
B


ATOM
1893
O
GLN
B
125
−61.124
25.336
−35.608
1.00
60.48
B


ATOM
1894
N
ARG
B
126
−61.672
27.096
−36.901
1.00
58.55
B


ATOM
1895
CA
ARG
B
126
−62.591
26.332
−37.740
1.00
58.45
B


ATOM
1896
CB
ARG
B
126
−63.192
27.230
−38.819
1.00
58.22
B


ATOM
1897
CG
ARG
B
126
−64.322
28.135
−38.334
1.00
56.82
B


ATOM
1898
CD
ARG
B
126
−64.632
29.227
−39.348
1.00
55.96
B


ATOM
1899
NE
ARG
B
126
−64.100
30.523
−38.925
1.00
56.75
B


ATOM
1900
CZ
ARG
B
126
−63.490
31.379
−39.738
1.00
57.05
B


ATOM
1901
NH1
ARG
B
126
−63.333
31.072
−41.013
1.00
56.86
B


ATOM
1902
NH2
ARG
B
126
−63.039
32.541
−39.282
1.00
57.49
B


ATOM
1903
C
ARG
B
126
−61.874
25.151
−38.384
1.00
59.08
B


ATOM
1904
O
ARG
B
126
−62.406
24.043
−38.425
1.00
58.89
B


ATOM
1905
N
ILE
B
127
−60.667
25.396
−38.888
1.00
59.70
B


ATOM
1906
CA
ILE
B
127
−59.862
24.351
−39.514
1.00
59.95
B


ATOM
1907
CB
ILE
B
127
−58.472
24.891
−39.914
1.00
59.73
B


ATOM
1908
CG2
ILE
B
127
−57.508
23.745
−40.190
1.00
57.13
B


ATOM
1909
CG1
ILE
B
127
−58.609
25.809
−41.126
1.00
60.37
B


ATOM
1910
CD1
ILE
B
127
−57.338
26.563
−41.468
1.00
62.06
B


ATOM
1911
C
ILE
B
127
−59.675
23.199
−38.538
1.00
60.89
B


ATOM
1912
O
ILE
B
127
−59.904
22.041
−38.884
1.00
60.80
B


ATOM
1913
N
THR
B
128
−59.264
23.543
−37.319
1.00
61.84
B


ATOM
1914
CA
THR
B
128
−59.012
22.583
−36.241
1.00
63.43
B


ATOM
1915
CB
THR
B
128
−58.598
23.320
−34.940
1.00
64.67
B


ATOM
1916
OG1
THR
B
128
−57.481
24.172
−35.212
1.00
67.07
B


ATOM
1917
CG2
THR
B
128
−58.204
22.331
−33.853
1.00
65.28
B


ATOM
1918
C
THR
B
128
−60.209
21.690
−35.918
1.00
63.22
B


ATOM
1919
O
THR
B
128
−60.045
20.515
−35.585
1.00
61.95
B


ATOM
1920
N
LEU
B
129
−61.407
22.256
−36.008
1.00
64.24
B


ATOM
1921
CA
LEU
B
129
−62.630
21.524
−35.716
1.00
66.29
B


ATOM
1922
CB
LEU
B
129
−63.771
22.505
−35.454
1.00
66.59
B


ATOM
1923
CG
LEU
B
129
−64.722
22.138
−34.313
1.00
67.84
B


ATOM
1924
CD1
LEU
B
129
−65.736
23.255
−34.140
1.00
67.06
B


ATOM
1925
CD2
LEU
B
129
−65.409
20.796
−34.595
1.00
67.62
B


ATOM
1926
C
LEU
B
129
−62.986
20.619
−36.886
1.00
68.37
B


ATOM
1927
O
LEU
B
129
−63.672
19.613
−36.720
1.00
70.05
B


ATOM
1928
N
TYR
B
130
−62.530
20.994
−38.077
1.00
69.17
B


ATOM
1929
CA
TYR
B
130
−62.780
20.208
−39.273
1.00
68.74
B


ATOM
1930
CB
TYR
B
130
−62.296
20.973
−40.507
1.00
69.94
B


ATOM
1931
CG
TYR
B
130
−62.397
20.200
−41.803
1.00
71.43
B


ATOM
1932
CD1
TYR
B
130
−63.627
19.990
−42.425
1.00
71.95
B


ATOM
1933
CE1
TYR
B
130
−63.719
19.273
−43.624
1.00
72.25
B


ATOM
1934
CD2
TYR
B
130
−61.258
19.671
−42.409
1.00
72.21
B


ATOM
1935
CE2
TYR
B
130
−61.340
18.950
−43.607
1.00
72.56
B


ATOM
1936
CZ
TYR
B
130
−62.571
18.756
−44.207
1.00
72.07
B


ATOM
1937
OH
TYR
B
130
−62.649
18.044
−45.383
1.00
71.77
B


ATOM
1938
C
TYR
B
130
−61.996
18.911
−39.115
1.00
69.00
B


ATOM
1939
O
TYR
B
130
−62.556
17.821
−39.175
1.00
68.44
B


ATOM
1940
N
LEU
B
131
−60.691
19.044
−38.896
1.00
68.64
B


ATOM
1941
CA
LEU
B
131
−59.821
17.890
−38.724
1.00
68.04
B


ATOM
1942
CB
LEU
B
131
−58.422
18.345
−38.310
1.00
66.02
B


ATOM
1943
CG
LEU
B
131
−57.471
18.856
−39.391
1.00
65.04
B


ATOM
1944
CD1
LEU
B
131
−56.264
19.481
−38.719
1.00
63.94
B


ATOM
1945
CD2
LEU
B
131
−57.043
17.716
−40.313
1.00
63.38
B


ATOM
1946
C
LEU
B
131
−60.347
16.891
−37.698
1.00
68.93
B


ATOM
1947
O
LEU
B
131
−60.523
15.714
−38.006
1.00
68.61
B


ATOM
1948
N
THR
B
132
−60.594
17.363
−36.478
1.00
70.61
B


ATOM
1949
CA
THR
B
132
−61.083
16.495
−35.406
1.00
71.92
B


ATOM
1950
CB
THR
B
132
−60.841
17.131
−34.008
1.00
71.89
B


ATOM
1951
OG1
THR
B
132
−61.250
16.214
−32.987
1.00
70.43
B


ATOM
1952
CG2
THR
B
132
−61.623
18.429
−33.860
1.00
72.59
B


ATOM
1953
C
THR
B
132
−62.565
16.161
−35.562
1.00
72.74
B


ATOM
1954
O
THR
B
132
−63.170
15.549
−34.683
1.00
73.16
B


ATOM
1955
N
GLY
B
133
−63.141
16.576
−36.687
1.00
73.71
B


ATOM
1956
CA
GLY
B
133
−64.539
16.301
−36.968
1.00
73.91
B


ATOM
1957
C
GLY
B
133
−64.582
15.208
−38.019
1.00
74.32
B


ATOM
1958
O
GLY
B
133
−65.606
14.556
−38.236
1.00
74.32
B


ATOM
1959
N
LYS
B
134
−63.442
15.015
−38.676
1.00
74.07
B


ATOM
1960
CA
LYS
B
134
−63.296
14.001
−39.708
1.00
73.57
B


ATOM
1961
CB
LYS
B
134
−62.847
14.629
−41.028
1.00
72.93
B


ATOM
1962
CG
LYS
B
134
−63.976
14.926
−42.004
1.00
73.33
B


ATOM
1963
CD
LYS
B
134
−64.905
16.035
−41.525
1.00
74.01
B


ATOM
1964
CE
LYS
B
134
−65.972
16.349
−42.583
1.00
74.15
B


ATOM
1965
NZ
LYS
B
134
−66.745
17.600
−42.317
1.00
72.79
B


ATOM
1966
C
LYS
B
134
−62.282
12.962
−39.262
1.00
73.93
B


ATOM
1967
O
LYS
B
134
−61.676
12.278
−40.082
1.00
72.76
B


ATOM
1968
N
LYS
B
135
−62.093
12.867
−37.951
1.00
75.07
B


ATOM
1969
CA
LYS
B
135
−61.184
11.890
−37.367
1.00
76.77
B


ATOM
1970
CB
LYS
B
135
−61.808
10.496
−37.485
1.00
77.37
B


ATOM
1971
CG
LYS
B
135
−63.245
10.428
−36.990
1.00
78.83
B


ATOM
1972
CD
LYS
B
135
−63.856
9.057
−37.231
1.00
81.28
B


ATOM
1973
CE
LYS
B
135
−63.278
8.000
−36.295
1.00
83.54
B


ATOM
1974
NZ
LYS
B
135
−63.708
8.200
−34.876
1.00
84.34
B


ATOM
1975
C
LYS
B
135
−59.773
11.878
−37.967
1.00
77.31
B


ATOM
1976
O
LYS
B
135
−59.174
10.815
−38.135
1.00
78.04
B


ATOM
1977
N
TYR
B
136
−59.246
13.056
−38.283
1.00
77.23
B


ATOM
1978
CA
TYR
B
136
−57.902
13.181
−38.845
1.00
76.63
B


ATOM
1979
CB
TYR
B
136
−56.861
12.989
−37.748
1.00
78.09
B


ATOM
1980
CG
TYR
B
136
−57.053
13.907
−36.564
1.00
82.10
B


ATOM
1981
CD1
TYR
B
136
−58.076
13.685
−35.638
1.00
83.03
B


ATOM
1982
CE1
TYR
B
136
−58.244
14.522
−34.529
1.00
84.37
B


ATOM
1983
CD2
TYR
B
136
−56.204
14.992
−36.359
1.00
83.46
B


ATOM
1984
CE2
TYR
B
136
−56.362
15.837
−35.255
1.00
85.30
B


ATOM
1985
CZ
TYR
B
136
−57.382
15.596
−34.341
1.00
85.81
B


ATOM
1986
OH
TYR
B
136
−57.524
16.419
−33.237
1.00
85.88
B


ATOM
1987
C
TYR
B
136
−57.615
12.202
−39.980
1.00
75.70
B


ATOM
1988
O
TYR
B
136
−56.528
11.625
−40.057
1.00
74.43
B


ATOM
1989
N
SER
B
137
−58.592
12.039
−40.867
1.00
75.24
B


ATOM
1990
CA
SER
B
137
−58.477
11.131
−42.001
1.00
74.25
B


ATOM
1991
CB
SER
B
137
−59.860
10.845
−42.580
1.00
73.68
B


ATOM
1992
OG
SER
B
137
−60.451
12.033
−43.072
1.00
73.31
B


ATOM
1993
C
SER
B
137
−57.578
11.668
−43.106
1.00
74.57
B


ATOM
1994
O
SER
B
137
−57.476
12.880
−43.312
1.00
73.85
B


ATOM
1995
N
PRO
B
138
−56.921
10.758
−43.842
1.00
74.56
B


ATOM
1996
CD
PRO
B
138
−56.984
9.296
−43.668
1.00
74.19
B


ATOM
1997
CA
PRO
B
138
−56.021
11.103
−44.940
1.00
74.13
B


ATOM
1998
CB
PRO
B
138
−55.832
9.771
−45.643
1.00
73.66
B


ATOM
1999
CG
PRO
B
138
−55.810
8.822
−44.486
1.00
73.91
B


ATOM
2000
C
PRO
B
138
−56.579
12.177
−45.859
1.00
74.15
B


ATOM
2001
O
PRO
B
138
−55.832
13.016
−46.362
1.00
74.48
B


ATOM
2002
N
CYS
B
139
−57.887
12.156
−46.081
1.00
74.19
B


ATOM
2003
CA
CYS
B
139
−58.488
13.163
−46.943
1.00
75.46
B


ATOM
2004
C
CYS
B
139
−58.702
14.457
−46.178
1.00
74.04
B


ATOM
2005
O
CYS
B
139
−58.472
15.545
−46.705
1.00
73.77
B


ATOM
2006
CB
CYS
B
139
−59.814
12.665
−47.538
1.00
79.16
B


ATOM
2007
SG
CYS
B
139
−59.600
11.373
−48.809
1.00
82.68
B


ATOM
2008
N
ALA
B
140
−59.136
14.342
−44.930
1.00
72.55
B


ATOM
2009
CA
ALA
B
140
−59.346
15.529
−44.115
1.00
71.12
B


ATOM
2010
CB
ALA
B
140
−59.704
15.128
−42.704
1.00
71.98
B


ATOM
2011
C
ALA
B
140
−58.063
16.364
−44.117
1.00
70.40
B


ATOM
2012
O
ALA
B
140
−58.104
17.576
−44.354
1.00
70.21
B


ATOM
2013
N
TRP
B
141
−56.929
15.706
−43.862
1.00
68.06
B


ATOM
2014
CA
TRP
B
141
−55.630
16.379
−43.839
1.00
66.09
B


ATOM
2015
CB
TRP
B
141
−54.511
15.405
−43.429
1.00
65.31
B


ATOM
2016
CG
TRP
B
141
−54.188
15.447
−41.954
1.00
64.66
B


ATOM
2017
CD2
TRP
B
141
−53.698
16.570
−41.215
1.00
63.91
B


ATOM
2018
CE2
TRP
B
141
−53.587
16.171
−39.868
1.00
63.61
B


ATOM
2019
CE3
TRP
B
141
−53.333
17.879
−41.564
1.00
63.30
B


ATOM
2020
CD1
TRP
B
141
−54.351
14.438
−41.046
1.00
64.31
B


ATOM
2021
NE1
TRP
B
141
−53.995
14.864
−39.793
1.00
63.47
B


ATOM
2022
CZ2
TRP
B
141
−53.140
17.031
−38.864
1.00
63.01
B


ATOM
2023
CZ3
TRP
B
141
−52.887
18.735
−40.566
1.00
63.15
B


ATOM
2024
CH2
TRP
B
141
−52.792
18.305
−39.231
1.00
62.58
B


ATOM
2025
C
TRP
B
141
−55.293
16.999
−45.190
1.00
65.08
B


ATOM
2026
O
TRP
B
141
−54.775
18.118
−45.263
1.00
64.05
B


ATOM
2027
N
GLU
B
142
−55.592
16.268
−46.259
1.00
63.17
B


ATOM
2028
CA
GLU
B
142
−55.324
16.750
−47.603
1.00
60.88
B


ATOM
2029
CB
GLU
B
142
−55.801
15.725
−48.635
1.00
59.86
B


ATOM
2030
CG
GLU
B
142
−55.595
16.126
−50.094
1.00
58.69
B


ATOM
2031
CD
GLU
B
142
−54.176
16.583
−50.414
1.00
57.82
B


ATOM
2032
OE1
GLU
B
142
−53.198
15.912
−50.004
1.00
58.06
B


ATOM
2033
OE2
GLU
B
142
−54.045
17.617
−51.096
1.00
54.99
B


ATOM
2034
C
GLU
B
142
−56.005
18.092
−47.825
1.00
60.14
B


ATOM
2035
O
GLU
B
142
−55.367
19.042
−48.265
1.00
61.06
B


ATOM
2036
N
VAL
B
143
−57.288
18.184
−47.505
1.00
58.83
B


ATOM
2037
CA
VAL
B
143
−58.006
19.437
−47.692
1.00
60.46
B


ATOM
2038
CB
VAL
B
143
−59.473
19.312
−47.217
1.00
63.38
B


ATOM
2039
CG1
VAL
B
143
−60.189
20.652
−47.353
1.00
64.93
B


ATOM
2040
CG2
VAL
B
143
−60.194
18.259
−48.044
1.00
62.82
B


ATOM
2041
C
VAL
B
143
−57.324
20.584
−46.937
1.00
60.05
B


ATOM
2042
O
VAL
B
143
−57.199
21.703
−47.453
1.00
60.09
B


ATOM
2043
N
VAL
B
144
−56.881
20.301
−45.716
1.00
58.84
B


ATOM
2044
CA
VAL
B
144
−56.207
21.307
−44.905
1.00
56.80
B


ATOM
2045
CB
VAL
B
144
−55.901
20.779
−43.475
1.00
56.37
B


ATOM
2046
CG1
VAL
B
144
−54.933
21.720
−42.756
1.00
53.83
B


ATOM
2047
CG2
VAL
B
144
−57.195
20.655
−42.688
1.00
53.78
B


ATOM
2048
C
VAL
B
144
−54.907
21.723
−45.570
1.00
55.71
B


ATOM
2049
O
VAL
B
144
−54.580
22.907
−45.619
1.00
56.30
B


ATOM
2050
N
ARG
B
145
−54.166
20.748
−46.083
1.00
54.57
B


ATOM
2051
CA
ARG
B
145
−52.904
21.039
−46.746
1.00
53.98
B


ATOM
2052
CB
ARG
B
145
−52.290
19.755
−47.301
1.00
54.48
B


ATOM
2053
CG
ARG
B
145
−50.776
19.805
−47.398
1.00
57.53
B


ATOM
2054
CD
ARG
B
145
−50.189
18.656
−48.226
1.00
59.32
B


ATOM
2055
NE
ARG
B
145
−50.007
19.028
−49.627
1.00
60.85
B


ATOM
2056
CZ
ARG
B
145
−51.000
19.146
−50.497
1.00
61.21
B


ATOM
2057
NH1
ARG
B
145
−52.245
18.912
−50.113
1.00
63.40
B


ATOM
2058
NH2
ARG
B
145
−50.750
19.516
−51.741
1.00
61.96
B


ATOM
2059
C
ARG
B
145
−53.163
22.034
−47.884
1.00
53.44
B


ATOM
2060
O
ARG
B
145
−52.508
23.072
−47.982
1.00
51.98
B


ATOM
2061
N
ALA
B
146
−54.141
21.724
−48.729
1.00
52.37
B


ATOM
2062
CA
ALA
B
146
−54.474
22.596
−49.844
1.00
52.73
B


ATOM
2063
CB
ALA
B
146
−55.476
21.927
−50.752
1.00
53.23
B


ATOM
2064
C
ALA
B
146
−55.013
23.937
−49.375
1.00
52.70
B


ATOM
2065
O
ALA
B
146
−54.678
24.964
−49.964
1.00
53.35
B


ATOM
2066
N
GLU
B
147
−55.841
23.937
−48.328
1.00
52.05
B


ATOM
2067
CA
GLU
B
147
−56.401
25.191
−47.799
1.00
51.29
B


ATOM
2068
CB
GLU
B
147
−57.351
24.913
−46.626
1.00
52.80
B


ATOM
2069
CG
GLU
B
147
−57.846
26.161
−45.865
1.00
56.59
B


ATOM
2070
CD
GLU
B
147
−58.780
27.066
−46.685
1.00
60.42
B


ATOM
2071
OE1
GLU
B
147
−59.760
26.554
−47.274
1.00
63.21
B


ATOM
2072
OE2
GLU
B
147
−58.546
28.294
−46.732
1.00
61.56
B


ATOM
2073
C
GLU
B
147
−55.295
26.129
−47.325
1.00
50.23
B


ATOM
2074
O
GLU
B
147
−55.338
27.332
−47.575
1.00
48.90
B


ATOM
2075
N
ILE
B
148
−54.308
25.561
−46.638
1.00
49.88
B


ATOM
2076
CA
ILE
B
148
−53.187
26.320
−46.099
1.00
48.21
B


ATOM
2077
CB
ILE
B
148
−52.368
25.443
−45.110
1.00
47.14
B


ATOM
2078
CG2
ILE
B
148
−51.030
26.118
−44.755
1.00
44.12
B


ATOM
2079
CG1
ILE
B
148
−53.223
25.162
−43.870
1.00
44.09
B


ATOM
2080
CD1
ILE
B
148
−53.734
26.429
−43.164
1.00
42.93
B


ATOM
2081
C
ILE
B
148
−52.292
26.883
−47.196
1.00
48.42
B


ATOM
2082
O
ILE
B
148
−51.653
27.925
−47.014
1.00
47.29
B


ATOM
2083
N
MET
B
149
−52.243
26.199
−48.335
1.00
49.13
B


ATOM
2084
CA
MET
B
149
−51.442
26.686
−49.452
1.00
51.23
B


ATOM
2085
CB
MET
B
149
−51.230
25.600
−50.494
1.00
51.00
B


ATOM
2086
CG
MET
B
149
−49.910
24.895
−50.350
1.00
53.30
B


ATOM
2087
SD
MET
B
149
−49.527
23.955
−51.813
1.00
56.01
B


ATOM
2088
CE
MET
B
149
−50.453
22.505
−51.485
1.00
54.85
B


ATOM
2089
C
MET
B
149
−52.176
27.855
−50.082
1.00
51.95
B


ATOM
2090
O
MET
B
149
−51.568
28.851
−50.492
1.00
52.45
B


ATOM
2091
N
ARG
B
150
−53.495
27.724
−50.150
1.00
51.47
B


ATOM
2092
CA
ARG
B
150
−54.333
28.767
−50.707
1.00
52.51
B


ATOM
2093
CB
ARG
B
150
−55.790
28.312
−50.658
1.00
55.92
B


ATOM
2094
CG
ARG
B
150
−56.784
29.125
−51.454
1.00
60.87
B


ATOM
2095
CD
ARG
B
150
−58.038
28.271
−51.662
1.00
67.39
B


ATOM
2096
NE
ARG
B
150
−59.207
29.025
−52.117
1.00
73.67
B


ATOM
2097
CZ
ARG
B
150
−59.231
29.827
−53.180
1.00
76.78
B


ATOM
2098
NH1
ARG
B
150
−58.140
30.001
−53.922
1.00
78.58
B


ATOM
2099
NH2
ARG
B
150
−60.354
30.456
−53.506
1.00
77.37
B


ATOM
2100
C
ARG
B
150
−54.109
30.009
−49.851
1.00
51.57
B


ATOM
2101
O
ARG
B
150
−53.689
31.046
−50.355
1.00
52.44
B


ATOM
2102
N
SER
B
151
−54.354
29.887
−48.549
1.00
50.14
B


ATOM
2103
CA
SER
B
151
−54.168
30.999
−47.633
1.00
49.46
B


ATOM
2104
CB
SER
B
151
−54.458
30.559
−46.207
1.00
48.27
B


ATOM
2105
OG
SER
B
151
−55.742
29.986
−46.112
1.00
48.71
B


ATOM
2106
C
SER
B
151
−52.760
31.574
−47.705
1.00
50.79
B


ATOM
2107
O
SER
B
151
−52.584
32.791
−47.687
1.00
50.33
B


ATOM
2108
N
PHE
B
152
−51.749
30.716
−47.778
1.00
52.18
B


ATOM
2109
CA
PHE
B
152
−50.380
31.225
−47.861
1.00
55.34
B


ATOM
2110
CB
PHE
B
152
−49.365
30.087
−47.739
1.00
55.53
B


ATOM
2111
CG
PHE
B
152
−48.768
29.954
−46.366
1.00
54.12
B


ATOM
2112
CD1
PHE
B
152
−49.502
29.406
−45.320
1.00
54.49
B


ATOM
2113
CD2
PHE
B
152
−47.476
30.391
−46.114
1.00
53.65
B


ATOM
2114
CE1
PHE
B
152
−48.954
29.297
−44.039
1.00
53.70
B


ATOM
2115
CE2
PHE
B
152
−46.925
30.286
−44.834
1.00
55.29
B


ATOM
2116
CZ
PHE
B
152
−47.668
29.737
−43.799
1.00
53.15
B


ATOM
2117
C
PHE
B
152
−50.095
32.024
−49.145
1.00
55.94
B


ATOM
2118
O
PHE
B
152
−49.423
33.062
−49.115
1.00
54.62
B


ATOM
2119
N
ALA
B
153
−50.603
31.541
−50.271
1.00
57.38
B


ATOM
2120
CA
ALA
B
153
−50.381
32.238
−51.526
1.00
59.97
B


ATOM
2121
CB
ALA
B
153
−50.910
31.408
−52.700
1.00
59.69
B


ATOM
2122
C
ALA
B
153
−51.083
33.587
−51.460
1.00
61.25
B


ATOM
2123
O
ALA
B
153
−50.514
34.607
−51.841
1.00
62.94
B


ATOM
2124
N
LEU
B
154
−52.312
33.588
−50.953
1.00
62.12
B


ATOM
2125
CA
LEU
B
154
−53.112
34.804
−50.833
1.00
63.13
B


ATOM
2126
CB
LEU
B
154
−54.510
34.437
−50.340
1.00
60.76
B


ATOM
2127
CG
LEU
B
154
−55.360
33.639
−51.331
1.00
59.42
B


ATOM
2128
CD1
LEU
B
154
−56.627
33.136
−50.660
1.00
58.68
B


ATOM
2129
CD2
LEU
B
154
−55.698
34.523
−52.513
1.00
57.64
B


ATOM
2130
C
LEU
B
154
−52.518
35.899
−49.932
1.00
65.86
B


ATOM
2131
O
LEU
B
154
−52.951
37.052
−49.982
1.00
65.99
B


ATOM
2132
N
SER
B
155
−51.525
35.546
−49.121
1.00
68.63
B


ATOM
2133
CA
SER
B
155
−50.899
36.509
−48.219
1.00
71.66
B


ATOM
2134
CB
SER
B
155
−50.675
35.871
−46.845
1.00
71.59
B


ATOM
2135
OG
SER
B
155
−49.726
34.820
−46.920
1.00
71.04
B


ATOM
2136
C
SER
B
155
−49.562
37.032
−48.750
1.00
74.34
B


ATOM
2137
O
SER
B
155
−48.873
37.802
−48.071
1.00
74.13
B


ATOM
2138
N
THR
B
156
−49.193
36.611
−49.958
1.00
76.74
B


ATOM
2139
CA
THR
B
156
−47.930
37.037
−50.556
1.00
78.25
B


ATOM
2140
CB
THR
B
156
−47.659
36.302
−51.909
1.00
78.41
B


ATOM
2141
OG1
THR
B
156
−48.703
36.602
−52.847
1.00
78.59
B


ATOM
2142
CG2
THR
B
156
−47.600
34.791
−51.697
1.00
77.83
B


ATOM
2143
C
THR
B
156
−47.930
38.547
−50.784
1.00
78.96
B


ATOM
2144
O
THR
B
156
−46.955
39.233
−50.479
1.00
77.97
B


ATOM
2145
N
ASN
B
157
−49.035
39.062
−51.313
1.00
80.60
B


ATOM
2146
CA
ASN
B
157
−49.146
40.489
−51.576
1.00
82.39
B


ATOM
2147
CB
ASN
B
157
−50.574
40.847
−52.011
1.00
83.54
B


ATOM
2148
CG
ASN
B
157
−50.923
40.286
−53.382
1.00
85.98
B


ATOM
2149
OD1
ASN
B
157
−50.166
40.449
−54.344
1.00
86.88
B


ATOM
2150
ND2
ASN
B
157
−52.075
39.628
−53.481
1.00
87.40
B


ATOM
2151
C
ASN
B
157
−48.752
41.307
−50.351
1.00
82.41
B


ATOM
2152
O
ASN
B
157
−48.015
42.290
−50.459
1.00
83.08
B


ATOM
2153
N
LEU
B
158
−49.234
40.889
−49.185
1.00
81.77
B


ATOM
2154
CA
LEU
B
158
−48.936
41.585
−47.941
1.00
80.56
B


ATOM
2155
CB
LEU
B
158
−49.732
40.974
−46.785
1.00
80.09
B


ATOM
2156
CG
LEU
B
158
−50.412
41.950
−45.821
1.00
79.10
B


ATOM
2157
CD1
LEU
B
158
−51.452
42.765
−46.569
1.00
79.09
B


ATOM
2158
CD2
LEU
B
158
−51.078
41.183
−44.702
1.00
79.49
B


ATOM
2159
C
LEU
B
158
−47.447
41.501
−47.647
1.00
80.15
B


ATOM
2160
O
LEU
B
158
−46.772
42.520
−47.568
1.00
80.43
B


ATOM
2161
N
GLN
B
159
−46.935
40.286
−47.494
1.00
80.14
B


ATOM
2162
CA
GLN
B
159
−45.519
40.095
−47.210
1.00
81.12
B


ATOM
2163
CB
GLN
B
159
−45.171
38.603
−47.275
1.00
81.69
B


ATOM
2164
CG
GLN
B
159
−45.683
37.807
−46.067
1.00
83.74
B


ATOM
2165
CD
GLN
B
159
−45.782
36.306
−46.320
1.00
84.02
B


ATOM
2166
OE1
GLN
B
159
−46.586
35.853
−47.141
1.00
84.95
B


ATOM
2167
NE2
GLN
B
159
−44.969
35.531
−45.611
1.00
81.86
B


ATOM
2168
C
GLN
B
159
−44.662
40.899
−48.189
1.00
81.34
B


ATOM
2169
O
GLN
B
159
−43.627
41.459
−47.813
1.00
80.91
B


ATOM
2170
N
GLY
B
160
−45.115
40.973
−49.438
1.00
81.50
B


ATOM
2171
CA
GLY
B
160
−44.389
41.716
−50.453
1.00
82.03
B


ATOM
2172
C
GLY
B
160
−44.444
43.224
−50.261
1.00
82.52
B


ATOM
2173
O
GLY
B
160
−43.401
43.875
−50.197
1.00
83.21
B


ATOM
2174
N
ALA
B
161
−45.652
43.783
−50.174
1.00
82.63
B


ATOM
2175
CA
ALA
B
161
−45.832
45.225
−49.989
1.00
82.61
B


ATOM
2176
CB
ALA
B
161
−47.318
45.575
−49.991
1.00
81.89
B


ATOM
2177
C
ALA
B
161
−45.193
45.672
−48.681
1.00
82.81
B


ATOM
2178
O
ALA
B
161
−44.989
46.865
−48.444
1.00
82.18
B


ATOM
2179
N
LEU
B
162
−44.892
44.691
−47.836
1.00
83.61
B


ATOM
2180
CA
LEU
B
162
−44.262
44.918
−46.542
1.00
83.73
B


ATOM
2181
CB
LEU
B
162
−44.569
43.741
−45.608
1.00
81.75
B


ATOM
2182
CG
LEU
B
162
−44.375
43.877
−44.097
1.00
80.23
B


ATOM
2183
CD1
LEU
B
162
−44.889
42.617
−43.433
1.00
79.72
B


ATOM
2184
CD2
LEU
B
162
−42.912
44.096
−43.755
1.00
80.03
B


ATOM
2185
C
LEU
B
162
−42.760
45.014
−46.802
1.00
84.64
B


ATOM
2186
O
LEU
B
162
−42.053
45.804
−46.167
1.00
84.99
B


ATOM
2187
N
GLY
B
163
−42.288
44.206
−47.752
1.00
84.65
B


ATOM
2188
CA
GLY
B
163
−40.881
44.207
−48.107
1.00
84.77
B


ATOM
2189
C
GLY
B
163
−40.469
45.480
−48.828
1.00
85.10
B


ATOM
2190
O
GLY
B
163
−39.592
46.201
−48.300
1.00
84.53
B


ATOM
2191
OXT
GLY
B
163
−41.021
45.762
−49.918
1.00
84.32
B


ATOM
2192
S
CXS
$
1001
−37.007
7.286
−12.909
1.00
89.60
$


ATOM
2193
O1
CXS
$
1001
−37.722
7.642
−11.758
1.00
90.92
$


ATOM
2194
O2
CXS
$
1001
−37.206
7.283
−14.330
1.00
90.52
$


ATOM
2195
O3
CXS
$
1001
−35.476
7.404
−12.678
1.00
90.21
$


ATOM
2196
C1
CXS
$
1001
−36.878
9.113
−13.140
1.00
86.35
$


ATOM
2197
C2
CXS
$
1001
−38.280
9.714
−13.449
1.00
82.21
$


ATOM
2198
C3
CXS
$
1001
−38.308
11.211
−13.660
1.00
78.87
$


ATOM
2199
N
CXS
$
1001
−39.730
11.610
−13.907
1.00
74.83
$


ATOM
2200
C4
CXS
$
1001
−39.806
13.069
−14.118
1.00
72.04
$


ATOM
2201
C5
CXS
$
1001
−38.946
13.813
−13.094
1.00
71.28
$


ATOM
2202
C6
CXS
$
1001
−38.989
15.336
−13.308
1.00
70.38
$


ATOM
2203
C7
CXS
$
1001
−38.608
15.704
−14.767
1.00
70.92
$


ATOM
2204
C8
CXS
$
1001
−39.501
14.945
−15.785
1.00
69.52
$


ATOM
2205
C9
CXS
$
1001
−39.379
13.417
−15.567
1.00
71.02
$


ATOM
2206
S
CXS
$
1002
−33.172
31.213
−33.664
1.00
59.12
$


ATOM
2207
O1
CXS
$
1002
−33.303
31.719
−34.982
1.00
61.00
$


ATOM
2208
O2
CXS
$
1002
−31.915
30.813
−33.130
1.00
59.84
$


ATOM
2209
O3
CXS
$
1002
−33.679
32.294
−32.738
1.00
61.33
$


ATOM
2210
C1
CXS
$
1002
−34.407
29.954
−33.375
1.00
56.21
$


ATOM
2211
C2
CXS
$
1002
−34.146
28.753
−34.253
1.00
51.82
$


ATOM
2212
C3
CXS
$
1002
−35.236
27.757
−33.951
1.00
52.23
$


ATOM
2213
N
CXS
$
1002
−35.098
26.561
−34.782
1.00
53.07
$


ATOM
2214
C4
CXS
$
1002
−36.180
25.616
−34.422
1.00
50.12
$


ATOM
2215
C5
CXS
$
1002
−37.574
26.289
−34.439
1.00
47.85
$


ATOM
2216
C6
CXS
$
1002
−38.645
25.266
−34.045
1.00
47.93
$


ATOM
2217
C7
CXS
$
1002
−38.644
24.095
−35.046
1.00
49.65
$


ATOM
2218
C8
CXS
$
1002
−37.263
23.410
−35.077
1.00
49.27
$


ATOM
2219
C9
CXS
$
1002
−36.157
24.435
−35.413
1.00
50.51
$


ATOM
2220
O
HOH
S
1
−55.089
30.721
−29.788
1.00
42.32
S


ATOM
2221
O
HOH
S
2
−51.354
16.117
−54.214
1.00
66.49
S


ATOM
2222
O
HOH
S
3
−35.292
43.228
−45.412
1.00
70.66
S


ATOM
2223
O
HOH
S
6
−36.194
33.341
−31.023
1.00
62.49
S


ATOM
2224
O
HOH
S
8
−42.460
34.031
−31.211
1.00
52.51
S


ATOM
2225
O
HOH
S
11
−51.117
14.500
−24.316
1.00
63.19
S


ATOM
2226
O
HOH
S
13
−34.186
35.241
−31.749
1.00
69.73
S


ATOM
2227
O
HOH
S
14
−46.886
23.354
−15.063
1.00
62.91
S


ATOM
2228
O
HOH
S
15
−67.379
16.745
−38.051
1.00
74.92
S


ATOM
2229
O
HOH
S
16
−48.149
52.600
−41.809
1.00
65.55
S


ATOM
2230
O
HOH
S
20
−37.533
46.814
−44.158
1.00
63.62
S


ATOM
2231
O
HOH
S
23
−26.090
20.564
−40.954
1.00
64.92
S


ATOM
2232
O
HOH
S
33
−66.641
27.143
−35.990
1.00
64.70
S


ATOM
2233
O
HOH
S
34
−34.278
43.389
−42.980
1.00
66.36
S


ATOM
2234
O
HOH
S
35
−40.575
14.233
−23.786
1.00
68.23
S


ATOM
2235
O
HOH
S
36
−26.941
28.813
−12.491
1.00
61.13
S


ATOM
2236
O
HOH
S
37
−30.827
27.593
−14.316
1.00
59.11
S


ATOM
2237
O
HOH
S
39
−44.040
36.979
−30.178
1.00
56.62
S


ATOM
2238
O
HOH
S
40
−33.347
44.688
−11.256
1.00
77.43
S


ATOM
2239
O
HOH
S
42
−64.966
36.711
−39.384
1.00
64.46
S


ATOM
2240
O
HOH
S
43
−14.994
28.360
−34.554
1.00
79.56
S


ATOM
2241
O
HOH
S
45
−58.115
31.298
−30.300
1.00
73.59
S


ATOM
2242
O
HOH
S
46
−36.924
25.549
−50.937
1.00
62.92
S


ATOM
2243
O
HOH
S
49
−20.930
37.291
−14.901
1.00
62.70
S


ATOM
2244
O
HOH
S
55
−35.088
9.503
−41.169
1.00
56.66
S


ATOM
2245
O
HOH
S
58
−45.523
36.927
−10.019
1.00
53.41
S


ATOM
2246
O
HOH
S
60
−24.940
43.426
−34.908
1.00
64.11
S


ATOM
2247
O
HOH
S
61
−43.094
16.769
−33.268
1.00
88.80
S


ATOM
2248
O
HOH
S
64
−52.392
52.632
−34.025
1.00
92.27
S


ATOM
2249
O
HOH
S
66
−14.474
29.522
−20.678
1.00
73.76
S


ATOM
2250
O
HOH
S
67
−61.923
12.568
−56.894
1.00
71.78
S


ATOM
2251
O
HOH
S
68
−17.930
11.026
−27.010
1.00
57.62
S


ATOM
2252
O
HOH
S
69
−26.009
23.821
−38.215
1.00
56.83
S


ATOM
2253
O
HOH
S
70
−34.979
17.848
−41.915
1.00
57.66
S


ATOM
2254
O
HOH
S
73
−53.375
25.113
−34.332
1.00
67.17
S


ATOM
2255
O
HOH
S
78
−3.369
14.903
−39.536
1.00
76.47
S


ATOM
2256
O
HOH
S
79
−49.809
52.012
−53.024
1.00
74.16
S


ATOM
2257
O
HOH
S
80
−52.873
32.569
−23.870
1.00
59.72
S


ATOM
2258
O
HOH
S
81
−69.907
24.040
−37.219
1.00
59.30
S


ATOM
2259
O
HOH
S
82
−42.669
56.555
−30.390
1.00
65.30
S


ATOM
2260
O
HOH
S
85
−29.842
34.315
−33.948
1.00
62.56
S


ATOM
2261
O
HOH
S
96
−54.795
49.118
−60.472
1.00
72.94
S


ATOM
2262
O
HOH
S
100
−16.120
34.824
−29.084
1.00
73.72
S


ATOM
2263
O
HOH
S
103
−41.801
10.188
−41.652
1.00
59.23
S


ATOM
2264
O
HOH
S
108
−72.826
20.167
−44.484
1.00
75.51
S


ATOM
2265
O
HOH
S
111
−31.210
25.257
−37.321
1.00
71.53
S


ATOM
2266
O
HOH
S
113
−35.456
11.432
−29.314
1.00
64.29
S


ATOM
2267
O
HOH
S
114
−14.615
14.030
−42.236
1.00
64.98
S


ATOM
2268
O
HOH
S
116
−30.150
46.628
−35.936
1.00
67.88
S


ATOM
2269
O
HOH
S
117
−33.711
52.716
−21.422
1.00
75.50
S


ATOM
2270
O
HOH
S
122
−42.524
31.582
−56.165
1.00
60.35
S


ATOM
2271
O
HOH
S
124
−57.788
19.390
−20.057
1.00
80.05
S


ATOM
2272
O
HOH
S
127
−8.352
21.156
−33.703
1.00
72.60
S


ATOM
2273
O
HOH
S
131
−65.658
4.703
−48.301
1.00
67.75
S


ATOM
2274
O
HOH
S
136
−31.961
29.091
−37.073
1.00
65.98
S


ATOM
2275
O
HOH
S
144
−32.295
17.761
−36.053
1.00
61.82
S


ATOM
2276
O
HOH
S
145
−16.099
20.782
−27.246
1.00
62.57
S


ATOM
2277
O
HOH
S
152
−40.098
47.171
−61.867
1.00
70.18
S


ATOM
2278
O
HOH
S
153
−16.949
16.723
−30.701
1.00
72.82
S


ATOM
2279
O
HOH
S
154
−49.102
54.760
−44.857
1.00
74.87
S


ATOM
2280
O
HOH
S
155
−33.241
36.181
−28.893
1.00
53.26
S


ATOM
2281
O
HOH
S
157
−28.846
4.566
−28.970
1.00
65.48
S


ATOM
2282
O
HOH
S
159
−18.078
6.979
−32.388
1.00
62.25
S


ATOM
2283
O
HOH
S
160
−49.927
12.224
−25.999
1.00
83.57
S


ATOM
2284
O
HOH
S
161
−35.384
38.748
−45.921
1.00
78.38
S


ATOM
2285
O
HOH
S
164
−19.431
9.631
−42.561
1.00
83.75
S


ATOM
2286
O
HOH
S
165
−24.757
7.452
−28.428
1.00
62.83
S


ATOM
2287
O
HOH
S
166
−26.095
40.110
−19.029
1.00
71.51
S


ATOM
2288
O
HOH
S
167
−33.517
28.875
−11.950
1.00
65.15
S


ATOM
2289
O
HOH
S
169
−23.559
26.637
−34.978
1.00
69.82
S


ATOM
2290
O
HOH
S
171
−35.911
32.089
−11.426
1.00
70.81
S


ATOM
2291
O
HOH
S
173
−29.541
39.675
−27.861
1.00
73.58
S


ATOM
2292
O
HOH
S
174
−42.366
9.773
−12.564
1.00
75.10
S


ATOM
2293
O
HOH
S
179
−37.615
36.321
−6.575
1.00
60.84
S


ATOM
2294
O
HOH
S
185
−37.396
54.966
−35.497
1.00
66.51
S


ATOM
2295
O
HOH
S
186
−34.811
40.197
−42.025
1.00
78.57
S


ATOM
2296
O
HOH
S
189
−41.472
38.031
−56.357
1.00
76.56
S


ATOM
2297
O
HOH
S
193
−31.145
43.929
−38.718
1.00
64.82
S


ATOM
2298
O
HOH
S
197
−44.621
37.091
−53.919
1.00
74.57
S


ATOM
2299
O
HOH
S
200
−26.601
47.858
−27.412
1.00
73.60
S


ATOM
2300
O
HOH
S
204
−34.070
22.759
−42.394
1.00
64.86
S


ATOM
2301
O
HOH
S
206
−56.104
23.451
−54.858
1.00
63.95
S


ATOM
2302
O
HOH
S
207
−42.623
14.939
−36.850
1.00
58.12
S


ATOM
2303
O
HOH
S
215
−57.916
20.611
−53.534
1.00
65.65
S


ATOM
2304
O
HOH
S
217
−68.703
19.492
−32.308
1.00
66.71
S


ATOM
2305
O
HOH
S
218
−34.288
47.462
−17.190
1.00
87.83
S


ATOM
2306
O
HOH
S
219
−47.023
49.480
−49.463
1.00
80.36
S


ATOM
2307
O
HOH
S
221
−36.167
35.091
−46.526
1.00
82.36
S


ATOM
2308
O
HOH
S
229
−5.120
14.056
−34.382
1.00
80.88
S


ATOM
2309
O
HOH
S
234
−61.102
28.009
−56.501
1.00
73.87
S


ATOM
2310
O
HOH
S
236
−50.038
53.208
−31.379
1.00
80.66
S


ATOM
2311
O
HOH
S
238
−63.210
5.594
−33.656
1.00
73.31
S


ATOM
2312
O
HOH
S
239
−18.979
25.474
−40.262
1.00
65.13
S


ATOM
2313
O
HOH
S
241
−9.247
22.473
−40.473
1.00
62.01
S


ATOM
2314
O
HOH
S
242
−23.581
0.874
−22.639
1.00
79.48
S


ATOM
2315
O
HOH
S
244
−37.921
9.795
−41.267
1.00
71.07
S


ATOM
2316
O
HOH
S
245
−68.213
16.294
−47.338
1.00
66.37
S


ATOM
2317
O
HOH
S
259
−54.297
15.702
−29.864
1.00
69.25
S


ATOM
2318
O
HOH
S
260
−53.332
29.741
−10.004
1.00
79.52
S


ATOM
2319
O
HOH
S
261
−58.281
47.179
−58.668
1.00
71.63
S


ATOM
2320
O
HOH
S
262
−61.633
19.952
−25.923
1.00
74.21
S


ATOM
2321
O
HOH
S
264
−59.854
24.019
−57.410
1.00
84.87
S


ATOM
2322
O
HOH
S
265
−34.910
13.726
−35.043
1.00
75.92
S


ATOM
2323
O
HOH
S
266
−65.206
−1.041
−22.378
1.00
67.71
S


ATOM
2324
O
HOH
S
267
−30.825
12.386
−15.339
1.00
53.22
S


ATOM
2325
O
HOH
S
268
−23.141
25.046
−40.085
1.00
77.62
S


ATOM
2326
O
HOH
S
273
−64.261
24.028
−29.410
1.00
61.30
S


ATOM
2327
O
HOH
S
281
−45.175
18.432
−30.051
1.00
88.80
S


ATOM
2328
O
HOH
S
285
−44.514
56.451
−43.099
1.00
73.84
S


ATOM
2329
O
HOH
S
298
−41.747
37.900
−7.567
1.00
67.96
S


ATOM
2330
O
HOH
S
301
−51.187
22.922
−27.202
1.00
59.87
S


ATOM
2331
O
HOH
S
308
−56.697
51.798
−45.311
1.00
76.39
S


ATOM
2332
O
HOH
S
310
−30.921
48.271
−19.130
1.00
67.15
S


ATOM
2333
O
HOH
S
315
−26.247
3.171
−24.345
1.00
70.11
S


ATOM
2334
O
HOH
S
317
−7.989
11.928
−10.219
1.00
69.93
S


ATOM
2335
O
HOH
S
323
−67.469
1.840
−28.352
1.00
73.34
S


ATOM
2336
O
HOH
S
327
−1.519
7.683
−30.620
1.00
68.63
S


ATOM
2337
O
HOH
S
330
−13.341
11.540
−27.689
1.00
66.95
S


ATOM
2338
O
HOH
S
334
−31.782
46.438
−31.042
1.00
84.75
S


ATOM
2339
O
HOH
S
337
−14.963
25.917
−41.978
1.00
64.34
S


ATOM
2340
O
HOH
S
341
−55.975
23.392
−31.423
1.00
74.05
S


ATOM
2341
O
HOH
S
347
−30.795
46.682
−44.519
1.00
85.03
S


ATOM
2342
O
HOH
S
348
−40.398
44.400
−17.941
1.00
78.54
S


ATOM
2343
O
HOH
S
351
−63.588
34.580
−53.000
1.00
64.83
S


ATOM
2344
O
HOH
S
352
−52.859
26.925
−10.393
1.00
76.36
S


ATOM
2345
O
HOH
S
360
−66.994
13.614
−58.601
1.00
80.08
S


ATOM
2346
O
HOH
S
362
−6.728
7.392
−14.487
1.00
66.11
S


ATOM
2347
O
HOH
S
363
−45.315
52.345
−44.599
1.00
70.94
S


ATOM
2348
O
HOH
S
364
−27.723
55.681
−25.949
1.00
80.92
S


ATOM
2349
O
HOH
S
365
−0.192
8.761
−14.858
1.00
65.43
S


ATOM
2350
O
HOH
S
366
−33.943
48.435
−9.023
1.00
73.21
S


ATOM
2351
O
HOH
S
369
−23.185
39.615
−20.816
1.00
75.14
S


ATOM
2352
O
HOH
S
371
−47.369
8.811
−24.333
1.00
90.58
S


ATOM
2353
O
HOH
S
378
−72.215
16.093
−37.276
1.00
79.02
S


ATOM
2354
O
HOH
S
382
−62.101
39.118
−53.345
1.00
91.47
S


ATOM
2355
O
HOH
S
399
−5.346
7.993
−18.480
1.00
82.98
S


ATOM
2356
O
HOH
S
404
−48.898
52.763
−34.937
1.00
79.67
S


ATOM
2357
O
HOH
S
408
−58.332
50.605
−57.798
1.00
73.84
S


ATOM
2358
O
HOH
S
414
−16.594
33.677
−18.292
1.00
67.72
S


ATOM
2359
O
HOH
S
421
−14.075
7.273
−31.446
1.00
75.74
S


ATOM
2360
O
HOH
S
425
−52.456
25.670
−30.099
1.00
68.36
S


ATOM
2361
O
HOH
S
429
−34.829
54.773
−17.284
1.00
73.77
S


ATOM
2362
O
HOH
S
438
−25.176
29.403
−40.958
1.00
77.48
S


ATOM
2363
O
HOH
S
444
−42.956
49.806
−10.829
1.00
87.00
S


ATOM
2364
O
HOH
S
458
−70.377
23.808
−46.086
1.00
78.30
S


ATOM
2365
O
HOH
S
476
−33.612
35.694
−43.631
1.00
66.61
S


ATOM
2366
O
HOH
S
488
−43.909
38.988
−59.269
1.00
90.04
S


ATOM
2367
O
HOH
S
490
−55.112
12.025
−28.305
1.00
69.08
S


ATOM
2368
O
HOH
S
497
−52.018
36.590
−59.300
1.00
73.00
S


ATOM
2369
O
HOH
S
498
−67.080
8.456
−47.025
1.00
77.54
S


ATOM
2370
O
HOH
S
501
−33.375
45.638
−46.606
1.00
67.04
S


ATOM
2371
O
HOH
S
504
−17.519
40.287
−29.824
1.00
75.48
S


ATOM
2372
O
HOH
S
508
−38.469
54.630
−22.566
1.00
81.92
S


ATOM
2373
O
HOH
S
548
−7.619
13.490
−18.323
1.00
80.70
S


ATOM
2374
O
HOH
S
562
−52.127
9.380
−31.442
1.00
93.77
S


ATOM
2375
O
HOH
S
574
−71.476
15.001
−51.047
1.00
83.08
S


ATOM
2376
O
HOH
S
581
−35.133
54.715
−54.265
1.00
79.21
S


ATOM
2377
O
HOH
S
598
−38.686
54.511
−51.645
1.00
83.16
S


END

## Claims

1. A method of treating a tumor in a subject, comprising the step of administering to said subject an effective amount of an interferon crystal, wherein said interferon consisting of the amino acid sequence of SEQ ID NO: 1, said crystal has a space group of P3121 and unit cell parameters of a=b=77.92 Å, c=125.935 Å, α=β=90°, and γ=120°.

2. The method of claim 1, wherein said interferon crystal contains two molecules in an asymmetric unit.

3. The method of claim 1, wherein said interferon crystal comprises covalently or non-covalently bound metal ions.

4. The method of claim 1, wherein said tumor is a solid tumor.

5. The method of claim 1, wherein said tumor is selected from: skin cancer, basal cell carcinoma, malignant melanoma, renal cell carcinoma, liver cancer, thyroid cancer, nasopharyngeal cancer, solid tumors, prostate cancer, stomach/abdominal cancer, esophageal cancer, rectal cancer, pancreatic cancer, breast cancer, ovarian cancer, superficial bladder cancer, hemangioma, epidermoid cancer, cervical cancer, non-small cell lung cancer, small cell lung cancer, glial stromal tumors, leukemia, acute leukemia, chronic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lymphadenoma, multiple myeloma, polycythemia and Kaposi's sarcoma.