# Patent

## Title
Human A2A adenosine receptor crystals and uses thereof

## Abstract

The invention provides the structure of human A2A adenosine receptor protein bound to an antagonist. Methods of using one or more binding sites and other features of this G-protein coupled receptor to develop new therapeutics are also disclosed.

## Background
RELATED APPLICATIONS
This applications claims the benefit of U.S. provisional application 61/194,961, filed Oct. 1, 2008, and incorporated herein by reference for all purposes.


STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
This invention was made with government support under Grant Nos. GM073197 and GM074961 awarded by the National Institutes of Health. The government has certain rights in the invention.
REFERENCE TO SEQUENCE LISTING
This specification includes a sequence listing submitted electronically as a text file named “16086_US_Sequence Listing.txt”, created Mar. 30, 2011, with a size of 84 kb. The sequence listing consists of 36 sequences and is incorporated by reference.


BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to the fields of chemistry, and biophysics.
2. Description of the Related Art
G-protein coupled receptors (GPCRs) comprise a broad class of membrane-bound proteins that share a variety of structural and functional attributes. See Friedricksson et al. Mol Pharmacol (63)6: p. 1256-1272, 2003; and Friedricksson et al. Mol Pharmacol (67)5: p. 1414-1425, 2005. GPCRs are classified into 1 of 6 classes: A, B, C, D, E, and F, see Friedricksson et al. (2003) and Friedricksson et al. (2005). GPCRs comprise seven transmembrane helical regions, as well as an extracellular portion that binds endogenous ligands.
Extracellular adenosine plays an important role in physiology and initiates most of its effects through the activation of four GPCR subtypes, A1, A2A, A2B and A3 (B. B. Fredholm et al., Annu Rev Pharmacol Toxicol 45, 385 (2005); B. B. Fredholm et al., Pharmacol Rev 53, 527 (2001)). Each of these four receptor subtypes plays an essential role in responding to adenosine in the central nervous system (T. V. Dunwiddie et al., Annu Rev Neurosci 24, 31 (2001); K. A. Jacobson et al., Nat Rev Drug Discov 5, 247 (2006)) regulating pain (J. Sawynok, X. J. Liu, Prog Neurobiol 69, 313 (2003)), cerebral blood flow (Y. Shi et al., J Cereb Blood Flow Metab 28, 111 (2008)), basal ganglia functions (M. A. Schwarzschild et al., Trends Neurosci 29, 647 (2006)), respiration (S. Lahiri et al., Respir Physiol Neurobiol 157, 123 (2007)) and sleep (R. Basheer et al., Prog Neurobiol 73, 379 (2004)). These receptor subtypes are primarily coupled to the cAMP second messenger system and each has its own unique pharmacological profile. The A2A adenosine subtype is linked to Gs and Golf proteins and upon receptor activation, the intracellular levels of cAMP increase. At least three of the four adenosine receptor subtypes (A1, A2A and A2B) are blocked by naturally occurring methylxanthines, such as caffeine, with modest affinity. Interestingly, strong epidemiological evidence suggests that coffee drinkers have a lower risk of Parkinson's disease (M. A. Hernan et al., Ann Neurol 52, 276 (2002)). This effect has been linked to caffeine's interaction with the A2A adenosine receptor, which controls locomotor behavior in basal ganglia together with dopamine D2 and metabotropic glutamate mGluR receptors (S. Ferre, J Neurochem 105, 1067 (2008); S. Ferre et al., Front Biosci 13, 2391 (2008)). Development of more selective compounds for adenosine receptor subtypes could provide a class of therapeutics for treating numerous human maladies, such as pain (J. Sawynok et al., Prog Neurobiol 69, 313 (2003)), Parkinson's disease (M. A. Schwarzschild et al., Trends Neurosci 29, 647 (2006); A. H. Schapira et al., Nat Rev Drug Discov 5, 845 (2006)), Huntington disease (D. Blum et al., S. N. Schiffmann, Lancet Neurol 2, 366 (2003)), asthma (R. A. Brown et al., Br J Pharmacol 153 Suppl 1, S446 (2008)), seizures (M. J. During et al., Ann Neurol 32, 618 (1992)) and many other neurological disorders (D. Blum et al., Lancet Neurol 2, 366 (2003); E. E. Benarroch, Neurology 70, 231 (2008)).
SUMMARY OF THE INVENTION
Described herein is the structure of the human A2A adenosine receptor in complex with the subtype selective high affinity antagonist (4-(2-[7-amino-2-(2-furyl)-[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl)-phenol (ZM241385) (E. Ongini et al., Naunyn Schmiedebergs Arch Pharmacol 359, 7 (1999); S. M. Poucher et al., Br J Pharmacol 115, 1096 (1995)). The basis for this compound's selectivity over the adenosine A1 and A3 receptors can now be analyzed in the context of its molecular interactions with the A2A receptor along with previously reported mutagenesis data. With an additional human GPCR structure, the analysis of structural differences as they pertain to receptor pharmacology, receptor activation, ligand recognition and ligand engineering is facilitated for all members of the class A receptor family.
In one embodiment, the invention provides a crystalline form of a human A2A adenosine receptor protein having an atomic arrangement of coordinates comprising the coordinates set forth in Table 6. In another embodiment, the invention provides a crystalline form of a human A2A adenosine receptor protein, where said form has unit cell dimensions of a=47.7±0.5 Angstroms, b=76.9±0.5 Angstroms, and c=86.8±0.5 Angstroms. In still another embodiment, the invention provides a crystalline form of a human A2A adenosine receptor protein, wherein said space group of said crystalline form is P21. In yet another embodiment, the invention provides a crystalline form of a human A2A adenosine receptor protein, wherein said crystalline form diffracts X-rays to a resolution of 2.6 Angstroms. In an embodiment related to the crystalline forms described above, the human A2A adenosine receptor protein is a chimeric receptor or fusion protein comprising a human A2A adenosine receptor protein and T4 lysozyme. In yet another related embodiment, a crystalline form such as that described above may comprise a xanthine ligand. In certain embodiments, the xanthine ligand is a ligand such as theophylline, xanthine, theobromine and caffeine. In still other embodiments, the crystalline human A2A adenosine receptor protein comprises a bound non-xanthine ligand, such as ZM241385.
In another related embodiment, the invention provides a crystalline form of human A2A adenosine receptor protein or a portion thereof, wherein said human A2A adenosine receptor protein or portion thereof comprises a binding pocket I site, and wherein said binding pocket I comprises a plurality of amino acid residues selected from the group consisting of Phe1685.29, Ile2747.39, Glu1695.30, Leu2496.51, and Asn2536.55. In a related embodiment, binding pocket I comprises a non-xanthine antagonist (e.g., ZM241385) in binding pocket I. In yet another embodiment, the invention provides a crystalline form of human A2A adenosine receptor protein or a portion thereof, wherein said human A2A adenosine receptor protein or portion thereof comprises a binding pocket II site, and wherein said binding pocket II comprises amino acid residues Phe622.60, Ile662.64, Ile803.28, Val843.32, Phe1685.29, Leu2496.51, Ile2747.39 and His2787.43. In a related embodiment, a xanthine ligand is bound by binding pocket II in the in the crystalline human A2A adenosine receptor. In yet another embodiment, the invention provides crystalline form of human A2A adenosine receptor protein or a portion thereof, wherein said human A2A adenosine receptor protein or portion thereof comprises a binding pocket III site, and wherein said binding pocket III site comprises a plurality of amino acid residues selected from the group consisting of Leu482.46, Ala512.49, Asp522.50, Val552.53, Val843.32, Leu873.35, Thr883.36, Ser913.39, Leu953.43, Ile2386.40, Phe2426.44, Trp2466.48, Ser2777.42, His2787.43, Asn2807.45, Ser2817.46 and Asn2847.49.
In another embodiment, the invention provides methods for identifying a compound that binds to a ligand binding site of a human A2A adenosine receptor protein by comparing a set of three-dimensional structures representing a set of candidate compounds with a three-dimensional molecular model of said ligand binding site, comprising: receiving a three-dimensional model of a ligand binding site on said human A2A adenosine receptor protein, wherein said three-dimensional model of said ligand binding site comprises atomic co-ordinates for a plurality of ligand-binding residues; determining, for each of the set of compound three-dimensional models, a plurality of distance values indicating distances between said atomic co-ordinates of said candidate compound of the set of candidate compounds and said atomic coordinates of said ligand-binding residues comprising said ligand binding site; determining, for each of the set of compound three-dimensional models, a binding strength value based on the plurality of distance values determined for the compound three-dimensional model, wherein the binding strength value indicates the stability of a complex formed by said human A2A adenosine receptor protein and a compound represented by the compound three-dimensional model; and storing or displaying a set of results indicating whether each candidate compound binds to the three-dimensional model based on the binding strength values. Displaying can include displaying all or a portion of the results on a monitor or on a printed sheet of paper. In certain related embodiments of the method, the set of candidate compounds or the set of three-dimensional structures or both contains one member, or more. The candidate compounds may include compounds derived from one or more known GPCR ligands, or they may be designed de novo based on the three-dimensional molecular model of the ligand binding site, e.g., the model described herein or a portion thereof. The invention also provides a related embodiment of the above-described method wherein the plurality of ligand-binding residues comprises residues that form a binding pocket, e.g., binding pocket I, binding pocket II, or binding pocket III of said human A2a adenosine receptor.
In another related embodiment of the above-described method for identifying a compound that binds to a ligand binding site of a human A2A adenosine receptor protein, the ligand-binding residues comprise a plurality of residues selected from the group consisting of Phe1685.29, Ile2747.39, Glu1695.30, Leu2496.51, and Asn2536.55. In yet another related embodiment of the method, the ligand-binding residues comprise a plurality of residues selected from the group consisting of Phe622.60, Ile662.64, Ile803.28, Val843.32, Phe1685.29, Leu2496.51, Ile2747.39 and His2787.43. In still another related embodiment, the ligand-binding residues comprise a plurality of residues selected from the group consisting of Leu482.46, Ala512.49, Asp522.50, Val552.53, Val843.32, Leu873.35, Thr883.36, Ser913.39, Leu953.43, Ile2386.40, Phe2426.44, Trp2466.48, Ser2777.42, His2787.43, Asn2807.45, Ser2817.46 and Asn2847.49.
In another related embodiment of the above-described method for identifying a compound that binds to a ligand binding site of a human A2A adenosine receptor protein, binding strength value is based on one or more of a hydrogen bonding strength, a hydrophobic interaction strength, or a Coulombic interaction binding strength. In related variations of the method, one or more of the steps of receiving, determining, or storing are carried out using a commercially-available software program. Example of appropriate programs include DOCK, QUANTA, Sybyl, CHARMM, AMBER, GRID, MCSS, AUTODOCK, CERIUS II, Flexx, CAVEAT, MACCS-3D, HOOK, LUDI, LEGEND, LeapFrog, Gaussian 92, QUANTA/CHARMM, Insight II/Discover, and ICM.
In yet another related embodiment of the above-described method for identifying a compound that binds to a ligand binding site of a human A2A adenosine receptor protein, the method comprises an additional step of contacting a human A2A adenosine receptor protein with a molecule comprising an identified candidate compound. In some embodiments, the molecule comprising an identified candidate compound additionally comprises a moiety capable of competitively displacing a ligand from a human A2A adenosine receptor protein, e.g., a ligand that binds to binding pocket I, II or III of a human A2A adenosine receptor protein. The invention provides another related embodiment of the method for identifying a compound that binds to a ligand binding site of a human A2A adenosine receptor protein, wherein the method further comprising characterizing a binding interaction between the human A2A adenosine receptor protein and the molecule comprising the identified candidate compound, and storing the result of that characterization, e.g., storing a measured value representative of the binding interaction. The characterization step of this embodiment may comprise, for example, determining an activation of a function of the human A2A adenosine receptor protein, an inhibition of a function of said human A2A adenosine receptor protein, an increase in expression of said human A2A adenosine receptor protein, a decrease in expression of said human A2A adenosine receptor protein, a displacement of a ligand bound to said ligand binding site, or a stability measure for said human A2A adenosine receptor protein, or a combination of one or more of these determinations. In addition or in the alternative to these characterizations, an association constant may be determined.
The invention also provides a human A2A adenosine receptor fusion protein, wherein said fusion protein comprises the amino acid sequence of T4 lysozyme, wherein said fusion protein comprises a deletion in the A2A adenosine receptor sequence between Leu2095.70 and Ala2216.23. In a related embodiment, the invention provides a fusion protein composition with an amino acid sequence at least 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:1. In yet another embodiment, the invention provides an isolated nucleic acid comprising a sequence encoding the above-described fusion protein, wherein the nucleic acid sequence encodes proteins whose primary sequence is at least 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO:1.
These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings.



BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
FIGS. 1A and 1B. Crystal structure of A2A-T4L-ΔC. A. Overall topology of A2A-T4L-ΔC. The transmembrane part of A2A-ΔC structure includes helices I-VIII and the T4L is located intracellularly. The structure is viewed perpendicular to the plasma membrane. ZM241385, the four lipid molecules, and the four disulfide bonds are also shown. The sulfate ions are omitted. The extracellular loops are labeled ECL1-3 are labeled ICL1-3. The membrane boundaries are adapted from the OPM database (found on the web at the site: opm.phar.umich.edu) using β2AR-T4L (2RH1) as a model. B. Rotated 180° around the x-axis. The images were created with PyMOL.
FIG. 2A-D. Ligand binding characteristics of A2A-WT, A2A-T4L and A2A-T4L-ΔC. A. Saturation binding isotherm for the binding of [3H]ZM241385 to different A2A-WT, A2A-T4L or A2A-T4L-ΔC receptors confined in membranes of Sf9 cells. The indicated preparations of A2A receptors were incubated with different concentrations of [3H]ZM241385 in the absence (filled shapes and solid lines) and presence (open shapes and dashed lines) of 1 M NaCl as described in SOM. The figure shown represents data combined from two separate experiments performed in triplicate. The equilibrium constant (Kd) values of [3H]ZM241385 in the absence and the presence of 1 M NaCl were 2.1±0.7 nM, 1.3±0.2 nM for A2A-WT; 2.0±0.3 nM, 0.9±0.1 nM for A2A-T4L and 1.8±0.2 nM, 1.0±0.1 nM for A2A-T4L-DC, respectively. B. One point binding assay demonstrating the binding of [3H]ZM241385 to membranes (5 μg/assay point) of HEK 293T cells transfected with A2A-WT, A2A-T4L or A2A-T4L-ΔC. [3H]ZM241385 was used at a concentration equivalent to the previously observed equilibrium constant (Kd). Lower panels—the ability of increasing concentrations of C. the agonist CGS21680 or D. the antagonist ZM241385 to compete with [3H]ZM241385 binding at A2A-WT (circles), A2A-T4L (triangles), A2A-T4L-ΔC (squares) constructs in HEK293T cells was tested in the absence (filled shapes and solid lines) or presence (open shapes and dashed lines) of 1 M NaCl. The figure shown represents data combined from three separate experiments performed in duplicate.
FIGS. 3A and 3B. Slight changes in helical positions alter the orientation of the ligand binding pocket. A. A surface rendering of the binding pocket for ZM241385 in the A2A adenosine receptor. Helical positions for A2A adenosine (“a”), β2AR (pdbid: 2RH1) (“b”) and rhodopsin (pdbid: 1U19) (“r”) are shown after alignment with the FatCat server (found on the web at the site: fatcat.burnham.org/). Ligands for each receptor are shown to illustrate the differences in binding orientation and the differences in the adenosine A2A binding pocket. B. A top view of the helical bundle illustrating the maximal helical positional shifts of A2A relative to β2AR.
FIG. 4A-C. Normalized occluded surface (NOS) area changes due to ligand binding. Increases in occluded surface area are represented as thickened areas of the protein backbone chain. A. Rhodopsin (pdbid: 1U19) with retinal is shown along with the position of ZM241385 for comparison. Retinal makes extensive contact with helices III, V, VI and VII deep in the binding pocket. B. β2AR bound to carazolol (pdbid: 2RH1) is shown along with the position of ZM241385 for comparison. Carazolol also makes extensive contacts with helices III, V, VI and VII deep in the binding pocket but is responsible for minimal changes in NOS of Trp 2866.48 the canonical “toggle switch”. C. A2A adenosine receptor bound to ZM241385 has a very different binding orientation relative to rhodopsin and β2AR having minimal interaction with helices III and V, but extensive interactions with helices VI and VII as well as residues in a ECL2 and ECL3. ZM241385 also forms significant contacts with Trp2466.48. All interacting positions on the receptor are displayed as thick areas and labeled by their corresponding Ballesteros-Weinstein designation. The amino-acid numbering is based on the human A2A adenosine receptor primary sequence (SEQ ID NO: 2; accession number P29274). In addition to numbering residue positions in the primary amino acid sequence, the residues have numbers in superscripts (X.YY) that indicate their position in each transmembrane helix (X, helix number, from 1 to 8)), relative to the most conserved reference residue in that helix (YY). This residue is arbitrarily assigned the number 50, numbers decreasing towards N-terminus and increasing towards C-terminus However, the numbering is not used in loop regions beyond residues X.20 and/or X.80 or T4L
FIG. 5A-D. A Comparison of interactions between helix III (E/DRY motif) and ICL2 for human A2A-T4L-ΔC, human β2AR-T4L (pdbid: 2RH1) and turkey β1AR (pdbid 2VT4). A. A2A-T4L-ΔC interactions. The DRY motif does not participate in any stabilizing ionic interactions similar to β2AR and β1AR. Instead Arg1023.50 may play a role in shifting the pKa of the adjacent Asp1013.49 allowing this residue to make stronger hydrogen bonding interactions with helix II and ICL2. B. Turkey β1AR participates in similar interactions as A2A-T4L-ΔC without the hydrogen bond to helix II. C. β2AR does not contain a helical segment in ICL2 and has a modified set of interactions. D. The canonical “ionic lock” in rhodopsin.
FIGS. 6A and 6B. Ligand binding cavity of A2A-T4L-ΔC with ZM241385 bound. A. Residues within 5 Å of the ZM241385 are shown in stick representation. Only the interacting helices, ECL3 and the interacting part of ECL2 are shown. The two disulfide bridges in close proximity to the binding cavity are also shown. ZM241385 is positioned co-linear with respect to the transmembrane helices V, VI and VII, and the binding cavity is elongated to the ECL3 and helical ends of TM VI and VII. For comparison to retinal chromophore or beta-blockers binding site, see FIG. 3 for details. The Phe1685.29 from ECL2 forms various aromatic stacking interactions with the bicyclic core of ZM241385. Trp2466.48 associated with stabilizing the antagonist structure is at 3 Å distance from the furan ring of ZM241385. The binding cavity includes four ordered water molecules shown as light spheres. B. Schematic representation of the interactions between A2A-T4L-ΔC and ZM241385 at the ligand binding cavity combined with mutation analysis for adenosine agonist/antagonists interactions. Mutations that are reported to disrupt antagonist and/or agonist binding are within darkened squares: Glu1695.30, His2506.25, Asn2536.55 and Ile2747.39.
FIGS. 7A and 7B. In silico docking of caffeine to binding pocket II of human A2A adenosine receptor. FIG. 7A shows that when His2787.43 is protonated and positively charged, caffeine binds adjacent to binding pocket I in a xanthine-binding site defined by hydrophobic interactions with: Phe622.60, Ile662.64, Ile803.28, Val843.32, Phe1685.29, Leu2496.51, Ile2747.39 and forming polar interactions with His2787.43. FIG. 7B: When His2787.43 is deprotonated, caffeine binds in a location similar to binding pocket I.
FIGS. 8A and 8B. Sequence alignment between human Adenosine receptor subtypes Al (SEQ ID NO: 29), A2A (SEQ ID NO: 2), A2B (SEQ ID NO: 30), A3 (SEQ ID NO: 31) and A2A-T4L-ΔC constructs (SEQ ID NO: 28) (A) and comparison of A2A from different species (Human (SEQ ID NO: 2), Rattus norvegicus (SEQ ID NO: 32), Mus musculus (SEQ ID NO: 33), Macaca mulatta (SEQ ID NO: 34) and Danio rerio (SEQ ID NO: 35)) (B). The residues within 4.5 Å from the ligand binding site of ZM241385 are indicated by an asterix. Ballesteros and Weinstein (S. C. Sealfon et al., J Biol Chem 270, 16683 (1995)) numbering is shown for each transmembrane region. The amino and carboxyl terminal purification tags and the T4L tag are also indicated. The assigned secondary structural elements are shown as alpha helix (α), beta-sheet (β) or turns (T). Residues which are conserved in other human subtypes, species and their level of conservation appear in boxes. Dark boxes indicate identical residues. Four disulfide bonds are numbered from 1 to 4.
FIG. 9A-C. Pharmacological validation of A2A-T4L-ΔC constructs. 9A. cAMP determination in HEK293T cells transfected with A2A constructs; A2A-WT and A2A-T4L or A2A-T4L-ΔC. Data from untransfected HEK293T cells is not shown but is equivalent to the data from A2A-T4L or A2A-T4L-ΔC. HEK293T (B) and Sf9 (C) cellular localization/trafficking 9B. Whole HEK293T cell ELISA experiment using a monoclonal anti-FLAG (M2) antibody demonstrates cell surface expression of the A2A-WT and A2A-T4L constructs but not the A2A-T4L-ΔC construct. 9C. Similar results were obtained from Sf9 cells using a monoclonal anti-FLAG (M2) antibody (M. A. Hanson et al., Protein Expr Purif, 56, 85 (2007)). For total expression cells were permeabilized with 0.15% TRITON X-100.
FIG. 10 A-D. Indirect evidence of receptor stabilization by ligands or allosteric modulators such as sodium ions or lipids: Effects of NaCl, cholesterol and ligands on A2A-T4L-wt and A2A-T4L-ΔC receptor thermal stability and conformation. A. Effect of NaCl on A2A-T4L-ΔC receptor thermal stability. Representative melting curves of 5 μg A2A-T4L receptor in 0.05% DDM in purification buffer containing 0, 150, 400, 800, 2000 and 4000 mM NaCl. Calculated Tm values in order of increasing salt concentration are: 45° C., 40° C., 50° C., 53 and 54° C. B. Effects of cholesterol-hemi-succinate and C. Synthetic cholesterol (Sigma) on A2A-T4L receptor thermal stability in low and high NaCl concentration. D. Effect of unligated, theophylline, ZM241385, SCH422416, SCH58261 and p-DITC-APEC on A2A-T4L-ΔC in high concentration. Calculated Tm values in order of affinity unligated, theophylline, p-DITC-APEC, SCH58261, ZM241385, and SCH422416 are 45° C., 42° C., 60° C., 40° C., 62 and 50° C., respectively. Data points are means of at least duplicate, in most case triplicate samples. The assay was done as in Alexandrov et al, Structure 16, 351 (2008).
FIG. 11A-F. Crystal packing and protein-lipids interactions in the in meso grown crystal of A2A-T4L-ΔC-ZM241385. A. Crystal packing. Note that the images in 11B and 11C are rotated 90° around x and y axis from A. FIG. 11D shows detailed crystallographic and non-crystallographic interactions. The values of interface areas and distances between interacting residues are given in Table 4. The interfaces are indicated by arrows and transparent surfaces. For clarity, the lipids are not-shown in this figure, but included in E. The main lipid binding site occurs at the crystallographic interface between two receptor monomers and is mediated by the lipid-lipid and lipid-receptor interactions. E. Closer view of the lipid binding site and the positively charged intracellular environment. The receptor surface is shaded according to calculated charge with the darkest regions corresponding to (−20 kbT/ec; e.g., the darkened regions near the ECL2 cleft) or (+20 kbT/ec; e.g., the surface of Helix VIII and the A2A-T4L interface) using dielectric constant of 80 using program APBS as implemented in the program PyMOL. F. Comparison of T4L orientation between Adenosine A2A-T4L and two β2-AR-T4L structures.
FIG. 12. Per-residue real space correlation coefficient and crystallographic B-factor for the final model.
FIG. 13A-C. Examples of the electron density in a σ-A weighted 2Fo-Fc map calculated from the refined model for A2A-T4L-ΔC. A. Electron density of helices VI and VII. B. Electron density associated with some lipids and helix interactions. Density from the final σ-A weighted 2Fo-Fc map is contoured at 1.4σ. C. The 2Fo-Fcσ-A weighted and Fo-Fc omit electron density maps of the Adenosine A2A antagonist ZM241385. Electron density is contoured at 1.4σ and 4σ from the 2Fo-Fc and Fo-Fc omit maps, respectively, and calculated without the contribution of ZM241385.
Additional information related to the forgoing Figures may be found in U.S. provisional application 61/194,961, filed Oct. 1, 2008, and in the paper by Jaakola et al., Science (2008) 322, 1211-1217.



DETAILED DESCRIPTION OF THE INVENTION
Advantages and Utility
Briefly, and as described in more detail below, described herein is the 2.6 Angstrom resolution structure of the human A2A adenosine receptor in complex with a high affinity subtype-selective antagonist, ZM241385. Advantages of this invention can include the ability to create or identify compounds with increased specificity and functionality with respect to this protein and with respect to related proteins. While much of the disclosure that follows deals specifically with the human A2A adenosine receptor, the invention contemplates and encompasses the application of findings and observations developed using this receptor to similar GPCRs.
Definitions
Terms used in the claims and specification are defined as set forth below unless otherwise specified.
As used herein, the term “binding site” or “binding pocket” refers to a region of a protein that binds or interacts with a particular compound.
As used herein, the terms “binding” or “interaction” refers to a condition of proximity between a chemical entity, compound, or portions thereof, with another chemical entity, compound or portion thereof. The association or interaction can be non-covalent—wherein the juxtaposition is energetically favored by hydrogen bonding or van der Waals or electrostatic interactions—or it can be covalent.
As used herein, the term “residue” refers to an amino acid residue is one amino acid that is joined to another by a peptide bond. Residue is referred to herein to describe both an amino acid and its position in a polypeptide sequence.
As used herein, the term “surface residue” refers to a surface residue is a residue located on a surface of a polypeptide. In contrast, a buried residue is a residue that is not located on the surface of a polypeptide. A surface residue usually includes a hydrophilic side chain. Operationally, a surface residue can be identified computationally from a structural model of a polypeptide as a residue that contacts a sphere of hydration rolled over the surface of the molecular structure. A surface residue also can be identified experimentally through the use of deuterium exchange studies, or accessibility to various labeling reagents such as, e.g., hydrophilic alkylating agents.
As used herein, the term “polypeptide” refers to a single linear chain of 2 or more amino acids. A protein is an example of a polypeptide.
As used herein, the term “homolog” refers to a gene related to a second gene by descent from a common ancestral DNA sequence. The term, homolog, can apply to the relationship between genes separated by the event of speciation or to the relationship between genes separated by the event of genetic duplication.
As used herein, the term “conservation” refers to conservation a high degree of similarity in the primary or secondary structure of molecules between homologs. This similarity is thought to confer functional importance to a conserved region of the molecule. In reference to an individual residue or amino acid, conservation is used to refer to a computed likelihood of substitution or deletion based on comparison with homologous molecules.
As used herein, the term “distance matrix” refers to the method used to present the results of the calculation of an optimal pairwise alignment score. The matrix field (i,j) is the score assigned to the optimal alignment between two residues (up to a total of i by j residues) from the input sequences. Each entry is calculated from the top-left neighboring entries by way of a recursive equation.
As used herein, the term “substitution matrix” refers to a matrix that defines scores for amino acid substitutions, reflecting the similarity of physicochemical properties, and observed substitution frequencies. These matrices are the foundation of statistical techniques for finding alignments.
As used herein, the term “pharmacophore” refers to an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger or block a biological response. A pharmacophore can be used to design one or more candidate compounds that comprise all or most of the ensemble of steric and electronic features present in the pharmacophore and that are expected to bind to a site and trigger or block a biological response.
As used herein, the term “atomic co-ordinates” refers to a set of three-dimensional co-ordinates for atoms within a molecular structure. In one embodiment, atomic-co-ordinates are obtained using X-ray crystallography according to methods well-known to those of ordinarily skill in the art of biophysics. Briefly described, X-ray diffraction patterns can be obtained by diffracting X-rays off a crystal. The diffraction data are used to calculate an electron density map of the unit cell comprising the crystal; said maps are used to establish the positions of the atoms (i.e., the atomic co-ordinates) within the unit cell. Those of skill in the art understand that a set of structure co-ordinates determined by X-ray crystallography contains standard errors. In other embodiments, atomic co-ordinates can be obtained using other experimental biophysical structure determination methods that can include electron diffraction (also known as electron crystallography) and nuclear magnetic resonance (NMR) methods. In yet other embodiments, atomic co-ordinates can be obtained using molecular modeling tools which can be based on one or more of ab initio protein folding algorithms, energy minimization, and homology-based modeling. These techniques are well known to persons of ordinary skill in the biophysical and bioinformatic arts, and are described in greater detail below.
Atomic co-ordinates for binding pockets, such as, e.g., binding pockets I, II and III of the human A2A adenosine receptor and it subtypes, and/or agonist/antagonist binding sites of the present invention are intended to encompass those co-ordinates set out in the .pdb file (Table 6) incorporated into this specification, as well as co-ordinates that are substantially equivalent. Substantially equivalent co-ordinates are those that can be related to a reference set of co-ordinates by transformation reflecting differences in the choice of origin or inter-axis angels for one or more axes used to define the coordinate system. Operationally, co-ordinates are “substantially equivalent” when the structures represented by those co-ordinates can be superimposed in a manner such that root mean square deviations (RMSD) of atomic positions for the structures differs by less than a predetermined threshold. In some embodiments that threshold is less than about 5 Angstroms, or less than about 4 Angstroms, or less than about 3 Angstroms, or less than about 2 Angstroms, or less than about 1 Angstrom, or less than about 0.9 Angstrom, or less than about 0.8 Angstrom, or less than about 0.7 Angstrom, or less than about 0.6 Angstrom, or less than about 0.5 Angstrom, or less than about 0.4 Angstrom, or less than about 0.3 Angstrom. Preferably, co-ordinates are considered “substantially equivalent” when the RMSD is less than about 1 Angstrom. Methods for structure superpositioning and RMSD calculations are well known to those of ordinary skill in the art, and can be carried out using programs such as, e.g., the programs listed in Table 5 below.
Structural similarity can be inferred from, e.g., sequence similarity, which can be determined by one of ordinary skill through visual inspection and comparison of the sequences, or through the use of well-known alignment software programs such as CLUSTAL (Wilbur et al., Proc. Natl. Acad. Sci. USA, 80, 726-730 (1983)) or CLUSTALW (Thompson et al., Nucleic Acids Research, 22:4673 4680 (1994)) or BLAST® (Altschul et al., J Mol. Biol., October 5; 215(3):403 10 (1990)), a set of similarity search programs designed to explore all of the available sequence databases regardless of whether the query is protein or DNA. CLUSTAL W is available at the EMBL-EBI website (found on the web at the site: ebi.ac.uk/clustalw); BLAST is available from the National Center for Biotechnology website (found on the web at the site: ncbi.nlm.nih.gov/BLAST). A residue within a first protein or nucleic acid sequence corresponds to a residue within a second protein or nucleic acid sequence if the two residues occupy the same position when the first and second sequences are aligned.
The term “a set” refers to a collection of one or more objects.
The term percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., BLASTP and BLASTN or other algorithms available to persons of skill) or by visual inspection. Depending on the application, the percent “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared.
For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence co-ordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.
Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra).
One example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol. 215:403-410 (1990). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (NCBI web-site)
The term “sterol” refers to a subgroup of steroids with a hydroxyl group at the 3-position of the A-ring (Subramaniam et al., J. Lipid Res. 46 (5):839-861 (2005)). Sterols are amphipathic lipids synthesized from acetyl-coenzyme A via the HMG-CoA reductase pathway. The overall molecule is quite flat. Sterols can include, e.g., cholesterol or CHS.
The term “atomic co-ordinates for residues” refers to co-ordinates for all atoms associated with a residue, or for some of the atoms such as, e.g., side chain atoms.
The term “atomic co-ordinates of a candidate compound” refers to co-ordinates for all atoms comprising the compound or a subset of atoms comprising the compound.
The term “characterizing a binding interaction” refers to characterizing any observable property of a first molecule and determining an whether there is a change in that observable property after contacting the first molecule with a second molecule under conditions in which said first and second molecules can potentially bind.
Ballesteros-Weinstein numbering is used throughout the text as superscripts to the protein numbering. Within each helix is a single most conserved residue among the class A GPCRs. This residue is designated X.50, where x is the number of the transmembrane helix. All other residues on that helix are numbered relative to this conserved position.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.
Introduction
G-protein coupled receptors are cell surface receptors that indirectly transduce extracellular signals to downstream effectors, e.g., intracellular signaling proteins, enzymes, or channels. G-protein coupled receptor membrane proteins are grouped into one of 6 classes: A, B, C, D, E, and F. The interaction between the receptor and the downstream effector is mediated by a G-protein, a heterotrimeric protein that binds GTP. Examples of mammalian G proteins include Gi, Go, Gq, Gs, and Gt. Changes in the activity of the G proteins then mediate subsequent cellular events.
G-protein coupled receptors (GPCRs) typically have seven transmembrane regions, along with an extracellular domain and a cytoplasmic tail at the C-terminus. These receptors form a large superfamily of related receptor molecules that play a key role in many signaling processes, such as sensory and hormonal signal transduction. An example of a mammalian G-protein coupled receptor is the adenosine A2A receptor, a receptor in the Class A subfamily of GPCRs.
Class A GPCRs function in a variety of physiological processes such as vasodilation, bronchodilation, neurotransmitter signaling, stimulation of endocrine secretions, gut peristalsis, development, mitogenesis, cell proliferation, cell migration, immune system function, and oncogenesis. Accordingly, class A GPCRs can be used as screening targets to identify modulators of these processes which can then function to ameliorate diseases associated with these processes, e.g., cancer and autoimmunity. A 2.8 Å resolution crystal structure of a thermally-stabilized human β2-adrenergic receptor bound to cholesterol and the partial inverse agonist timolol has been previously described (see, e.g., D. M. Rosenbaum et al., Science 318: 1266 (2007); V. Cherezov et al., Science 318: 1258 (2007); U.S. Prov. App. No. 60/999,51, filed Oct. 22, 2007; U.S. Prov. App. No. 61/000,325, filed Oct. 24, 2007; and U.S. Prov. App. No. 61,0606,107, filed Jun. 9, 2008). That work indicated a structurally relevant cholesterol binding site between helices I, II, III, and IV. Thermal stability analysis using isothermal denaturation confirmed that cholesterol enhances the stability of the β2-adrenergic receptor and identified a consensus binding site.
The Crystal Structure Co-Ordinates of the Human Adenosine A2A Receptor Bound to ZM241385
The 2.6 Angstrom structure of human A2A adenosine receptor bound to ZM241385 can be used as a model for rationally designing pharmacophore and/or candidate compounds, either de novo or by modification of known compounds. As noted below, the multiple ligand binding sites in this structure include amino acids that are highly conserved across a large number of class A G protein coupled receptors (GPCRs) indicating that the 2.6 Angstrom structure of human A2A adenosine receptor can be used for the rational designing of ligands (e.g., therapeutic compounds) that bind to this receptor and others. Pharmacophore and candidate compounds identified through the use of the crystal structure co-ordinates will have utility as pharmaceuticals due to their ability to alter the structure and/or binding properties of the A2A adenosine receptor. Pharmacophores and candidate compounds can be determined according to any method known in the art, including the methods described in U.S. Pat. No. 5,888,738 to Hendry, and the methods described in U.S. Pat. No. 5,856,116 to Wilson et al. the disclosures of which both are incorporated by reference in their entirety for all purposes.
The structure data provided herein can be used in conjunction with computer-modeling techniques to develop models of sites on the human A2A adenosine receptor or related GPCRs selected by analysis of the crystal structure data. The site models characterize the three-dimensional topography of site surface, as well as factors including van der Waals contacts, electrostatic interactions, and hydrogen-bonding opportunities. Computer simulation techniques can be used to map interaction positions for functional groups including protons, hydroxyl groups, amine groups, divalent cations, aromatic and aliphatic functional groups, amide groups, alcohol groups, etc. that are designed to interact with the model site. These groups can be designed into a pharmacophore or candidate compound with the expectation that the candidate compound will specifically bind to the site. Pharmacophore design thus involves a consideration of the ability of the candidate compounds falling within the pharmacophore to interact with a site through any or all of the available types of chemical interactions, including hydrogen bonding, van der Waals, electrostatic, and covalent interactions, although, in general, and preferably, pharmacophores interact with a site through non-covalent mechanisms.
The ability of a pharmacophore or candidate compound to bind to the human A2A adenosine receptor can be analyzed prior to actual synthesis using computer modeling techniques. Only those candidates that are indicated by computer modeling to bind the target with sufficient binding energy (i.e., binding energy corresponding to a dissociation constant with the target on the order of 10−2 M or tighter) can be synthesized and tested for their ability to bind to the human A2A adenosine receptor using binding assays or functional assays known to those of skill in the art. The computational evaluation step thus avoids the unnecessary synthesis of compounds that are unlikely to bind the human A2A adenosine receptor or one or more of its constitutive binding sites, or the related binding sites of another GPCR with adequate affinity.
A human A2A adenosine receptor or candidate compound(s) can be computationally evaluated and designed by means of a series of steps in which chemical entities or fragments are screened and selected for their ability to associate with individual binding target sites on the human A2A adenosine receptor or binding site thereof, including, but not limited to binding pockets I, II, and III of the human A2A adenosine receptor. One skilled in the art can use one of several methods to screen chemical entities or fragments for their ability to associate with one or more of these human A2A adenosine receptor binding sites. For example, increased affinity and specificity may be designed into caffeine and other xanthine molecules by combining interactions with both xanthine and non-xanthine binding sites.
The process can begin by visual inspection of, for example a target site on a computer screen, based on the human A2A adenosine receptor co-ordinates, or a subset of those co-ordinates (e.g., binding Pockets I, II or III), as set forth in Table 6. Selected fragments or chemical entities can then be positioned in a variety of orientations or “docked” within a target site of the human A2A adenosine receptor as defined from analysis of the crystal structure data. Docking can be accomplished using software such as Quanta (Molecular Simulations, Inc., San Diego, Calif.) and Sybyl (Tripos, Inc. St. Louis, Mo.) followed by energy minimization and molecular dynamics with standard molecular mechanics forcefields such as CHARMM (Molecular Simulations, Inc., San Diego, Calif.), ICM (Molsoft, San Diego, Calif.), and AMBER (University of California, San Francisco).
Specialized computer programs can also assist in the process of selecting fragments or chemical entities. These include but are not limited to: GRID (Goodford et al., J. Med. Chem., 28, pp. 849 857 (1985)); GRID is available from Oxford University, Oxford, UK; MCSS (Miranker, A. and M. Karplus, Proteins: Structure, Function and Genetics, 11, pp. 29 34 (1991)); MCSS is available from Molecular Simulations, Inc., San Diego, Calif.; AUTODOCK (Goodsell, D. S, and A. J. Olsen, Proteins: Structure, Function, and Genetics, 8, pp. 195 202 (1990)); AUTODOCK is available from Scripps Research Institute, La Jolla, Calif.; DOCK (Kuntz, I. D., et al., J. Mol. Biol., 161, pp. 269 288 (1982)); DOCK is available from University of California, San Francisco, Calif.; CERIUS II (available from Molecular Simulations, Inc., San Diego, Calif.); and Flexx (Raret et al., J. Mol. Biol., 261, pp. 470 489 (1996)).
After selecting suitable chemical entities or fragments, they can be assembled into a single compound. Assembly can proceed by visual inspection of the relationship of the fragments to each other on a three-dimensional image of the fragments in relation to the human A2A adenosine receptor or its binding sites or those of a related GPCR receptor structure or portion thereof displayed on a computer screen. Visual inspection can be followed by manual model building using software such as the Quanta or Sybyl programs described above.
Software programs also can be used to aid one skilled in the art in connecting the individual chemical entities or fragments. These include, but are not limited to CAVEAT (Bartlett, P. A., et al. “CAVEAT: A Program to Facilitate the Structure-Derived Design of Biologically Active Molecules” In “Molecular Recognition in Chemical and Biological Problems,” Special Publ, Royal Chem. Soc., 78, pp. 182-196 (1989)); CAVEAT is available from the University of California, Berkeley, Calif.; 3D Database systems such as MACCS-3D (MDL Information Systems, San Leandro, Calif.); this area is reviewed in Martin, Y. C., J. Med. Chem., 35:2145 2154 (1992)); and HOOK (available from Molecular Simulations Inc., San Diego, Calif.).
As an alternative to building candidate pharmacophores or candidate compounds up from individual fragments or chemical entities, they can be designed de novo using the structure of the A2A adenosine receptor, its constituent binding pockets I, II and III, or the homologous cavities in a related GPCR, optionally, including information from co-factor(s) or known activators or inhibitor(s) that bind to the target site. De novo design can be implemented by programs including, but not limited to LUDI (Bohm, H. J., J. Comp. Aid. Molec. Design, 6, pp. 61 78 (1992)); LUDI is available from Molecular Simulations, Inc., San Diego, Calif.; LEGEND (Nishibata, Y., and Itai, A., Tetrahedron 47, p. 8985 (1991); LEGEND is available from Molecular Simulations, San Diego, Calif.; and LeapFrog (available from Tripos Associates, St. Louis, Mo.).
The functional effects of known A2A adenosine receptor ligands also can be altered through the use of the molecular modeling and design techniques described herein. This can be carried out by docking the structure of the known ligand on a human A2A adenosine receptor or a model structure of one or more binding sites of the human A2A adenosine receptor (e.g., binding pockets I, II and/or III describes herein) and modifying the shape and charge distribution of the ligand or protein model structure to optimize the binding interactions between the ligand and protein. The modified structure can be synthesized or obtained from a library of compounds and tested for its binding affinity and/or effect on ribosome function. Of course, where the crystal structure of a complex between a human A2A adenosine receptor (or subunit thereof) and a ligand is known, comparisons between said complex and the structures of the present invention can be made to gain additional information about alterations in human A2A adenosine receptor conformation that occur upon ligand binding. This information can be used in design of optimized ligands. Compounds that interfere or activate human A2A adenosine receptor function (e.g., by interacting with binding pockets I, II or III) are especially well suited for the docking, co-crystallization, and optimization applications of the present invention.
Additional molecular modeling techniques also can be employed in accordance with the invention. See, e.g., Cohen, N. C., et al. J. Med. Chem., 33, pp. 883 894 (1990); Hubbard, Roderick E., Curr. Opin. Biotechnol. 8, pp. 696-700 (1997); and Afshar, et al. “Structure-Based and Combinatorial Search for New RNA-Binding Drugs,” Curr. Opin. Biotechnol. 10, pp. 59-63 (1999).
Following pharmacophore or candidate compound design or selection according to any of the above methods or other methods known to one skilled in the art, the efficiency with which a candidate compound falling within the pharmacophore definition binds to the human A2A adenosine receptor or at least one its three preferred binding sites, or alternatively binds to a related GPCR or homologous portions thereof, can be tested and optimized using computational evaluation. A candidate compound can be optimized, e.g., so that in its bound state it would preferably lack repulsive electrostatic interaction with the target site. These repulsive electrostatic interactions include repulsive charge-charge, dipole-dipole, and charge-dipole interactions. It is preferred that the sum of all electrostatic interactions between the candidate compound and the human A2A adenosine receptor, including its binding pockets I, II, and/or III (collectively “target”) when the candidate compound is bound to the target make a neutral or favorable contribution to the binding enthalpy or free energy.
Specific computer software is available in the art to evaluate compound deformation energy and electrostatic interactions. Examples of programs designed for such uses include, but are not limited to Gaussian 92, revision C (Frisch, M. J., Gaussian, Inc., Pittsburgh, Pa. (1992)); AMBER, version 4.0 (Kollman, P. A., University of California at San Francisco, (1994)); QUANTA/CHARMM (Molecular Simulations, Inc., San Diego, Calif. (1994)); and Insight II/Discover (Biosym Technologies Inc., San Diego, Calif. (1994)). These programs can be run, using, e.g., a Silicon Graphics workstation, Indigo, 02-R10000 or IBM RISC/6000 workstation model 550. Other hardware and software combinations can be used to carry out the above described functions, and are known to those of skill in the art. In general, the methods described herein, particularly computer-implemented methods, comprise a step of recording or storing data onto a medium, wherein the medium can include a computer-readable medium. Additionally, or alternatively, the methods comprise a step of reporting or communicating the data to a user of interest, e.g., an operator of the device and/or computer that is employed in the method; or the computer can perform an additional useful task, e.g., alert the operator of the computer that a function has been completed, upon completing one or more determining steps of the method.
Once a pharmacophore or candidate compound has been optimally selected or designed, as described above, substitutions can then be made in some of its atoms or side groups to improve or modify its binding properties. Generally, initial substitutions are conservative in that the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original group. Components known in the art to alter conformation should be avoided in making substitutions. Substituted candidates can be analyzed for efficiency of fit to the human A2A adenosine receptor (or one or more binding sites selected from binding pockets I, II and III of the human A2A adenosine receptor) using the same methods described above.
Assays
Any one of a number of assays of function known to those of skill in the art can be used to determine the biological activity of candidate compounds.
Candidate compound interaction with the human A2A adenosine receptor (or one or more binding sites selected from binding pockets I, II and III of the human A2A adenosine receptor) or to a related GPCR or portion thereof can be evaluated using direct binding assays including filter binding assays, such as are known to those skilled in the art. Binding assays can be modified to evaluate candidate compounds that competitively inhibit the binding of, e.g., known human A2A adenosine receptor binding compounds including xanthine and xanthine-based compounds such as theophylline, theobromine and caffeine. These and other assays are described in International Publication WO 00/69391, the entire disclosure of which is incorporated by reference in its entirety for all purposes. Methods of assaying for modulators of ligand binding and signal transduction include in vitro ligand binding assays using GPCRs, such as human A2A adenosine receptor (or one or more binding sites selected from the binding pockets I, II and III of the human A2A adenosine receptor), portions thereof such as the extracellular domain, or chimeric proteins comprising one or more domains of a GPCR, oocyte GPCR expression or tissue culture cell GPCR expression, either naturally occurring or recombinant; membrane expression of a GPCR, either naturally occurring or recombinant; tissue expression of a GPCR; expression of a GPCR in a transgenic animal, etc.
As noted above, GPCRs and their alleles and polymorphic variants are G-protein coupled receptors that participate in signal transduction and are associated with cellular function in a variety of cells, e.g., neurons, immune system cells, kidney, liver, colon, adipose, and other cells. The activity of GPCR polypeptides can be assessed using a variety of in vitro and in vivo assays to determine functional, chemical, and physical effects, e.g., measuring ligand binding, (e.g., radioactive ligand binding), second messengers (e.g., cAMP, cGMP, IP3, DAG, or Ca2+), ion flux, phosphorylation levels, transcription levels, neurotransmitter levels, and the like. Such assays can be used to test for inhibitors and activators of a GPCR. In particular, the assays can be used to test for compounds that modulate natural ligand-induced GPCR activity, for example, by modulating the binding of the natural ligand to the receptor and/or by modulating the ability of the natural ligand to activate the receptor. Typically in such assays, the test compound is contacted with the GPCR in the presence of the natural ligand. The natural ligand can be added to the assay before, after, or concurrently with the test compound. The results of the assay, for example, the level of binding, calcium mobilization, etc. is then compared to the level in a control assay that comprises the GPCR and natural ligand in the absence of the test compound.
Screening assays of the invention are used to identify modulators that can be used as therapeutic agents, e.g., antagonists of GPCR activity. For example, ZM241385 is a known high-affinity specific antagonist of the human A2A adenosine receptor.
The effects of test compounds upon the function of the GPCR polypeptides can be measured by examining any of the parameters described above. Any suitable physiological change that affects GPCR activity can be used to assess the influence of a test compound on the GPCRs and natural ligand-mediated GPCR activity. When the functional consequences are determined using intact cells or animals, one can also measure a variety of effects such as transmitter release, hormone release, transcriptional changes to both known and uncharacterized genetic markers (e.g., northern blots), changes in cell metabolism such as cell growth or pH changes, and changes in intracellular second messengers such as Ca2+, IP3 or cAMP.
For a general review of GPCR signal transduction and methods of assaying signal transduction, see, e.g., Methods in Enzymology, vols. 237 and 238 (1994) and volume 96 (1983); Bourne et al., Nature 10:349:117-27 (1991); Bourne et al., Nature 348:125-32 (1990); Pitcher et al., Annu. Rev. Biochem. 67:653-92 (1998).
Modulators of GPCR activity are tested using GPCR polypeptides, either recombinant or naturally occurring. The protein can be isolated, expressed in a cell, expressed in a membrane derived from a cell, expressed in tissue or in an animal, either recombinant or naturally occurring. For example, neurons, cells of the immune system, adipocytes, kidney cells, transformed cells, or membranes can be used. Modulation is tested using one of the in vitro or in vivo assays described herein or others as generally known in the art. Signal transduction can also be examined in vitro with soluble or solid state reactions, using a chimeric molecule such as an extracellular domain of a receptor covalently linked to a heterologous signal transduction domain, or a heterologous extracellular domain covalently linked to the transmembrane and or cytoplasmic domain of a receptor. Furthermore, ligand-binding domains of the protein of interest can be used in vitro in soluble or solid state reactions to assay for ligand binding.
Ligand binding to a human A2A adenosine receptor (or one or more binding sites selected from binding pockets I, II and III of the human A2A adenosine receptor) or a chimeric protein derivative can be tested in a number of formats. For example, binding can be performed in solution, in a bilayer membrane, attached to a solid phase, in a lipid monolayer, or in vesicles. Typically, in an assay of the invention, the binding of the natural ligand to its receptor is measured in the presence of a candidate modulator. Alternatively, the binding of the candidate modulator can be measured in the presence of the natural ligand. Often, competitive assay that measure the ability of a compound to compete with binding of the natural ligand to the receptor are used. Binding can be measured by assessing GPCR activity or by other assays: binding can be tested by measuring e.g., changes in spectroscopic characteristics (e.g., fluorescence, absorbance, refractive index), hydrodynamic (e.g., shape) changes, or changes in chromatographic or solubility properties.
Receptor-G-protein interactions can also be used to assay for modulators. For example, in the absence of GTP, binding of an activator such as the natural ligand will lead to the formation of a tight complex of a G protein (all three subunits) with the receptor. This complex can be detected in a variety of ways, as noted above. Such an assay can be modified to search for inhibitors. For example, a ligand can be added to the human A2A adenosine receptor and G protein in the absence of GTP to form a tight complex Inhibitors can be identified by looking at dissociation of the receptor-G protein complex. In the presence of GTP, release of the alpha subunit of the G protein from the other two G protein subunits serves as a criterion of activation.
An activated or inhibited G-protein will in turn alter the properties of downstream effectors such as proteins, enzymes, and channels. The classic examples are the activation of cGMP phosphodiesterase by transducin in the visual system, adenylate cyclase by the stimulatory G-protein, phospholipase C by Gq and other cognate G proteins, and modulation of diverse channels by Gi and other G proteins. Downstream consequences such as generation of diacyl glycerol and IP3 by phospholipase C, and in turn, for calcium mobilization e.g., by IP3 can also be examined. Thus, modulators can be evaluated for the ability to stimulate or inhibit ligand-mediated downstream effects. In other examples, the ability of a modulator to activate a GPCR expressed in adipocytes in comparison to the ability of a natural ligand, can be determined using assays such as lipolysis (see, e.g., WO01/61359).
Activated GPCRs become substrates for kinases that phosphorylate the C-terminal tail of the receptor (and possibly other sites as well). Thus, activators will promote the transfer of 32P from gamma-labeled GTP to the receptor, which can be assayed with a scintillation counter. The phosphorylation of the C-terminal tail will promote the binding of arrestin-like proteins and will interfere with the binding of G-proteins. The kinase/arrestin pathway plays a key role in the desensitization of many GPCR receptors. Modulators can therefore also be identified using assays involving beta-arrestin recruitment. Beta-arrestin serves as a regulatory protein that is distributed throughout the cytoplasm in unactivated cells. Ligand binding to an appropriate GPCR is associated with redistribution of beta-arrestin from the cytoplasm to the cell surface, where it associates with the GPCR. Thus, receptor activation and the effect of candidate modulators on ligand-induced receptor activation, can be assessed by monitoring beta-arrestin recruitment to the cell surface. This is frequently performed by transfecting a labeled beta-arrestin fusion protein (e.g., beta-arrestin-green fluorescent protein (GFP)) into cells and monitoring its distribution using confocal microscopy (see, e.g., Groarke et al., J. Biol. Chem. 274(33):23263-69 (1999)).
Receptor internalization assays can also be used to assess receptor function. Upon ligand binding, the G-protein coupled receptor—ligand complex is internalized from the plasma membrane by a clathrin-coated vesicular endocytic process; internalization motifs on the receptors bind to adaptor protein complexes and mediate the recruitment of the activated receptors into clathrin-coated pits and vesicles. Because only activated receptors are internalized, it is possible to detect ligand-receptor binding by determining the amount of internalized receptor. In one assay format, cells are transiently transfected with radiolabeled receptor and incubated for an appropriate period of time to allow for ligand binding and receptor internalization. Thereafter, surface-bound radioactivity is removed by washing with an acid solution, the cells are solubilized, and the amount of internalized radioactivity is calculated as a percentage of ligand binding. See, e.g., Vrecl et al., Mol. Endocrinol. 12:1818-29 (1988) and Conway et al., J. Cell Physiol. 189(3):341-55 (2001). In addition, receptor internalization approaches have allowed real-time optical measurements of GPCR interactions with other cellular components in living cells (see, e.g., Barak et al., Mol. Pharmacol. 51(2)177-84 (1997)). Modulators can be identified by comparing receptor internalization levels in control cells and cells contacted with candidate compounds. For example, candidate modulators the human A2A adenosine receptor are assayed by examining their effects on receptor internalization upon binding of the natural ligand, e.g., adenosine.
Another technology that can be used to evaluate GPCR-protein interactions in living cells involves bioluminescence resonance energy transfer (BRET). A detailed discussion regarding BRET can be found in Kroeger et al., J. Biol. Chem., 276(16):12736-43 (2001).
Receptor-stimulated guanosine 5′-O-(.gamma.-Thio)-Triphosphate ([35S]GTP.gamma.S) binding to G-proteins can also be used as an assay for evaluating modulators of GPCRs. [35S]GTPγS is a radiolabeled GTP analog that has a high affinity for all types of G-proteins, is available with a high specific activity and, although unstable in the unbound form, is not hydrolyzed when bound to the G-protein. Thus, it is possible to quantitatively assess ligand-bound receptor by comparing stimulated versus unstimulated [35S]GTP.gamma.S binding utilizing, for example, a liquid scintillation counter. Inhibitors of the receptor-ligand interactions would result in decreased [35S]GTPγS binding. Descriptions of [35S]GTPγS binding assays are provided in Traynor and Nahorski, Mol. Pharmacol. 47(4):848-54 (1995) and Bohn et al., Nature 408:720-23 (2000).
The ability of modulators to affect ligand-induced ion flux can also be determined. Ion flux can be assessed by determining changes in polarization (i.e., electrical potential) of the cell or membrane expressing a GPCR. One means to determine changes in cellular polarization is by measuring changes in current (thereby measuring changes in polarization) with voltage-clamp and patch-clamp techniques, e.g., the “cell-attached” mode, the “inside-out” mode, and the “whole cell” mode (see, e.g., Ackerman et al., New Engl. J. Med. 336:1575-1595 (1997)). Whole cell currents are conveniently determined using the standard methodology (see, e.g., Hamil et al., Pflügers. Archiv. 391:85 (1981). Other known assays include: radiolabeled ion flux assays and fluorescence assays using voltage-sensitive dyes (see, e.g., Vestergarrd-Bogind et al., J. Membrane Biol. 88:67-75 (1988); Gonzales & Tsien, Chem. Biol. 4:269-277 (1997); Daniel et al., J. Pharmacol. Meth. 25:185-193 (1991); Holevinsky et al., J. Membrane Biology 137:59-70 (1994)). Generally, the compounds to be tested are present in the range from 1 pM to 100 mM.
Preferred assays for G-protein coupled receptors include cells that are loaded with ion or voltage sensitive dyes to report receptor activity. Assays for determining activity of such receptors can also use known agonists and antagonists for other G-protein coupled receptors and the natural ligands disclosed herein as negative or positive controls to assess activity of tested compounds. In assays for identifying modulatory compounds (e.g., agonists, antagonists), changes in the level of ions in the cytoplasm or membrane voltage are monitored using an ion sensitive or membrane voltage fluorescent indicator, respectively. Among the ion-sensitive indicators and voltage probes that can be employed are those disclosed in the Molecular Probes 1997 Catalog. For G-protein coupled receptors, promiscuous G-proteins such as Gα15 and Gα16 can be used in the assay of choice (Wilkie et al., Proc. Nat'l Acad. Sci. USA 88:10049-10053 (1991)). Such promiscuous G-proteins allow coupling of a wide range of receptors to signal transduction pathways in heterologous cells.
Receptor activation by ligand binding typically initiates subsequent intracellular events, e.g., increases in second messengers such as IP3, which releases intracellular stores of calcium ions. Activation of some G-protein coupled receptors stimulates the formation of inositol triphosphate (IP3) through phospholipase C-mediated hydrolysis of phosphatidylinositol (Berridge & Irvine, Nature 312:315-21 (1984)). IP3 in turn stimulates the release of intracellular calcium ion stores. Thus, a change in cytoplasmic calcium ion levels, or a change in second messenger levels such as IP3 can be used to assess G-protein coupled receptor function. Cells expressing such G-protein coupled receptors can exhibit increased cytoplasmic calcium levels as a result of contribution from both intracellular stores and via activation of ion channels, in which case it can be desirable although not necessary to conduct such assays in calcium-free buffer, optionally supplemented with a chelating agent such as EGTA, to distinguish fluorescence response resulting from calcium release from internal stores.
Other assays can involve determining the activity of receptors which, when activated by ligand binding, result in a change in the level of intracellular cyclic nucleotides, e.g., cAMP or cGMP, by activating or inhibiting downstream effectors such as adenylate cyclase. There are cyclic nucleotide-gated ion channels, e.g., rod photoreceptor cell channels and olfactory neuron channels that are permeable to cations upon activation by binding of cAMP or cGMP (see, e.g., Altenhofen et al., Proc. Natl. Acad. Sci. U.S.A. 88:9868-9872 (1991) and Dhallan et al., Nature 347:184-187 (1990)). In cases where activation of the receptor results in a decrease in cyclic nucleotide levels, it can be preferable to expose the cells to agents that increase intracellular cyclic nucleotide levels, e.g., forskolin, prior to adding a receptor-activating compound to the cells in the assay. Cells for this type of assay can be made by co-transfection of a host cell with DNA encoding a cyclic nucleotide-gated ion channel, GPCR phosphatase and DNA encoding a receptor (e.g., certain glutamate receptors, muscarinic acetylcholine receptors, dopamine receptors, serotonin receptors, and the like), which, when activated, causes a change in cyclic nucleotide levels in the cytoplasm.
In one embodiment, changes in intracellular cAMP or cGMP can be measured using immunoassays. The method described in Offermanns & Simon, J. Biol. Chem. 270:15175-15180 (1995) can be used to determine the level of cAMP. Also, the method described in Felley-Bosco et al., Am. J. Resp. Cell and Mol. Biol. 11:159-164 (1994) can be used to determine the level of cGMP. Further, an assay kit for measuring cAMP and/or cGMP is described in U.S. Pat. No. 4,115,538, herein incorporated by reference.
In another embodiment, phosphatidyl inositol (PI) hydrolysis can be analyzed according to U.S. Pat. No. 5,436,128, herein incorporated by reference. Briefly, the assay involves labeling of cells with 3H-myoinositol for 48 or more hrs. The labeled cells are treated with a test compound for one hour. The treated cells are lysed and extracted in chloroform-methanol-water after which the inositol phosphates are separated by ion exchange chromatography and quantified by scintillation counting. Fold stimulation is determined by calculating the ratio of cpm in the presence of agonist to cpm in the presence of buffer control. Likewise, fold inhibition is determined by calculating the ratio of cpm in the presence of antagonist to cpm in the presence of buffer control (which can or can not contain an agonist).
In another embodiment, transcription levels can be measured to assess the effects of a test compound on ligand-induced signal transduction. A host cell containing the protein of interest is contacted with a test compound in the presence of the natural ligand for a sufficient time to effect any interactions, and then the level of gene expression is measured. The amount of time to effect such interactions can be empirically determined, such as by running a time course and measuring the level of transcription as a function of time. The amount of transcription can be measured by using any method known to those of skill in the art to be suitable. For example, mRNA expression of the protein of interest can be detected using northern blots or their polypeptide products can be identified using immunoassays. Alternatively, transcription based assays using reporter genes can be used as described in U.S. Pat. No. 5,436,128, herein incorporated by reference. The reporter genes can be, e.g., chloramphenicol acetyltransferase, firefly luciferase, bacterial luciferase, beta-galactosidase and alkaline phosphatase. Furthermore, the protein of interest can be used as an indirect reporter via attachment to a second reporter such as green fluorescent protein (see, e.g., Mistili & Spector, Nature Biotechnology 15:961-964 (1997)).
The amount of transcription is then compared to the amount of transcription in either the same cell in the absence of the test compound, or it can be compared with the amount of transcription in a substantially identical cell that lacks the protein of interest. A substantially identical cell can be derived from the same cells from which the recombinant cell was prepared but which had not been modified by introduction of heterologous DNA. Any difference in the amount of transcription indicates that the test compound has in some manner altered the activity of the protein of interest.
Samples that are treated-with a potential GPCR inhibitor or activator are compared to control samples comprising the natural ligand without the test compound to examine the extent of modulation. Control samples (untreated with activators or inhibitors) are assigned a relative GPCR activity value of 100 Inhibition of a GPCR is achieved when the GPCR activity value relative to the control is about 90%, optionally 50%, optionally 25-0%. Activation of a GPCR is achieved when the GPCR activity value relative to the control is 110%, optionally 150%, 200-500%, or 1000-2000%.
In one embodiment the invention provides soluble assays using molecules such as a domain, e.g., a ligand binding domain, an extracellular domain, a transmembrane domain (e.g., one comprising seven transmembrane regions and cytosolic loops), the transmembrane domain and a cytoplasmic domain, an active site, a subunit association region, etc.; a domain that is covalently linked to a heterologous protein to create a chimeric molecule; a GPCR; or a cell or tissue expressing a GPCR, either naturally occurring or recombinant. In another embodiment, the invention provides solid phase based in vitro assays in a high throughput format, where the domain, chimeric molecule, GPCR, or cell or tissue expressing a GPCR is attached to a solid phase substrate.
Certain screening methods involve screening for a compound that modulates the expression of the GPCRs described herein, or the levels of natural ligands, e.g., ASP and stanniocalcins. Such methods generally involve conducting cell-based assays in which test compounds are contacted with one or more cells expressing the GPCR or ligand and then detecting an increase or decrease in expression (either transcript or translation product). Such assays are typically performed with cells that express the endogenous GPCR or ligand.
Expression can be detected in a number of different ways. As described herein, the expression levels of the protein in a cell can be determined by probing the mRNA expressed in a cell with a probe that specifically hybridizes with a transcript (or complementary nucleic acid derived therefrom) of the GPCR or protein ligand. Probing can be conducted by lysing the cells and conducting Northern blots or without lysing the cells using in situ-hybridization techniques (see above). Alternatively, protein can be detected using immunological methods in which a cell lysate is probed with antibodies that specifically bind to the protein.
Other cell-based assays are reporter assays conducted with cells that do not express the protein. Certain of these assays are conducted with a heterologous nucleic acid construct that includes a promoter that is operably linked to a reporter gene that encodes a detectable product. A number of different reporter genes can be utilized. Some reporters are inherently detectable. An example of such a reporter is green fluorescent protein that emits fluorescence that can be detected with a fluorescence detector. Other reporters generate a detectable product. Often such reporters are enzymes. Exemplary enzyme reporters include, but are not limited to, beta-glucuronidase, CAT (chloramphenicol acetyl transferase), luciferase, beta-galactosidase and alkaline phosphatase.
In these assays, cells harboring the reporter construct are contacted with a test compound. A test compound that either modulates the activity of the promoter by binding to it or triggers a cascade that produces a molecule that modulates the promoter causes expression of the detectable reporter. Certain other reporter assays are conducted with cells that harbor a heterologous construct that includes a transcriptional control element that activates expression of the GPCR or ligand and a reporter operably linked thereto. Here, too, an agent that binds to the transcriptional control element to activate expression of the reporter or that triggers the formation of an agent that binds to the transcriptional control element to activate reporter expression, can be identified by the generation of signal associated with reporter expression.
In one embodiment the invention provides soluble assays using molecules such as a domain, e.g., a ligand binding domain, an extracellular domain, a transmembrane domain (e.g., one comprising seven transmembrane regions and cytosolic loops), the transmembrane domain and a cytoplasmic domain, an active site, a subunit association region, etc.; a domain that is covalently linked to a heterologous protein to create a chimeric molecule; a GPCR; or a cell or tissue expressing a GPCR, either naturally occurring or recombinant. In another embodiment, the invention provides solid phase based in vitro assays in a high throughput format, where the domain, chimeric molecule, GPCR, or cell or tissue expressing a GPCR is attached to a solid phase substrate.
In the high throughput assays of the invention, it is possible to screen up to several thousand different modulators or ligands in a single day. In particular, each well of a microtiter plate can be used to run a separate assay against a selected potential modulator, or, if concentration or incubation time effects are to be observed, every 5-10 wells can test a single modulator. Thus, a single standard microtiter plate can assay about 100 (e.g., 96) modulators. If 1536 well plates are used, then a single plate can easily assay from about 100-1500 different compounds. It is possible to assay several different plates per day; assay screens for up to about 6,000-20,000 different compounds are possible using the integrated systems of the invention.
The molecule of interest can be bound to the solid state component, directly or indirectly, via covalent or non covalent linkage e.g., via a tag. The tag can be any of a variety of components. In general, a molecule which binds the tag (a tag binder) is fixed to a solid support, and the tagged molecule of interest (e.g., the signal transduction molecule of interest) is attached to the solid support by interaction of the tag and the tag binder.
A number of tags and tag binders can be used, based upon known molecular interactions well described in the literature. For example, where a tag has a natural binder, for example, biotin, protein A, or protein G, it can be used in conjunction with appropriate tag binders (avidin, streptavidin, neutravidin, the Fc region of an immunoglobulin, etc.). Antibodies to molecules with natural binders such as biotin are also widely available and are appropriate tag binders; see, SIGMA Immunochemicals 1998 catalogue SIGMA, St. Louis Mo.).
Similarly, any haptenic or antigenic compound can be used in combination with an appropriate antibody to form a tag/tag binder pair. Thousands of specific antibodies are commercially available and many additional antibodies are described in the literature. For example, in one common configuration, the tag is a first antibody and the tag binder is a second antibody which recognizes the first antibody. In addition to antibody-antigen interactions, receptor-ligand interactions are also appropriate as tag and tag-binder pairs. For example, agonists and antagonists of cell membrane receptors (e.g., cell receptor-ligand interactions such as transferrin, c-kit, viral receptor ligands, cytokine receptors, chemokine receptors, interleukin receptors, immunoglobulin receptors and antibodies, the cadherin family, the integrin family, the selectin family, and the like; see, e.g., Pigott & Power, The Adhesion Molecule Facts Book I (1993). Similarly, toxins and venoms, viral epitopes, hormones (e.g., opiates, steroids, etc.), intracellular receptors (e.g. which mediate the effects of various small ligands, including steroids, thyroid hormone, retinoids and vitamin D; peptides), drugs, lectins, sugars, nucleic acids (both linear and cyclic polymer configurations), oligosaccharides, proteins, phospholipids and antibodies can all interact with various cell receptors.
Synthetic polymers, such as polyurethanes, polyesters, polycarbonates, polyureas, polyamides, polyethyleneimines, polyarylene sulfides, polysiloxanes, polyimides, and polyacetates can also form an appropriate tag or tag binder. Many other tag/tag binder pairs are also useful in assay systems described herein, as would be apparent to one of skill upon review of this disclosure.
Common linkers such as peptides, polyethers, and the like can also serve as tags, and include polypeptide sequences, such as poly-gly sequences of between about 5 and 200 amino acids. Such flexible linkers are known to persons of skill in the art. For example, poly(ethylene glycol) linkers are available from Shearwater Polymers, Inc. Huntsville, Ala. These linkers optionally have amide linkages, sulfhydryl linkages, or heterofunctional linkages.
Tag binders are fixed to solid substrates using any of a variety of methods currently available. Solid substrates are commonly derivatized or functionalized by exposing all or a portion of the substrate to a chemical reagent which fixes a chemical group to the surface which is reactive with a portion of the tag binder. For example, groups which are suitable for attachment to a longer chain portion would include amines, hydroxyl, thiol, and carboxyl groups. Aminoalkylsilanes and hydroxyalkylsilanes can be used to functionalize a variety of surfaces, such as glass surfaces. The construction of such solid phase biopolymer arrays is well described in the literature. See, e.g., Merrifield, J. Am. Chem. Soc. 85:2149-2154 (1963) (describing solid phase synthesis of, e.g., peptides); Geysen et al., J. Immun. Meth. 102:259-274 (1987) (describing synthesis of solid phase components on pins); Frank & Doring, Tetrahedron 44:60316040 (1988) (describing synthesis of various peptide sequences on cellulose disks); Fodor et al., Science, 251:767-777 (1991); Sheldon et al., Clinical Chemistry 39(4):718-719 (1993); and Kozal et al., Nature Medicine 2(7):753759 (1996) (all describing arrays of biopolymers fixed to solid substrates). Non-chemical approaches for fixing tag binders to substrates include other common methods, such as heat, cross-linking by UV radiation, and the like.
Modulators
Inhibitors and/or activators identified according to the methods of the invention can be provided from libraries of compounds available from a number of sources or can be derived by combinatorial chemistry approaches known in the art. Such libraries include but are not limited to the available Chemical Director, Maybridge, and natural product collections. In one embodiment of the invention libraries of compounds with known or predicted structures can be docked to the human A2A adenosine receptor structures of the invention. In another embodiment, the libraries for ligands binding to binding pockets I, II and/or III can include xanthines and xanthine derivatives. In another embodiment, the libraries can include a linker component or moiety. In some embodiments, the linker can include from about 10-22 atoms and can include one or more of C, O, N, S, and/or H atoms. In another embodiment, the libraries can include a ligand binding site (also known as the ligand, agonist, or antagonist binding pocket) component or moiety. In some embodiments, the libraries can include drug-like molecules, i.e., molecules having structural attributes of one or more compounds known to bind to and/or affect a physiologic function of a GPCR.
In some embodiments, the invention includes compounds that can be tested as modulators of GPCR activity. Compounds tested as modulators of GPCRs can be any small chemical compound or biological entity. Typically, test compounds will be small chemical molecules and peptides. Essentially any chemical compound can be used as a potential modulator or ligand in the assays of the invention, although most often compounds can be dissolved in aqueous or organic (especially DMSO-based) solutions. The assays are designed to screen large chemical libraries by automating the assay steps. The assays are typically run in parallel (e.g., in microtiter formats on microtiter plates in robotic assays). It will be appreciated that there are many suppliers of chemical compounds, including Sigma (St. Louis, Mo.), Aldrich (St. Louis, Mo.), Sigma-Aldrich (St. Louis, Mo.), Fluka Chemika-Biochemica Analytika (Buchs Switzerland) and the like.
In one preferred embodiment, high throughput screening methods involve providing a combinatorial chemical or peptide library containing a large number of potential therapeutic compounds (potential modulator or ligand compounds). Such “combinatorial chemical libraries” or ligand libraries are then screened in one or more assays, as described herein, to identify those library members (particular chemical species or subclasses) that display a desired characteristic activity. The compounds thus identified can serve as conventional “lead compounds” or can themselves be used as potential or actual therapeutics.
A combinatorial chemical library is a collection of diverse chemical compounds generated by either chemical synthesis or biological synthesis, by combining a number of chemical “building blocks” such as reagents. For example, a linear combinatorial chemical library such as a polypeptide library is formed by combining a set of chemical building blocks (amino acids) in every possible way for a given compound length (i.e., the number of amino acids in a polypeptide compound). Millions of chemical compounds can be synthesized through such combinatorial mixing of chemical building blocks.
Preparation and screening of combinatorial chemical libraries is well known to those of skill in the art. Such combinatorial chemical libraries include, but are not limited to, peptide libraries (see, e.g., U.S. Pat. No. 5,010,175, Furka, Int. J. Pept. Prot. Res. 37:487-493 (1991) and Houghton et al., Nature 354:84-88 (1991)). Other chemistries for generating chemical diversity libraries can also be used. Such chemistries include, but are not limited to: peptoids (e.g., PCT Publication No. WO 91/19735), encoded peptides (e.g., PCT Publication WO 93/20242), random bio-oligomers (e.g., PCT Publication No. WO 92/00091), benzodiazepines (e.g., U.S. Pat. No. 5,288,514), diversomers such as hydantoins, benzodiazepines and dipeptides (Hobbs et al., Proc. Nat. Acad. Sci. USA 90:6909-6913 (1993)), vinylogous polypeptides (Hagihara et al., J. Amer. Chem. Soc. 114:6568 (1992)), nonpeptidal peptidomimetics with glucose scaffolding (Hirschmann et al., J. Amer. Chem. Soc. 114:9217-9218 (1992)), analogous organic syntheses of small compound libraries (Chen et al., J. Amer. Chem. Soc. 116:2661 (1994)), oligocarbamates (Cho et al., Science 261:1303 (1993)), and/or peptidyl phosphonates (Campbell et al., J. Org. Chem. 59:658 (1994)), nucleic acid libraries (see Ausubel, Berger and Russell & Sambrook, all supra), peptide nucleic acid libraries (see, e.g., U.S. Pat. No. 5,539,083), antibody libraries (see, e.g., Vaughn et al., Nature Biotechnology, 14(3):309-314 (1996) and PCT/US96/10287), carbohydrate libraries (see, e.g., Liang et al., Science, 274:1520-1522 (1996) and U.S. Pat. No. 5,593,853), small organic molecule libraries (see, e.g., benzodiazepines, Baum C&EN, January 18, page 33 (1993); isoprenoids, U.S. Pat. No. 5,569,588; thiazolidinones and metathiazanones, U.S. Pat. No. 5,549,974; pyrrolidines, U.S. Pat. Nos. 5,525,735 and 5,519,134; morpholino compounds, U.S. Pat. Nos. 5,506,337; benzodiazepines, 5,288,514, and the like).
Devices for the preparation of combinatorial libraries are commercially available (see, e.g., 357 MPS, 390 MPS, Advanced Chem Tech, Louisville Ky., Symphony, Rainin, Woburn, Mass., 433A Applied Biosystems, Foster City, Calif., 9050 Plus, Millipore, Bedford, Mass.). In addition, numerous combinatorial libraries are themselves commercially available (see, e.g., ComGenex, Princeton, N.J., Tripos, Inc., St. Louis, Mo., 3D Pharmaceuticals, Exton, Pa., Martek Biosciences, Columbia, Md., etc.).
It is noted that modulators that compete with the binding and/or activity of the known ligands for binding pockets I, II and III of the human A2A adenosine receptor can be used to treat various diseases including, but not limited to, coronary artery disease, atherosclerosis, thrombosis, obesity, diabetes, stroke, and other diseases.
In one embodiment, a modulator binds to a site on a GPCR, e.g., a human A2A adenosine receptor. In one aspect, the site is a xanthine binding site, e.g., the protonated form of binding pocket II. In another aspect, the site is a non-xanthine binding site, e.g., binding pocket I or the non-protonated form of binding pocket II. In another aspect, the site is an approximately 29 Angstrom3 cavity site corresponding to binding pocket III. In another aspect, the site is a ligand binding site. In another aspect, the modulator has a first moiety that binds to one of the binding sites (e.g., binding pocket I, II or III). In another aspect, the first moiety is connected to a linker. In another aspect, the first moiety and the linker are connected to at least one additional moiety that binds to a site other than that bound by the first moiety. In another aspect, the two or more moieties are not connected by a linker and are both present in a composition.
Computer-based Modeling of Adenosine A2A Receptors
Protein-ligand docking aims to employ principles by which protein receptors, e.g., human A2A adenosine receptors, recognize, interact, and associate with molecular substrates and compounds to predict the structure arising from the association between a given compound and a target protein of known three-dimensional structure.
In protein-ligand docking, the search algorithm can allow the degrees of freedom of the protein-ligand system to be sampled sufficiently as to include the true binding modes. Three general categories of algorithms have been developed to address this problem of ligand flexibility: systematic methods; random or stochastic methods; and simulation methods.
Systematic search algorithms attempt to explore all degrees of freedom in a molecule. These algorithms can be further divided into three types: conformational search methods, fragmentation methods, and database methods.
In conformational search methods, all rotatable bonds in the ligand are systematically rotated through 360° using a fixed increment, until all possible combinations have been generated and evaluated. As the number of structures generated increases immensely with the number of rotatable bonds (combinatorial explosion), the application of this type of method, in its purest form, is very limited.
Fragmentation methods use two different approaches to incrementally grow the ligands into the active site. One approach is by docking the several fragments into a site, e.g., a xanthine binding site (such as the protonated form of binding pocket II) or non-xanthine binding site of a human A2A adenosine receptor, and linking them covalently to recreate the initial ligand (“the place-and-join approach”). Another approach is by dividing the ligand into a rigid core-fragment that is docked in first place and flexible regions that are subsequently and successively added (“the incremental approach”). DOCK (see above) is an example of s docking programs that use a fragmentation search method.
Database methods using libraries of pre-generated conformations or conformational ensembles to address the combinatorial explosion problem. A example of a docking program using database methods is FLOG which generates a small set of 25 database conformations per molecule based on distance geometry, that are subsequently subject to a rigid docking protocol.
Random search algorithms sample the conformational space by performing random changes to a single ligand or a population of ligands. At each step, the alteration performed is accepted or rejected based on a predefined probability function. There are three basic types of methods based on random algorithms: Monte Carlo methods (MC), Genetic Algorithm methods (GA), and Tabu Search methods.
Simulation methods employ a rather different approach to the docking problem, based on the calculation of the solutions to Newton's equations of motion. Two major types exist: molecular dynamics (MD) and pure energy minimization methods.
Scoring functions normally employed in protein-ligand docking are generally able to predict binding free energies within 7-10 kJ/mol and can be divided into three major classes: force field-based, empirical, and knowledge-based scoring functions.
In force-field based scoring, standard force fields quantify the sum of two energies: the interaction energy between the receptor and the ligand, and the internal energy of the ligand. The energies are normally accounted through a combination of a van der Waals with an electrostatic energy terms. A Lennard-Jones potential is used to describe the van der Waals energy term, whereas the electrostatic term is given by a Coulombic formulation with a distance-dependent dielectric function that lessens the contribution from charge-charge interactions.
Empirical scoring functions are based on the idea that binding energies can be approximated by a sum of several individual uncorrelated terms. Experimentally determined binding energies and sometimes a training set of experimentally resolved receptor-ligand complexes are used to determine the coefficients for the various terms by means of a regression analysis.
Knowledge-based scoring functions focus on following the rules and general principles statistically derived that aim to reproduce experimentally determined structures, instead of binding energies, trying to implicitly capture binding effects that are difficult to model explicitly. Typically, these methods use very simple atomic interactions-pair potentials, allowing large compound databases to be efficiently screened. These potentials are based on the frequency of occurrence of different atom-atom pair contacts and other typical interactions in large datasets of protein-ligand complexes of known structure. Therefore, their derivation is dependent on the information available in limited sets of structures.
Consensus Scoring combines the information obtained from different scores to compensate for errors from individual scoring functions, therefore improving the probability of finding the correct solution. Several studies have demonstrated the success of consensus scoring methods in relation to the use of individual functions schemes.
Using the Protein-ligand docking methods described above, a predicted association can be made between a selected chemical library compound (see above for examples) and the binding sites in the human A2A adenosine structure described in Table 6. These methods will therefore allow the generation of a binding profile for any known compound in any of the binding sites or cavities of the human A2A adenosine receptor based on the simulated docking of the compound.
In another embodiment, a form of computer-assisted drug design is employed in which a computer system is used to generate a three-dimensional structure of the candidate class A GPCR based on the structural information encoded by the amino acid sequence. This will allow use of the methods described above to identify candidate compounds based on their ability to dock in one or more of the predicted GPCR structure binding sites. In one aspect, the input amino acid sequence of the GPCR interacts directly and actively with a pre-established algorithm in a computer program to yield secondary, tertiary, and quaternary structural models of the class A GPCR. The models of the class A GPCR structure are then examined to identify the position and structure of the binding sites, e.g., binding pocket I, II and/or III. The position and structure of the predicted binding site(s) is then used to identify various compounds that modulate ligand-receptor binding using the methods described above.
The three-dimensional structural model of the GPCR is generated by entering protein amino acid sequences of at least 10 amino acid residues or corresponding nucleic acid sequences encoding a GPCR polypeptide into the computer system. The amino acid sequence represents the primary sequence or subsequence of the protein, which encodes the structural information of the protein. At least 10 residues of the amino acid sequence (or a nucleotide sequence encoding 10 amino acids) are entered into the computer system from computer keyboards, computer readable substrates that include, but are not limited to, electronic storage media (e.g., magnetic diskettes, tapes, cartridges, and chips), optical media (e.g., CD ROM), information distributed by internet sites, and by RAM. The three-dimensional structural model of the GPCR is then generated by the interaction of the amino acid sequence and the computer system, using software known to those of skill in the art. Any method of protein structure modeling such as ab-initio modeling, threading or sequence-sequence based methods of fold recognition. In one embodiment, the AS2TS system of protein structure modeling is used. In other embodiments, a sequence alignment in combination with a threshold protein sequence similarity to determine a set of protein sequences for which to model protein structure is used. In one aspect, sequence alignments are generated for the set of sequences to be modeled with sequences of proteins with solved empirical structure in a protein structure databank known to one of skill in the art. If the sequences to be modeled have a sufficient similarity to one or more sequences with known protein structure, then the three dimensional structure of the sequence can be modeled.
The amino acid sequence represents a primary structure that encodes the information necessary to form the secondary, tertiary and quaternary structure of the GPCR of interest. In one embodiment, software can look at certain parameters encoded by the primary sequence to generate the structural model. These parameters are referred to as “energy terms,” and primarily include electrostatic potentials, hydrophobic potentials, solvent accessible surfaces, and hydrogen bonding. Secondary energy terms include van der Waals potentials. Biological molecules form the structures that minimize the energy terms in a cumulative fashion. The computer program is therefore using these terms encoded by the primary structure or amino acid sequence to create the secondary structural model.
The tertiary structure of the protein encoded by the secondary structure is then formed on the basis of the energy terms of the secondary structure. The user at this point can enter additional variables such as whether the protein is membrane bound or soluble, its location in the body, and its cellular location, e.g., cytoplasmic, surface, or nuclear. These variables along with the energy terms of the secondary structure are used to form the model of the tertiary structure. In modeling the tertiary structure, the computer program matches hydrophobic faces of secondary structure with like, and hydrophilic faces of secondary structure with like.
In another embodiment, protein structure alignments can be used to determine the structure of GPCRs using the known structure of the human A2A adenosine receptor (Table 6). Protein structure alignments preferably are sets of correspondences between spatial co-ordinates of sets of carbon alpha atoms which form the ‘backbone’ of the three-dimensional structure of polypeptides, although alignments of other backbone or side chain atoms also can be envisioned. These correspondences are generated by computationally aligning or superimposing two sets of atoms order to minimize distance between the two sets of carbon alpha atoms. The root mean square deviation (RMSD) of all the corresponding carbon alpha atoms in the backbone is commonly used as a quantitative measure of the quality of alignment. Another quantitative measure of alignment is the number of equivalent or structurally aligned residues.
In another embodiment, a GPCR structure is calculated based on the solved structure of the human A2A adenosine receptor by computationally aligning or superimposing two sets of atoms to minimize distance between the two sets of carbon alpha atoms (i.e., the alpha carbon atoms of the human A2A adenosine receptor and an unknown GPCR structure), followed by one or more of simulated annealing and energy minimization. The result of this calculation is a computed structure for a GPCR that provides atomic co-ordinates for the alpha carbon backbone as well as side chain atoms.
A variety of methods for generating an optimal set of correspondences can be used in the present invention. Some methods use the calculation of distance matrices to generate an optimal alignment. Other methods maximize the number of equivalent residues while RMSD is kept close to a constant value.
In the calculation of correspondences, various cutoff values can be specified to increase or decrease the stringency of the alignment. These cutoffs can be specified using distance in Angstroms. Depending on the level of stringency employed in the present invention, the distance cutoff used is less than 10 Angstroms or less than 5 Angstroms, or less than 4 Angstroms, or less than 3 Angstroms. One of ordinary skill will recognize that the utility of stringency criterion depends on the resolution of the structure determination.
In another embodiment of the present invention, the set of residue-residue correspondences are created using a local-global alignment (LGA), as described in US Patent Publication Number 2004/0185486. In this method, a set of local superpositions are created in order to detect regions which are most similar. The LGA scoring function has two components, LCS (longest continuous segments) and GDT (global distance test), established for the detection of regions of local and global structure similarities between proteins. In comparing two protein structures, the LCS procedure is able to localize and superimpose the longest segments of residues that can fit under a selected RMSD cutoff. The GDT algorithm is designed to complement evaluations made with LCS searching for the largest (not necessary continuous) set of ‘equivalent’ residues that deviate by no more than a specified distance cutoff.
Using the protein structure alignments described above, the structure of human A2A adenosine receptor in Table 6 can be used as a model on which to discern the structure of other GPCRs and/or their predicted ligand-binding sites, e.g., binding pockets I, II, and III.
Once the GPCR structure has been generated, binding pockets I, II, and III are identified by the computer system. Computational models seek to identify the regions by characterization of the three dimensional structure of the GPCR.
Some methods of identifying binding pockets I, II, and III use triangulation such as weighted Delaunay triangulation to determine pocket volumes (castP). Other methods use spheres to determining protein pocket volumes (Q-site-finder, UniquePocket).
Conserved binding-site identification seeks to identify conserved regions such as binding pockets I, II, and III through associating the residues which form the aforementioned regions with conserved residues in homologous protein sequences or structures, e.g., see the alignments in FIG. 8.
One method of identifying binding pockets I, II, and III in a GPCR entails filling the three dimensional protein structures with spheres, creating a “negative image” of the structure. A cutoff distance, such as 8 Angstroms, is used to determine spheres which interact with residues. Spheres are labeled as conserved or not-conserved based on their interaction with residues which form a conserved binding site. The conserved spheres are clustered based on their three dimensional co-ordinates to identify a set of spheres with interact with conserved residues and are proximal in three dimensional space forming a cluster. Three-dimensional structures for potential compounds are generated by entering chemical formulas of compounds. The three-dimensional structure of the potential compound is then compared to that of the GPCR protein ligand-binding site(s) (e.g., binding pockets I, II or III) to identify compounds that bind to the GPCR binding site(s). Binding affinity between the GPCR binding site(s) and the compound is determined using energy terms to determine which ligands have an enhanced probability of binding to the protein.
While the invention has been particularly shown and described with reference to a preferred embodiment and several alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.
It should be noted that the language used in the specification has been principally selected for readability and instructional purposes, and can not have been selected to delineate or circumscribe the inventive subject matter. Accordingly, the disclosure of the present invention is intended to be illustrative, but not limiting, of the scope of the invention, which is set forth in the claims.
The following examples are set forth so that the invention can be understood more fully. The examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
EXAMPLES
Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.
The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., T. E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A. L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rd Ed. (Plenum Press) Vols. A and B (1992).
Methods
Molecular biology for generation of mammalian and Spodoptera frugiperda(Sf9) expression A2A-WT, A2A-T4L-WT and A2A-T4L-AC constructs. The commercially available pBac5 vector (EMD biosciences was modified as follows to generate pBac5b. The 5′ coding region of pBac5 was eliminated by digesting the vector with restriction enzyme NcoI (New England Biolabs) followed by generation of a blunt end by digestion with Mung Bean nuclease (New England Biolabs). The resulting linear DNA was further digested with SmaI to eliminate the N-terminal tags associated with the pBac5 vector. The resulting linear DNA was recircularized by ligation to generate pBac5b. Expression cassettes containing hemagluttinin signal sequence, FLAG epitope tag, precission protease site and 10x histidine tag (SEQ ID NO: 36) were sub cloned into pBac5b using the BamHI and HindIII restriction sites to yield the expression vector pBac5b-830400. Construction of A2A-WT was completed utilizing standard PCR techniques to amplify the wild type A2A (found on the web at the site: cDNA.org) gene using modified PCR primers encoding exogenous restriction sites AscI at the 5′, GGC GCG CCG CCC ATC ATG GGC TCC TCG GTG TAC ATC A (SEQ ID NO: 13), and FseI at the 3′, AGG CCG GCC GGA CAC TCC TGC TCC ATC CTG GGC fSEQ ID NO: 14), termini, which was sub-cloned into a pBac5b-830400 vector using the aforementioned restriction sites. Subcloning into pcDNA3.1(−) was achieved using PCR with primer pairs encoding endogenous restriction sites BamHI at the 5′, GGA TCC ATG AAG ACG ATC ATC GCC CTG AGC TAC ATC TTC TG (SEQ ID NO: 15), and HindIII at the 3′, AAG CTT CTA ATG GTG ATG GTG ATG GTG ATG GTG ATG GTG AGG fSEQ ID NO: 16), termini of pBac5b+830400+A2A with subsequent ligation into the corresponding restriction sites found in pcDNA3.1(−).
A2A-T4L-WT construction involved a two-step cloning strategy with the first step using splicing by overlap extension (SOE) PCR (K. L. Heckman, L. R. Pease, Nat Protoc 2, 924 (2007)) to insert a modified (Cysteines were mutated to Serines) bacteriophage T4 lysozyme (D. M. Rosenbaum et al., Science 318, 1266 (2007)) within the wild type A2A ICL3 region. The second step utilized standard PCR techniques to amplify the resulting A2A-T4L fusion using PCR primers encoding exogenous restriction sites BamHI at the 5′ GGA TCC ATG AAG ACG ATC ATC GCC CTG AGC TAC ATC TTC TG fSEQ ID NO: 15) and HindIII at the 3′ AGG CCG GCC GGA CAC TCC TGC TCC ATC CTG GGC fSEQ ID NO: 14) termini. This allowed for standard subcloning into the pBac5b vector. Subcloning into pcDNA3.1(−) was achieved using PCR with primer pairs encoding endogenous restriction sites BamHI at the 5′, GGA TCC ATG AAG ACG ATC ATC GCC CTG AGC TAC ATC TTC TG fSEQ ID NO: 15), and HindIII at the 3′, AAG CTT CTA ATG GTG ATG GTG ATG GTG ATG GTG ATG GTG AGG (SEQ ID NO: 16), termini of pBac5b-830400- A2A-T4L with subsequent ligation into the corresponding restriction sites found in pcDNA3.1(−).
A2A-T4L-ΔC is the result of a ligation between A2A-T4L and A2A-ΔC (Δ317-412). A2A-ΔC (Δ317-412) was constructed by using PCR with primers encoding exogenous restriction sites BamHI at the 5′, GGA TCC ATG AAG ACG ATC ATC GCC CTG AGC TAC ATC TTC TG (SEQ ID NO: 15) and HindIII at the 3′, AAG CTT TCA GTG ATG GTG ATG GTG ATG GTG ATG GTG GTG TGC CTT GAA AGG TTC (SEQ ID NO: 17). Both A2A-T4L and A2A-ΔC (Δ317-412) were digested in two separate restriction digest reactions using Bsu36I and PciI restriction enzymes. After digestion the larger fragment of A2A-T4L, which contained the A2A-T4L fusion, was treated as the vector while the smaller fragment of A2A-ΔC (Δ317-412), containing a C-terminal truncation, was used as the insert. Standard cloning methods were implemented and after the resulting A2A-T4L-ΔC fusion was DNA sequence verified, subcloning into pcDNA3.1(−) was performed using PCR with primer pairs encoding endogenous restriction sites NheI at the 5′, GCTA GCA TGA AGA CGA TCA TCG CCC TGA GCT ACA TCT TCT G (SEQ ID NO: 18), and HindIII at the 3′, AAG CTT TCA GTG ATG GTG ATG GTG ATG GTG ATG GTG GT (SEQ ID NO: 19), termini of the resultant A2A-T4L-ΔC fusion.
Purification of A2A-T4L Constructs
High-titer recombinant baculovirus (>108 viral particles per ml) was obtained following transfection protocol from Expression Systems (found on the web at the site: expressionsystems.com/). Briefly, recombinant baculoviruses were generated by co-transfecting 2 μg of transfer plasmid containing the target coding sequence with 0.5 μg of SapphireTM baculovirus DNA (Orbigen) into Sf9 cells using 6 μl of FuGENE 6 Transfection Reagent (Roche) and Transfection Medium (Expression Systems). Cell suspension was incubated for 4 days while shaking at 27° C. P0 viral stock was isolated after 4 days and used to produce high-titer baculovirus stock. Expression of gp64 was detected by staining with gp64-PE. Viral titers were performed by flow cytometric method (M. A. Hanson et al., Protein Expr Purif 56, 85 (2007)).
Insect cell membranes were initially disrupted by nitrogen cavitation pump in a hypotonic buffer containing 10 mM HEPES (pH 7.5), 20 mM KCl, and 10 mM MgCl2. Extensive washing of the isolated raw membranes was performed by repeated centrifugation (typically six-to-nine times) in a high osmotic buffer containing 1.0 M NaCl, 10 mM HEPES (pH 7.5), 10 mM MgCl2, 20 mM KCl, and protease inhibitor cocktail (Roche), followed by Dounce homogenization to resuspend the membranes in fresh wash buffer thereby separating soluble and membrane associated proteins from integral transmembrane proteins. Highly purified membranes were resuspended in 10 mM HEPES (pH 7.5), 10 mM MgCl2, 20 mM KCl, and 40% glycerol then flash-frozen with liquid nitrogen and stored at −80° C. until further use.
Prior to solubilization, purified membranes were thawed on ice in the presence of 4 mM theophylline, 2.0 mg/ml iodoacetamide (Sigma), and protease inhibitor cocktail. Membranes were then solubilized by incubation in the presence of 0.5% (w/v) DDM (Anatrace) and 0.01% (w/v) cholesteryl hemisuccinate (CHS) (Sigma) for two to three hours at 4° C. After solubilization, the unsolubilized material was removed by centrifugation at 150,000×g for 45 minutes. The supernatant was separated, supplemented with fresh ligand, 25 mM buffered imidazole and incubated with TALON IMAC resin (Clontech) overnight at 4° C.; typically 1.5 ml of resin per one liter of original culture volume was used. After binding the resin was washed with ten column volumes of 25 mM HEPES (pH 7.5), 800 mM NaCl, 10% (v/v) glycerol, 55 mM imidazole, 4.0 mM theophyline, 0.05% (w/v) DDM and 0.001% (w/v) CHS, followed by four column volume of 25 mM HEPES (pH 7.5), 800 mM NaCl, 10% (v/v) glycerol, 25 mM imidazole, 4.0 mM theophyline, 0.05% (w/v) DDM, 0.001% (w/v) CHS, 8 mM ATP (Sigma) and 10 mM MgCl2. The receptor was eluted with 25 mM HEPES (pH 7.5), 800 mM NaCl, 10% (v/v) glycerol, 4.0 mM theophyline, 0.05% (w/v) DDM, 0.001% (w/v) CHS, 10 mM ATP (Sigma) and 10 mM MgCl2. The ATP and MgCl2 were removed by PD10 buffer exchange columns (GE Lifescience). An additional Ni IMAC (GE LifeScience) column step after desalting was used to concentrate, deglycosylate (PNGase F, New England Biolab) and exchange the ligand to 200 μM ZM241385 (Tocris). Ni IMAC column was washed with 4 column volumes of 25 mM HEPES (pH 7.5), 800 mM NaCl, 10% (v/v) glycerol, 55 mM imidazole, 200 μM ZM241385, 0.05% (w/v) DDM and 0.001% (w/v) CHS and receptor was eluted with 25 mM HEPES (pH 7.5), 800 mM NaCl, 10% (v/v) glycerol, 200 mM imidazole, 200 μM ZM241385, 0.05% (w/v) DDM and 0.001% (w/v) CHS. Receptor was concentrated from  ̃3 mg/ml to 70 mg/ml with a 100 kDa molecular weight cut-off Vivaspin concentrator (Vivascience). Receptor purity and monodispersity was followed using SDS-PAGE, Maldi-TOF and analytical size-exclusion chromatography (aSEC).
In Meso Crystallization of A2A-T4L-ΔC with ZM241385
For lipidic cubic phase (LCP) crystallization, nanovolume robotic trials were carried-out using an in meso crystallization robot as previously described (V. Cherezov, A. Peddi, L. Muthusubramaniam, Y. F. Zheng, M. Caffrey, Acta Crystallogr D Biol Crystallogr, 60, 1795 (2004)). Glass sandwich plates (V. Cherezov, et al., Acta Crystallogr D Biol Crystallogr, 60, 1795 (2004)) were filled with 50 nl receptor-cholesterol-monoolein LCP drops overlaid by 0.8 μl of precipitant solution in each well and sealed with a glass coverslip. Lipid:receptor LCP mixture typically contained monoolein:cholesterol (54%:6% (w/w)) and receptor (40% (w/w)). Crystallization set-ups were performed at ambient temperature (22±2° C.). Plates were incubated and imaged at 20° C. using an automated incubator/imager (RockImager 1000, Formulatrix). Data-collection quality crystals ( ̃100 μm×10 μm×5 μm) were obtained in 30% (v/v) PEG 400 (range of 28-32%), 186 mM Lithium sulfate (range of 180 to 220 mM), 100 mM Sodium citrate (pH 6.5) (Range of 5.5 to 6.5) and 200 μM ZM241385. The protein crystallized in the primitive monoclinic space group P21 with one molecule per asymmetric unit and an estimated solvent content of 52%.
Data Collection and Structure Solution
Crystallographic data were collected on the 23ID-B beamline (GM/CA CAT) at the Advanced Photon Source, Argonne, Ill. using a 10 μm minibeam (wavelength 1.0332 Å) and a MarMosaic 300 CCD detector. Crystals were invisible after flash-freezing into liquid nitrogen, and a similar alignment and data-collection strategy was followed as has been previously described (M. A. Hanson et al., Structure 16, 897 (2008); V. Cherezov et al., Science 318, 1258 (2007)). A nearly complete dataset was collected from a single crystal at 3.5 Å resolution using 20× attenuated beam, 3 s exposure and 1° oscillation per frame. High-resolution data was obtained by collecting 10-15° wedges from 13 crystals, 2-5 s exposure with 1× attenuated beam and optimizing the data collection strategy using the software program XDS (W. Kabsch, J. Appl. Cryst. 26 (1993)). High resolution frames were merged and scaled using the lower resolution dataset as a reference for scaling to obtain a complete 2.6 Å data using the software program XDS (Table 2).
Initial phase information was obtained by molecular replacement using the receptor and T4L portion of β2AR-T4L (PDB-code: 2RH1) independently with the program Phaser (A. J. McCoy, R. W. Grosse-Kunstleve, L. C. Storoni, R. J. Read, Acta Crystallogr D Biol Crystallogr 61, 458 (2005)). Initial refinement was performed iteratively using the Phenix software suite (P. D. Adams et al., Acta Crystallogr D Biol Crystallogr 58, 1948 (2002)), Lafire software suite (M. Yao, Y. Zhou, I. Tanaka, Acta Crystallogr D Biol Crystallogr 62, 189 (2006)) and Refmac5 software suite (G. N. Murshudov, A. A. Vagin, E. J. Dodson, Acta Crystallogr D Biol Crystallogr 53, 240 (1997)) followed by manual examination and rebuilding of the refined coordinates in program Coot (P. Emsley, K. Cowtan, Acta Crystallogr D Biol Crystallogr 60, 2126 (2004)) using both |2Fo-Fc| sigma-A weighted and |Fo-Fc| maps, as well as omit maps calculated using programs Bhat's (T. N. Bhat, Acta Crystallogr A 45 (Pt 1), 145 (1989)) and CNS1.2 (A. T. Brunger et al., Acta Crystallogr D Biol Crystallogr 54, 905 (1998)).
Ligand Binding Assays and Functional Assays Using Sf9 and HEK293 Membranes
Saturation Isotherm using Sf9 membranes: Cell pellets of A2A-WT, A2A-T4L-WT and A2A-T4L-ΔC constructs were suspended in ice-cold 25 mM Hepes, pH 7.5 as a lysis buffer, containing protease inhibitors (Complete protease inhibitor cocktail tablet, Roche Applied Science, USA) and homogenized with 20 strokes using a Dounce homogenizer. Cellular debris and nucleoli were removed by centrifugation at 400×g for 5 minutes at 4° C., and the supernatants were collected. Crude plasma membranes were isolated by centrifugation of the supernatants at 150,000×g for 60 minutes at 4° C., and crude plasma membranes were further washed three times by repeat centrifugation and resuspension in 25 mM Hepes, 1000 mM NaCl, pH 7.5, and containing protease inhibitors. Prior to the ligand binding assays, the membrane pellets were resuspended in ligand binding buffer either low salts buffer (TME: 50 mM Tris-HCl, 10 mM MgCl2, 0.5 mM EDTA, pH 7.4) or high salt buffer TME supplemented with 1000 mM NaCl. The samples were tested for binding with [2-3H]-4-(2-[7-amino-2-{2-furyl} {1,2,4}triazolo {2,3-a} {1,3,5}triazin-5-yl amino]ethyl)phenol [3H]ZM241385 (42.5 Ci/mmol, from Perkin Elmer Life Sciences). Crude plasma membranes (0.2 μg of total protein per reaction) were incubated for 30 min at room temperature with serial dilutions of the radioligand (0.05-10 nM). Incubations were rapidly terminated by filtration using a Tomtec Mach III cell harvester (Tomtec) through a 96-well GF/B filter plate (MultiScreen Harvest plate, Millipore Corp.), and rinsed five times with 500 μl of ice-cold buffer (50 mM Tris-HCl, pH 7.4). The harvest plates were dried, and 30 μl of OptiPhase “HiSafe” III scintillation liquid (Perkin-Elmer Life Sciences) were added. The bound radioactivity was measured using a Packard's TopCounter NTX. Nonspecific binding was determined in parallel reactions in the presence of an excess of Theophylline (100 μM, Sigma-Aldrich, USA), and specific binding was defined as the difference between total and nonspecific binding. Protein concentrations were determined with the BCA protein assay (Pierce, USA), using serum albumin as a reference. All incubations were performed in triplicate, and independent experiments were repeated at least two times. Equilibrium dissociation constants (Kd) and maximal receptor levels (Bmax) were calculated from the results of saturation experiments using GraphPad Prism version 4 Software.
Competition Binding Assays using HEK membranes. [3H]ZM241385 (27.4 Ci/mmol) was obtained from ARC Inc., St. Louis, USA. DPCPX and CGS21680 were obtained from Sigma. All other materials were purchased from commercial sources and were of the highest available purity. HEK293T cells were grown as monolayers in DMEM medium supplemented with 2 mM glutamine, 10% newborn calf serum at 37° C. in a moist, 7% CO2 atmosphere. Cells were transfected with the indicated plasmids using the calcium phosphate precipitation method. Experiments were performed 48 h after transfection. Membranes were prepared as follows. Cells were detached from the plates by scraping them into 5 mL PBS, collected and centrifuged at 200×g for 5 minutes. Cell pellets were resuspended in 20 ml of ice-cold 50 mM Tris-HCl buffer, pH 7.4. An Ultra-turrax was used to homogenise the cell suspension. The cytosolic and membrane fractions were separated using a high speed centrifugation step of 100,000×g, (31,000 rpm in a Beckman Optima LE-80K ultracentrifuge) at 4° C. for 20 minutes. The pellet was resuspended in 10 mL of Tris buffer and the homogenisation and centrifugation step repeated. The resulting pellet was resuspended in 50 mM Tris-HCl buffer, pH7.4. Adenosine deaminase (ADA) was added to a final concentration of 0.8 IU/ml.
Binding assays were performed in a 100 μl reaction volume. The assay mixture contained 50 mM Tris-HCL buffer, pH 7.4, membrane protein (25 μg/assay point for single point assays, 5 μg/assay point for competition curves).
The ability of increasing concentrations of the antagonist ZM241385 and agonist CGS21680 to compete with [3H]ZM241385 binding at the various A2A receptor constructs was tested in the absence or presence of 1M NaCl. Nonspecific binding was determined in the presence of an excess of CGS21680 (100 μM). The radioligand concentrations were close to equilibrium dissociation constants (Kd ̃1.0 nM). Incubation was for 2 hours at 25° C. Binding reactions were terminated by filtration through Whatman GF/B filters under reduced pressure using a MY-24 cell harvester (Brandell). Filters were washed three times with ice cold buffer and placed in scintillation vials. Radioactivity was determined using a Tri-Carb 2900TR liquid scintillation analyzer (Perkin Elmer, Shelton, Conn.).
Cell-surface Receptor Measurement and Enzyme-Linked Immunosorbent Assay. Twenty-four hours after transfection cells were split into 96-well poly-n-lysine-coated plates at a density of 100,000 cells per well. After an additional 24 h, cell-surface receptors were labeled with anti-FLAG (M2) antibody (Sigma) (1:1000) in growth medium for 30 min at 30° C. The cells were then washed once with 20 mM HEPES and Dulbecco's modified Eagle's medium and then incubated for another 30 min at 37° C. in growth medium supplemented with horseradish peroxidase-conjugated anti-mouse IgG (Sigma) (1:5000) as the secondary antibody. The cells were washed twice with phosphate-buffered saline. Finally, the cells were incubated with TMB for 5 min in the dark at room temperature and then the reaction stopped with 1M H3PO4 and the absorbance was read at 450 nm using a VICTOR2 plate reader (PerkinElmer Life Sciences). Control experiments were performed in which no secondary or primary antibody was added. In both cases no absorbance was observed.
Demonstration of downstream signaling by intracellular cAMP determination. HEK293T cells were grown and transfected as described above. Experiments were performed 48 h after transfection. Cells were harvested, resuspended in ‘stimulation buffer’ and added to 384 well Optiplates at a concentration of 7500 cells/well. The assay was performed following the protocol recommended in the LANCE cAMP 384 kit (PerkinElmer Life and Analytical Sciences). The assay tracer, antibody and detection mix are components of the kit. Deviations from the kit protocol are as follows. The stimulation buffer used was PBS with the addition of 5 mM HEPES, 0.1% BSA, 50 μM rolipram, 50 μM cilostamide and 0.8 IU/ml adenosine deaminase. The assay was performed in white 384-well OptiPlates (PerkinElmer Life and Analytical Sciences). Treatment of cells with agonist or antagonist was for 45 min. Following addition of the detection/antibody mix plates were left for 3 h prior to reading using a VICTOR2 plate reader (PerkinElmer Life Sciences).
Thermal stability assay. Thermal stability assays using a fluorescent probe was done as previously described (A. I. Alexandrov et al., Structure 16, 351 (2008)).
Example 1
Crystal Generation and Structure Solution
GPCRs possess numerous thermodynamic conformations (B. E. Cohen et al., Proc Natl Acad Sci USA 102, 965 (2005); B. K. Kobilka, X. Deupi, Trends Pharmacol Sci 28, 397 (2007)), implying an inherent structural flexibility (V. P. Jaakola, J. Prilusky, J. L. Sussman, A. Goldman, Protein Eng Des Sel 18, 103 (2005); S. G. Rasmussen et al., Nature 450, 383 (2007); D. M. Rosenbaum et al., Science 318, 1266 (2007)). This flexibility manifests itself as thermal instability upon detergent extraction from lipid membranes and is one of the primary challenges in generating crystals of GPCRs (F. Magnani, Y. Shibata, M. J. Serrano-Vega, C. G. Tate, Proc Natl Acad Sci USA, (2008); M. J. Serrano-Vega, F. Magnani, Y. Shibata, C. G. Tate, Proc Natl Acad Sci USA 105, 877 (2008)). In order to overcome this obstacle with the human A2A adenosine receptor, a T4L fusion strategy (D. M. Rosenbaum et al., Science 318, 1266 (2007); V. Cherezov et al., Science 318, 1258 (2007); C. K. Engel, L. Chen, G. G. Prive, Biochim Biophys Acta 1564, 38 (2002)) was applied. Specifically, most of the third cytoplasmic loop (Leu2095.70-Ala2216.23) was replaced with lysozyme from T4 bacteriophage. The carboxyl-terminal tail (Ala317-Ser412) was also. The resulting recombinant construct (A2A-T4L-ΔC) was further stabilized during purification with (i) sodium chloride, which has a beneficial effect on adenosine receptor stability, (ii) a saturating concentration of the nonspecific adenosine receptor antagonist theophylline (ZM241385 was exchanged from theophylline in the last purification step) and (iii) including cholesteryl hemisuccinate throughout the purification. Purified A2A-T4L-ΔC bound to ZM241385 was crystallized using the in meso crystallization methodology where the lipid phase consisted of a mixture of monoolein and cholesterol.
Diffraction data from thirteen of the best crystals were combined to yield a 2.6 Å dataset (Table 1). Phases were obtained by molecular replacement using the coordinates of the β2-adrenergic receptor (β2AR) fused to T4-lysozyme (PDB accession number, 2RH1). The final refined model includes residues Ile3 to Gln310 of the human A2A adenosine receptor, residues 2 to 161 of T4-lysozyme, five lipid hydrocarbon chains modeled as stearic acid, eight sulfate ions and the antagonist ZM241385 bound in the ligand binding cavity (FIG. 1). The experimental electron density for the amino (Met1-Pro2) and carboxyl (Glu311-Ala316) termini did not support modeling of these regions. In addition, the tip of second extracellular loop (Gln148-Ser156) was not modeled due to weak experimental electron density. Although cholesterol does have a significant stabilizing effect on the A2A adenosine receptor and was included in the crystallization trials, in contrast to the β2-adrenergic receptor structure which has cholesterol bound in a pocket referred to as the cholesterol consensus motif (M. A. Hanson et al., Structure 16, 897 (2008)), the A2A adenosine receptor structure has phospholipid bound in the same area.
Example 2
Biochemical characterization of A2A-T4L-ΔC
The functionality of A2A-T4L-ΔC was verified by comparing its binding properties to A2A-T4and A2A-WT. A2A-T4 refers to a construct in which the third cytoplasmic loop (residues Leu2085.69 to Ala2216.23) was replaced with the lysozyme from T4 bacteriophage and the full carboxy terminus intact (Ala317 to Ser412). A2A-WT refers to the wild-type construct without the T4 lysozyme. All constructs have a FLAG purification tag in the amino terminus and ten histidine residues (SEQ ID NO: 36) in the carboxy terminus. The A2A-T4L-ΔC, A2A-T4 and A2A-WT constructs expressed in Sf9 cells bind [3H]ZM241385 with similar affinity as the same constructs transiently expressed in HEK293 as judged by radioligand saturation experiments. This finding was corroborated in competition binding assays, as the two A2A-T4L constructs had IC50 values similar to A2A-WT for ZM241385 (FIG. 2; FIG. 9 and Table 3). However, A2A-T4L and A2A-T4L-ΔC displayed significantly higher affinity for the subtype-selective agonist CGS21680 as compared to the A2A-WT construct, possibly indicating a shift toward the activated state induced by the incorporation of the T4L moiety. A comparable construct of the β2AR behaved in a similar fashion (D. M. Rosenbaum et al., Science 318, 1266 (2007)); however, unlike β2AR, the A2A-WT has no associated basal activity (G protein signalling in the absence of agonist). The inclusion of a high concentration of sodium chloride in the assay medium induced a substantial decrease in the agonist affinity for all of the tested constructs (FIG. 2b) but did not appreciably affect antagonist affinity. The pKi values for the agonist in the presence of sodium chloride were virtually identical for all constructs tested (Table 3) indicating that sodium chloride induced a shift in receptor equilibrium to an inactive state (Z. G. Gao, A. P. Ijzerman, Biochem Pharmacol 60, 669 (2000)). In addition, sodium chloride induced a 10° C. increase in thermal stability for A2A-T4L-ΔC solubilized in n-Dodecyl -β-D-maltoside (FIG. 10). Thus, radioligand binding experiments support the conclusion that the construct used for crystallization is a functional receptor with an increased affinity for agonist, and wild-type affinity for antagonist.
Example 3
Architecture of the Human A2A Adenosine Receptor
The residues constituting the transmembrane α-helices are: Gly51.31-Trp321.58 (helix I); Thr412.39-Ser672.65 (helix II); His753.23-Arg 1073.55 (helix III); Thr1194.40-Leu1404.61 (helix IV); Asn1755.36-Ala2045.65 (helix V); Arg2226.24-Phe2586.60 (helix VI); Leu2697.34-Arg2917.56 (helix VII) (33). A small non-transmembrane helix is located at the membrane-cytoplasm interface and comprises Arg2968.47-Leu3088.59 (helix VIII). The A2A adenosine receptor does not contain the canonical palmitoylation site(s) found in the majority of GPCRs; instead, helix VIII is stabilized by interactions with helix I. In this crystal form, the crystallographic contacts are mostly driven by the T4L protein where receptor-to-lysozyme and lysozyme-to-lysozyme mainly form the lattice contacts. A relatively large receptor-to-receptor crystallographic interface ( ̃520 Å2) forms anti-parallel receptor dimers (FIG. 11). The total surface interface between receptor and T4L moieties is 1300 Å2, whereas lysozyme-to-lysozyme is  ̃200 Å2. The largest contact interface ( ̃500 Å2) between receptor and T4L is non-crystallographic, and is located in the cytoplasmic site, where receptor is fused to the T4L. The other receptor-to-lysozyme surface interfaces are crystallographic (260 Å2). In comparison to the previously solved β2AR-T4L fusion proteins, the T4L domain is significantly tilted from the membrane plane, and creates more surface interactions than seen in human β2AR-T4L constructs that were solved in different space groups.
The residues defining intracellular and extracellular loops (ICLs and ECLs) are: Leu331.59-Val402.38 (ICL1); Ile1083.56-Gly1184.39 (ICL2); Leu2085.69-Ala2216.23 (ICL3); Thr682.66-Cys743.22 (ECL1); Leu1414.62-Met1745.35 (ECL2); Cys2596.61-Trp2687.33 (ECL3). In our structure ICL3 has been replaced by 160 residues from T4L lysozyme (see FIG. 8 and SEQ ID NO:1). Additionally, The N-linked glycan associated with Asn1544.75 has been removed enzymatically to improve crystallization.
The crystallographic model of A2A-T4L-ΔC bound to ZM241385 reveals three features distinct from the previously reported GPCR structures. First, the organization of the extracellular loops is markedly different from β1AR, β2AR and bovine/squid rhodopsins (S. G. Rasmussen et al., Nature 450, 383 (2007); D. M. Rosenbaum et al., Science 318, 1266 (2007); M. A. Hanson et al., Structure 16, 897 (2008); M. Murakami, T. Kouyama, Nature 453, 363 (2008); K. Palczewski et al., Science 289, 739 (2000); T. Warne et al., Nature 454, 486 (2008)). Secondly, ZM241385 binds in an extended conformation perpendicular to the plane of the membrane and co-linear with transmembrane helix VII interacting with both ECL2 and ECL3. This is somewhat incongruous with earlier molecular modeling studies based on β2AR and rhodopsin homology models where ZM241385 and other antagonists were docked into a binding site emulating that of β2AR and rhodopsin (for examples see (A. Martinelli et al., Med Res Rev 28, 247 (2008); 0. Yuzlenko et al., J Comput Chem, (2008)), and references therein). Finally, a subtle divergence in the helical positions and orientations relative to rhodopsin and β2AR redefines the antagonist binding cavity so that it is located closer to helices VI and VII and allowing only limited interactions with helices III and V.
Example 4
Helical Position and Binding Pocket in the A2A Adenosine Receptor Versus Other Receptors
Among the class A GPCRs, the sequence identity is highest within the α-helical transmembrane regions and ranges from 20-50% (P. Joost, A. Methner, Genome Biol 3, RESEARCH0063 (2002); D. K. Vassilatis et al., Proc Natl Acad Sci USA 100, 4903 (2003)). Not surprisingly, the helical arrangement is similar among the human β2AR, turkey β1AR and squid/bovine rhodopsins structures determined to date. However, shifts in the relative positions of the various helices results in a root mean square deviation (RMSDs) between 2.0 to 2.5 Å (depending on how the alignment is carried out and which structures are being compared) that has structural, and biochemical implications. Most of the structural divergence arises in the extracellular portions of helices I, II, III and V, where the variation in the positions of helices II, III and V appears to redefine the location of the ligand binding pocket (the FatCat server (found on the web at the site: fatcat.burnham.org/) was used for structural alignment of the TMs with the rhodopsin structure 1U19 as a reference taken directly from that server: “It simultaneously addresses the two major goals of flexible structure alignment; optimizing the alignment and minimizing the number of rigid-body movements (twists) around pivot points (hinges) introduced in the reference structure”). However, comparisons between ground-state rhodopsin bound to retinal and β2AR bound to carazolol show minimal differences as the relative helical shifts are smaller (FIGS. 3a and 3b) (V. Cherezov et al., Science 318, 1258 (2007)). The position of the retinal and carazolol binding pocket is very similar and making most contact with helices III, V, VI (FIG. 3a and FIG. 4). The binding pocket of the A2A adenosine receptors is shifted closer to helices VI and VII which contribute the majority of the binding interactions associated with helical regions, as judged by occluded surface area calculations (G. S. Ratnaparkhi, R. Varadarajan, Biochemistry 39, 12365 (2000); the program occluded surface (OS) was used which calculates the occluded surface and atomic packing of protein model structures: found on the web at the site: csb.yale.edu/userguides/datamanip/os/ (FIG. 3b and FIG. 4). A concomitant shift of helices II and V (7 Å and 3 Å, respectively) toward the binding pocket, and a lateral shift of helix III toward helix V by 3 Å, compensates for the absence of ligand interactions in this region by increasing protein packing interactions (FIGS. 3a and 3b).
Example 5
Conformational Equilibrium and Receptor Activation
A common feature of the class A GPCRs is the presence of a tryptophan residue (at position 6.48) on helix VI whose rotameric position is thought to control the equilibrium between the active and inactive states of each receptor (it has been speculated that the general activation mechanism include following changes 6.47 (gauche+conformers)/6.48 (trans−conformers)/6.52 (trans−conformers) represent the active state (R*) and 6.47 (trans−conformers)/6.48 (gauche+conformers)/6.52 (gauche+conformers) represent inactive state (R)). Based on the position of retinal in the rhodopsin structure it had been proposed that ligand interactions with this key residue could modulate receptor equilibrium (D. L. Farrens, C. Altenbach, K. Yang, W. L. Hubbell, H. G. Khorana, Science 274, 768 (1996)). Interestingly, the contact area between ligand and the “toggle switch” tryptophan residue at position 6.48 varies considerably among the solved receptor structures. For instance, rhodopsin and β2AR have a similar binding mode as noted; however, retinal in rhodopsin has a contact area of 36 Å2, whereas carazolol bound to β2AR lacks any direct contact with Trp2866.48 (V. Cherezov et al., Science 318, 1258 (2007)).
Basal or constitutive activity is the spontaneous production of cellular response in the absence of a ligand. Inverse agonist shifts the equilibrium towards inactive state. Agonist shifts the conformation towards the active state. Neutral antagonist binds to receptors and block the active site but not shift the equilibrium. A typical GPCRs can “dial” almost any conformational equilibrium between fully inactive and fully active therefore agonist/inverse agonist are classified as weak/partial/full. Depending on a receptor and cellular environment, the nature of an invert agonism and truly neutral antagonism can be difficult to detect. Ground-state rhodopsin has virtually no basal activity, whereas β2AR has a relatively high basal activity which is suppressed somewhat by carazolol as an inverse agonist (S. G. Rasmussen et al., Nature 450, 383 (2007)).
The observed increase in contact area may have direct implications for inverse agonist efficacy or suppressed basal activity by limiting the range of motion of the “toggle switch” tryptophan. The competitive antagonist ZM241385 has a 14 Å2 contact area with Trp2466.48 despite an altered binding mode relative to rhodopsin (FIG. 4c). This finding indicates that this ligand has the ability to stabilize the A2A adenosine receptor in an inactive state.
Interactions between the cytoplasmic end of helix III (conserved D/ERY (Asp3.49 Arg3.50 Tyr3.51 sequence motif) and helix VI (Glu6.30) have been proposed to constitute an “ionic-lock” that may play a role in restraining the fully inactive conformation of rhodopsin and other class A receptors (K. Palczewski et al., Science 289, 739 (2000); R. Vogel et al., J Mol Biol 380, 648 (2008); T. Okada et al., J Mol Biol 342, 571 (2004)). Of particular note is that with the exception of the rhodopsins, none of the GPCR structures solved to date have the ionic lock interaction, including the A2A adenosine receptor. Instead, as in β1AR and β2AR, the D/ERY motif in the A2A adenosine receptor participates in interactions that restrain the conformation of ICL2. In the A2A adenosine receptor, Asp1013.49 forms a hydrogen bond with Tyr1123.60 in ICL2 and Thr412.39 at the base of helix II (FIG. 5a). Similar hydrogen bonding interactions were reported in the turkey β1AR structure (T. Warne et al., Nature 454, 486 (2008)), but not in any of the β2AR structures where Asp1303.49 forms a hydrogen bond with Ser1433.62 although there is a tyrosine at the 3.60 position (FIGS. 5b and 5c) (S. G. Rasmussen et al., Nature 450, 383 (2007); D. M. Rosenbaum et al., Science 318, 1266 (2007); M. A. Hanson et al., Structure 16, 897 (2008)). This discrepancy is caused by a short helical section in the ICL2 loop of both β1AR and the A2A adenosine receptor that is not present in any of the β2AR structures (FIG. 5). It has been proposed that ICL2 serves as a control switch facilitating G protein activation through a select set of interactions (E. S. Burstein, T. A. Spalding, M. R. Brann, J Biol Chem 273, 24322 (1998)). Interestingly the basal activity profile among the β1AR, β2AR and the A2A adenosine receptors correlates with the presence of this short helix in ICL2 and the presence of hydrogen bonding interactions between tyrosine at position 3.60 in ICL2 and Asp at position 3.49. In β1AR and A2A adenosine receptor, both of which have low basal activity, this interaction is present (L. Birnbaumer, F. O. Levy, X. Zhu, A. J. Kaumann, Texas Heart Inst J 21, 16 (1994); J. Zezula, M. Freissmuth, Br J Pharmacol 153 Suppl 1, S184 (2008)). In contrast, β2AR exhibits high basal activity and lacks helical structure within its ICL2 resulting in altered interactions with the DRY motif (L. Birnbaumer, F. O. Levy, X. Zhu, A. J. Kaumann, Texas Heart Inst J 21, 16 (1994)). Thus, instead of participating in an ‘ionic lock’ as in rhodopsin, the arginine residue in the D/ERY motif cam play a role in stabilizing the deprotonated state of the adjacent aspartate or glutamate residue, which would strengthen the polar interactions between the D/ERY motif and both ICL2, and helix II. This set of interactions may have direct implications in G protein activation (R. Vogel et al., J Mol Biol 380, 648 (2008)).
Example 5
Extracellular Loops: Mediation of Ligand Entry and Binding in the A2A Adenosine Receptor Versus other GPCRs
The extracellular surface properties of the A2A adenosine receptor is largely dictated by its second extracellular loop (ECL2), which is considerably different from that of β1AR, β2AR and rhodopsin (FIG. 1 and FIG. 4). The ECL2 of the A2A adenosine receptor lacks the prominent secondary structural elements, such as β-sheet and α-helix, which were observed in the rhodopsin and β-adrenergic receptors, respectively. Instead, the ECL2 of the A2A adenosine receptor is mainly a spatially constrained random coil possessing three disulfide linkages with ECL1 (FIG. 4C). Two of the three disulfide bonds (Cys712.69-Cys1595.20 and Cys743.22-Cys1464.67) are unique to the A2A adenosine receptor while the third (Cys773.25-Cys1665.27) is conserved among many class A GPCRs. In addition, a fourth intraloop disulfide bond is formed in ECL3 between Cys2596.61 and Cys2626.64 with the sequence CPDC which creates a kink in the loop that constrains the position of ECL3 and orients His2646.66 at the top of the ligand binding site.
The extensive disulfide bond network forms a rigid, open structure exposing the ligand binding cavity to solvent and should allow free access for small molecule ligands. In addition, the family conserved disulfide bridge (Cys773.25-Cys1665.27) is adjacent to a short helical segment that presents two crucial residues for ligand binding interactions (Phe 1685.29 and Glu1695.30). The missing tip of the loop (Gln148-Ser156) is spatially distinct from the ligand binding site, and therefore should not directly interact with the binding cavity. Mutation of Cys2626.64 to Gly did not affect binding to radioligand agonist or antagonist, indicating that the kink in ECL3 is either unnecessary for receptor function or that the other disulfide bonds are sufficient to constrain extracellular loop architecture (D. J. Scholl, J. N. Wells, Biochem Pharmacol 60, 1647 (2000)). Mutational studies on the A1 adenosine receptor indicate that these cysteine residues (Cys803.25-Cys1695.27 in the A1 receptor) (FIG. 8) are critical for expression due to a complete loss of radiolabeled antagonist binding in the absence of this disulfide bond.
Example 6
Binding of Non-Xanthine Antagonists by the Adenosine A2a Receptor
Prior to this invention, methods for generating structural and biophysical data relating to class A GPCRs with diffusible ligands have used primarily the biogenic amine receptors, e.g., the adrenergic, dopamine, and serotonin families. These amine ligands are all positively charged at physiologic pH and are known to interact with a key negatively charged aspartate residue (Asp3.32) on helix III. Indeed, in all three of the available β-adrenergic structures, each co-crystallized ligand interacts with this residue and binds in a pocket quite similar to that of retinal in rhodopsin.
In contrast to the 3-adrenergic ligands and retinal, ZM241385 bound to human A2A adenosine receptor occupies a significantly different position in the transmembrane network (FIG. 4) where its orientation is almost perpendicular to the membrane plane (FIGS. 4c and 6). The bicyclic triazolotriazine core of ZM241385 is anchored by an aromatic stacking interaction with Phe1685.29, an aliphatic hydrophobic interaction with Ile2747.39 and a hydrogen bonding interaction with Asn2536.55 (FIG. 6). Adjacent to Phe1685.29 a polar residue (Glu1695.30) interacts with the exocyclic amino group (N15 atom) linked to the bicyclic core of ZM241385 (FIG. 6b). This binding pocket is referred to as binding pocket I.
Mutation of Glu1695.30 to alanine reduces the affinity for both antagonists and agonists and causes a 1000-fold reduction in agonist efficacy (J. Kim et al., Mol Pharmacol 49, 683 (1996)). However, mutating this position to glutamine did not have a substantial impact on antagonist binding affinity, suggesting hydrogen bonding as the predominant means of interacting with N15 of ZM241385 as opposed to Coulombic interactions (FIG. 6b). Early studies indicate that mutation of Asn2536.55 to alanine, which would disrupt an important polar contact with the exocyclic N15 atom of ZM241385, results in a complete loss of both agonist and antagonist binding (J. Kim, J. Wess, A. M. van Rhee, T. Schoneberg, K. A. Jacobson, J Biol Chem 270, 13987 (1995)). The structure also shows that Ile2747.39 forms a hydrophobic contact with the C12 atom of ZM241385; accordingly mutation of Ile2747.39 to alanine results in negligible antagonist binding and a 30-fold reduction in agonist potency (J. Kim, J. Wess, A. M. van Rhee, T. Schoneberg, K. A. Jacobson, J Biol Chem 270, 13987 (1995)). Phe1685.29 and Leu249 both anchor the bicyclic ring of ZM241385 through π stacking and hydrophobic interactions, respectively, and are proposed to be involved in ligand binding (S. Moro et al., Chem Commun (Camb), 2949 (2003)). The phenolic hydroxyl group extending from the ethylamine chain of ZM241385 forms a hydrogen bond with an ordered water molecule. The phenyl ring forms hydrophobic interactions with Leu2677.32 and Met2707.35 that is consistent with hydrophobicity rather than aromaticity as means of interaction with the phenolic substituent, A ZM241385 derivative, with a cycloalkyl substituent (LUF5477) instead of phenylmethylene, also has high affinity for the A2A adenosine receptor. In a recent study on new antagonists for the A2A adenosine receptor it was demonstrated that tremendous substituent flexibility exists in this area of the pharmacophore (M. Mantri et al., J Med Chem 51, 4449 (2008)). This observation correlates well with the directionality of the phenylethylamine substituent in ZM241385 as it is directed towards the more solvent exposed extracellular region (ECL2 and ECL3) rather than towards the transmembrane domain of the receptor as was previously proposed (A. Martinelli, T. Tuccinardi, Med Res Rev 28, 247 (2008); O. Yuzlenko, K. Kiec-Kononowicz, J Comput Chem, (2008)). The other substituent in ZM241385 is the furan ring, a feature that occurs in many A2A adenosine receptor antagonists. This moiety is located deep in the ligand binding cavity and directed towards helices V and VII, where it hydrogen bonds to Asn2536.55 and forms a water-mediated interaction with His 2506.52 (FIG. 6A). Hydrophobic interactions of the furan ring system include His2506.52 with C23 and Leu2496.51 with the C22 and C21 atoms of ZM241385. Mutation of His2506.52 to alanine completely abolishes ligand binding, whereas mutation to phenylalanine or tyrosine residues modestly affects agonist binding but not antagonist binding (J. Kim, J. Wess, A. M. van Rhee, T. Schoneberg, K. A. Jacobson, J Biol Chem 270, 13987 (1995); Q. Jiang, B. X. Lee, M. Glashofer, A. M. van Rhee, K. A. Jacobson, J Med Chem 40, 2588 (1997)); replacement with an asparagine slightly increases ligand affinity (Q. Jiang, B. X. Lee, M. Glashofer, A. M. van Rhee, K. A. Jacobson, J Med Chem 40, 2588 (1997)). The furan ring is approximately 3 Å away from the highly conserved Trp2466.48, an important residue in receptor activation as discussed above (M. Audet, M. Bouvier, Nat Chem Biol 4, 397 (2008)). The hydrophobic interactions between ZM241385's furan ring and this residue are expected to hinder the structural rearrangements necessary for activation, constraining the receptor in an inactive state.
Example 7
Two Additional Binding Pockets in the Adenosine A2a Receptor
In addition to the empirically delineated binding site associated with ZM241385 (i.e., binding pocket I described above), the present invention provides a crystal structure comprising two additional water-filled binding sites in the general vicinity of the non-xanthine binding site that can be used for designing novel drugs.
(1) Binding pocket II. In silico docking studies were carried out on the adenosine A2a structure using four xanthine-based ligands: theophylline, xanthine, theobromine and caffeine. The resulting binding interactions were similar for all four and the results for caffeine are presented herein. The location of the xanthine binding pocket (binding pocket II) appears to be dependent on the protonation state of His2787.43. When this residue is protonated and positively charged, caffeine is expected to bind adjacent to the non-xanthine binding site defined by hydrophobic interactions with: Phe622.60, Ile662.64, Ile803.28, Val843.32, Phe1685.29, Leu2496.51, Ile2747.39 and forming polar interactions with His2787.43 (FIG. 7A). However, when His2787.43 is deprotonated, the xanthine binding site is found in a location similar to the binding pocket I (FIG. 7B), a non-xanthine binding pocket. Physiologically, the protonated form of His2787.43 will be more prevalent because of a charge coupling interaction with Glu131.29.
(2) Binding pocket III, the 29 Angstrom3 lower binding cavity. The invention also provides an A2A adenosine receptor crystal structure comprising a third cavity, referred to herein as binding pocket III. This third cavity corresponds to the water filled cavity in β2-AR and rhodopsin. However, in the case of the A2A adenosine receptor the water filled cavity is much larger (29 Angstroms3) and shows some connectivity with the base of binding pocket I. In the model described herein, this binding cavity (binding pocket III) is formed by the following polar and hydrophobic amino acids: Leu482.46, Ala512.49, Asp522.50, Val552.53, Val843.32, Leu873.35, Thr883.36, Ser913.39, Leu953.43, Ile2386.40, Phe2426.44, Trp2466.48, Ser2777.42, His2787.43, Asn2807.45, Ser2817.46 and Asn2847.49. In certain embodiments, therefore, the invention provides methods for designing small molecules to bind selectively in this site and affect a response from the receptor. Because water bound in this area is likely to play a significant role in signal transduction, stabilizing the interactions in this site can provide a more effective intervention strategy than targeting the more canonical ligand binding sites of GPCRs.
The invention thus provides in certain embodiments the use of three binding sites, i.e., binding pockets I, II and/or III, for designing novel A2A adenosine receptor ligands. The invention provides methods of exploiting the xanthine binding site that lies adjacent to the site of ZM241385 to study the binding mode of caffeine and other xanthine molecules that differ significantly from the mode of binding observed in higher-affinity non-xanthine molecules. Increased affinity and specificity may be designed into existing ligands by combining interactions with both xanthine and non-xanthine binding sites (e.g., binding pockets I and II). The invention also provides methods for designing molecules that interact with the 29 Angstrom3 ligand-binding cavity, which can be accessed from the extracellular space, thereby increasing the specificity and functionality of ligands that target the A2A adenosine receptor and other class A GPCRs with conserved sequences in this region.
All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.







TABLE 1







Data collection and refinement statistics









A2A-T4L-ΔC













Data collection (APS GM/CA CAT ID-B,




10 μm beam)




Space group
P21



Cell dimensions




a, b, c (Å)
47.7, 76.9, 86.6



(°)
101.3



No. of reflections processed
64,526 (8165)  



No. unique reflections
18,465 (356)  



Resolution (Å)
20.0-2.6 (2.8-2.6) 



Rsym
 9.8 (38.9)



Mean I/σ(I)
7.0 (2.3)



Completeness (%)
96.8 (93.9)



Multiplicity
3.5 (2.3)



Refinement




Resolution (Å)
20.0-2.6



No. reflections (reference set)
18,461 (937)  



Rcrys/Rfree
19.6/23.1



No. atoms
3769



Protein
3521



Ions, lipids, ligand and other
165



Water oxygen
83



B-values (Å2)




All atoms
70.6



Protein
69.4



Ligand
66.7



Lipid
94.4



R.m.s deviations from ideality




Bond lengths (Å)
0.002



Bond angles (°)
0.78



Ramachandran plot statistics (%) (excl.




Gly, Pro):




Most favored regions
92.8



Additionally allowed regions
7.2



Generously allowed regions
0.0



Disallowed regions
0.0





*Highest resolution shell is shown in parenthesis.


Rsym = 100 Σn (ΣI|Ii − I|)/Σn (ΣIi)


Rcrys = 100 Σhkl|Fobs − Fcalc|Σhkl Fobs.


Rfree = test set 5%.













TABLE 2







Analysis of crystallographic data quality using the software program XDS (W. Kabsch,


J. Appl. Cryst. 26 (1993)). Data was processed and merged together using data-sets


collected from 13 individual crystals. A comparison is performed between the complete data


set and data filtered by σ cut-off value. Cut-off value was not used in the structure solution or


refinement process.
















Number of



R-





Resolution
reflections


Completeness
factor





[Å]
Observed
Unique
Multiplicity
[%]
Rsym
I/σ
Rmeas
Rmrgd-F










Signal/noise ≧ −3















10
1069
283
3.8
80.2
4.8
14.66
5.5
3.3


8
1200
324
3.7
97.3
5
14.03
5.8
3.7


6
3318
897
3.7
98.8
7.2
12.05
8.3
6


5
4250
1138
3.7
98.9
8.8
11.6
10.1
6.8


4.5
3688
978
3.8
98.1
9.2
12.23
10.6
7


4
5740
1529
3.8
98.3
10.3
11.29
11.9
8.1


3.5
9577
2508
3.8
97.7
13
9.18
15
11.1


3.2
8924
2336
3.8
97.5
19.2
6.75
22.1
16.9


3
8156
2143
3.8
97.8
26.8
4.87
30.8
26.2


2.8
10439
2769
3.8
97.9
35.5
3.78
40.9
36.2


2.6
8165
3560
2.3
93.9
38.9
2.32
48.8
57.1


Σ
64526
18465
3.5
96.8
9.8
7.03
11.3
12.9







Signal/noise ≧ 0















10
1069
283
3.8
80.2
4.8
14.66
5.5
3.3


8
1200
324
3.7
97.3
5
14.03
5.8
3.7


6
3312
894
3.7
98.5
7.2
12.09
8.3
5.9


5
4238
1134
3.7
98.5
8.8
11.64
10.1
6.8


4.5
3679
974
3.8
97.7
9.2
12.28
10.6
6.9


4
5714
1521
3.8
97.8
10.3
11.35
11.9
7.9


3.5
9496
2486
3.8
96.8
13
9.26
14.9
10.8


3.2
8766
2284
3.8
95.3
19
6.91
21.9
15.8


3
7822
2042
3.8
93.2
26
5.13
29.9
23.6


2.8
10010
2633
3.8
93.1
34.3
4
39.5
32.8


2.6
7382
3157
2.3
83.3
35.8
2.69
44.8
47


Σ
62688
17732
3.5
93
9.7
7.35
11.2
12





Rsym = 100 Σn (ΣI|Ii − Î|)/Σn (ΣIi)


Rmeas = 100 n ΣI| {circumflex over (|I)} − Ii|/Σhkl (n − 1) ΣiIi, where Î is the mean intensity of symmetry-related reflections


Rmrgd-F as defined by (K. Diederichs, P. A. Karplus, Nat Struct Biol 4, 269 (1997)) is a quality measure of the reduced structure factor amplitudes


R = 100 Σhkl|Fobs − Fcalc|Σhkl Fobs.


Test set size 5%.


I/σ = mean of intensity/σ,


σ = standard deviation of reflection intensity I estimated from sample statistics













TABLE 3





Binding affinities of subtype specific agonists and antagonists for 


the wild-type A2A-WT, full length fusion protein A2A-T4L-WT and


carboxy-terminally truncated A2A-T4-ΔC in the presence and


absence of NaCl as an allosteric modulator. The competition binding


curves were fitted for one-site competition or two-site (only for agonists)


binding models, using the program GraphPad Prism version 4. Apparent


affinity (Ki) values were calculated using the Cheng-Prusoff equation as


Ki = IC50/(1 + [ligand]/Kd). (A) Competition binding of [3H]ZM241385


versus CGS21680: agonist affinity is decreased at both the wild type


and modified A2A constructs in the presence of 1M NaCl. The modified


A2A receptor constructs A2A-T4L-WT and A2A-T4-ΔC show a


significantly higher affinity for the agonist CGS21680 than the wild type


receptor. (B) Competition binding of [3H]ZM241385 versus CGS21680:


antagonist affinity is not affected by the presence of 1M NaCl at 


both the wild type A2A and modified A2A constructs. The modified


A2A receptor constructs A2A-T4L-WT and A2A-T4-ΔC


show a wild type affinity for the antagonist ZM241385.







(A)










CGS21680 +












CGS21680
1M NaCL
Fold shift












Construct
pKi (±S.D.)
Ki, nM
pKi (±S.D)
Ki, nM
in affinity





A2A-WT
6.27 (0.1)
545
5.35**
4491
8


A2A-T4L-
6.74 (0.06) τ
181
5.36***
4327
24


WT







A2A-T4-ΔC
7.08 (0.21) τττ, ‡
 83
5.28***
5204
63










(B)












ZM241385 +




ZM241385
1M NaCL
Fold shift












Construct
pKi (±S.D.)
Ki, nM
pKi (±S.D)
Ki, nM
in affinity





A2A-WT
8.67 (0.21)
2.13
8.9 
1.27
1.7


A2A-T4L-
8.74 (0.1)
1.83
8.93
1.17
1.6


WT







A2A-T4-ΔC
8.87 (0.1)
1.38
8.87
1.08
1.2





Data relates to experiments described in FIG. 2.


The differences in pKi observed between control and + 1M NaCl conditions were analysed using a Student's t-test and significant differences noted as below (p < 0.01 = **, p < 0.001 = ***).


Differences in pKi observed between various A2A constructs was analysed using a one-way anova analysis followed by a bonferroni post-hoc test.


Significant differences were only observed in the control conditions and are noted as follows:


τ = pKi (A2A-WT) > pKi (A2A-T4L-WT) − p < 0.05,


τττ = pKi (A2A-WT) > pKi (A2A-T4L-ΔC) − p < 0.001,


‡ = pKi (A2A-T4L-WT) > pKi (A2A-T4L-ΔC*) − p < 0.05.


The differences in pKi observed between control and + 1M NaCl conditions were analysed using a Student's t-test.


Differences in pKi observed between various A2A constructs was analysed using a one way anova analysis followed by a bonferroni post-hoc test. Significant differences were not observed (ns).













TABLE 4







Molecular interactions in the A2A-T4L-ΔC structure. Only a very limited number of interactions


are present between A2A and T4L. Table 4A: The contact surfaces between receptor and T4L.


The data was obtained using the PISA server (found on the web at the site: ebi.ac.uk)


Table 4B: The atomic contacts between A2A-T4L-ΔC and ZM241385 (ZMA), co-factors (SO4) 


and various lipids (DGR) found in the structure. The results were obtained using


WHAT IF server (found on the web at the site: swift.cmbi.ru.nl/servers/html/index.html).





Table 4A











Domain 1

Domain 2


















Range
iNat
Nres

Range
iNat
iNres
Interface area, Å2
NHB
NSB





A2A
59
21
X
A2A
55
15
517.8
5



T4L
63
17
NX
A2A
46
11
500.1
8
2


A2A
42
13
NX
T4L
36
11
347.1
7



A2A
24
9
NX
T4L
35
9
260.9
1



T4L
20
6
X
T4L
22
7
189.5
2



A2A
9
3
X
T4L
14
5
79.2




A2A
6
2
NX
T4L
8
3
68.8




A2A
2
1
NX
T4L
1
1
22.5










iNat: indicates the number of interfacing atoms in the corresponding structure


iNres: indicates the number of interfacing residues in the corresponding structure


NHB: indicates the number of potential hydrogen bonds across the interface.


NSB: indicates the number of potential salt bridges across the interface.


X: the interface is crystallographically related


NX: the interface is not crystallographically related





Table 4B











Type
Protein residue and atoms
<>
Co-factor residue and atom
Distance




















(B-D)
21
GLY (23)
A
CA
<>
454
DRG (5)
D
CAN
D = 3.75


(S-D)
27
TRP (29)
A
CZ3
<>
454
DRG (5)
D
CAE
D = 3.53


(S-D)
44
VAL (46)
A
CG1
<>
450
DRG (1)
D
CAS
D = 3.64


(S-D)
44
VAL (46)
A
CG1
<>
451
DRG (2)
D
CAT
D = 3.74


(S-D)
48
ALA (50)
A
CB
<>
451
DRG (2)
D
CAP
D = 3.72


(S-D)
51
ILE (53)
A
CG2
<>
450
DRG (1)
D
CAK
D = 3.80


(S-D)
55
VAL (57)
A
CG1
<>
450
DRG (1)
D
CAH
D = 3.50


(S-D)
55
VAL (57)
A
CG1
<>
450
DRG (1)
D
CAF
D = 3.75


(B-D)
55
VAL (57)
A
O
<>
452
DRG (3)
D
CAI
D = 3.17


(B-D)
55
VAL (57)
A
O
<>
452
DRG (3)
D
CAH
D = 2.86


(S-D)
56
LEU (58)
A
CG
<>
450
DRG (1)
D
CAH
D = 3.67


(S-D)
56
LEU (58)
A
CD1
<>
450
DRG (1)
D
CAH
D = 3.49


(S-D)
56
LEU (58)
A
CD2
<>
452
DRG (3)
D
CAI
D = 3.71


(S-D)
56
LEU (58)
A
CD1
<>
453
DRG (4)
D
CAH
D = 3.65


(S-D)
60
PHE (62)
A
CE1
<>
452
DRG (3)
D
CAM
D = 3.53


(S-D)
72
CYS (74)
A
CB
<>
458
SO4 (5)
E
O4
D = 3.45


(S-D)
73
HIS (75)
A
ND1
<>
458
SO4 (5)
E
S
D = 3.77


(S-D)
73
HIS (75)
A
CD1
<>
458
SO4 (5)
E
O4
D = 2.92


(S-D)
78
ILE (80)
A
CD1
<>
452
DRG (3)
D
CAP
D = 3.82


(S-D)
78
ILE (80)
A
CD1
<>
453
DRG (4)
D
CAT
D = 3.64


(S-D)
78
ILE (80)
A
CD1
<>
453
DRG (4)
D
CAS
D = 3.38


(S-D)
83
LEU (85)
A
CD2
<>
449
ZMA (1)
C
C22
D = 3.84


(S-D)
83
LEU (85)
A
CD2
<>
449
ZMA (1)
C
C23
D = 3.70


(S-D)
105
ARG (107)
A
CG
<>
457
SO4 (3)
E
O3
D = 3.40


(S-D)
105
ARG (107)
A
CD
<>
457
SO4 (3)
E
O3
D = 3.35


(S-D)
127
TRP (129)
A
CD2
<>
451
DRG (2)
D
CAK
D = 3.75


(S-D)
127
TRP (129)
A
CE2
<>
451
DRG (2)
D
CAO
D = 3.73


(S-D)
127
TRP (129)
A
CE2
<>
451
DRG (2)
D
CAM
D = 3.84


(S-D)
127
TRP (129)
A
CE3
<>
451
DRG (2)
D
CAK
D = 3.64


(S-D)
127
TRP (129)
A
CZ2
<>
451
DRG (2)
D
CAO
D = 3.72


(S-D)
127
TRP (129)
A
CZ2
<>
451
DRG (2)
D
CAM
D = 3.65


(S-D)
127
TRP (129)
A
CZ3
<>
451
DRG (2)
D
CAM
D = 3.71


(S-D)
127
TRP (129)
A
CH2
<>
451
DRG (2)
D
CAM
D = 3.57


(S-D)
159
PHE (168)
A
CB
<>
449
ZMA (1)
C
C9
D = 3.47


(S-D)
159
PHE (168)
A
CB
<>
449
ZMA (1)
C
N10
D = 3.26


(S-D)
159
PHE (168)
A
CB
<>
449
ZMA (1)
C
C11
D = 3.43


(S-D)
159
PHE (168)
A
CB
<>
449
ZMA (1)
C
N13
D = 3.75


(S-D)
159
PHE (168)
A
CG
<>
449
ZMA (1)
C
N10
D = 3.74


(S-D)
159
PHE (168)
A
CG
<>
449
ZMA (1)
C
C11
D = 3.37


(S-D)
159
PHE (168)
A
CG
<>
449
ZMA (1)
C
N12
D = 3.50


(S-D)
159
PHE (168)
A
CG
<>
449
ZMA (1)
C
N13
D = 3.62


(S-D)
159
PHE (168)
A
CD1
<>
449
ZMA (1)
C
N12
D = 3.69


(S-D)
159
PHE (168)
A
CD2
<>
449
ZMA (1)
C
C11
D = 3.51


(S-D)
159
PHE (168)
A
CD2
<>
449
ZMA (1)
C
N12
D = 3.70


(S-D)
159
PHE (168)
A
CD2
<>
449
ZMA (1)
C
N13
D = 3.26


(S-D)
159
PHE (168)
A
CD2
<>
449
ZMA (1)
C
C14
D = 3.23


(S-D)
159
PHE (168)
A
CD2
<>
449
ZMA (1)
C
N16
D = 3.43


(S-D)
159
PHE (168)
A
CD2
<>
449
ZMA (1)
C
C18
D = 3.67


(S-D)
159
PHE (168)
A
CE2
<>
449
ZMA (1)
C
C14
D = 3.47


(S-D)
159
PHE (168)
A
CE2
<>
449
ZMA (1)
C
N16
D = 3.23


(S-D)
159
PHE (168)
A
CE2
<>
449
ZMA (1)
C
N17
D = 3.46


(S-D)
159
PHE (168)
A
CE2
<>
449
ZMA (1)
C
C18
D = 3.57


(S-D)
159
PHE (168)
A
CZ
<>
449
ZMA (1)
C
C18
D = 3.67


(S-D)
159
PHE (168)
A
CZ
<>
449
ZMA (1)
C
N19
D = 3.68


(S-D)
159
PHE (168)
A
CZ
<>
449
ZMA (1)
C
C20
D = 3.76


(S-D)
168
MET (177)
A
CE
<>
449
ZMA (1)
C
C21
D = 3.56


(S-D)
168
MET (177)
A
CE
<>
449
ZMA (1)
C
C24
D = 3.38


(S-D)
168
MET (177)
A
CE
<>
449
ZMA (1)
C
O25
D = 3.00


(S-D)
200
ARG (222)
A
NH2
<>
455
SO4 (1)
E
S
D = 3.31


(S-D)
200
ARG (222)
A
NH2
<>
455
SO4 (1)
E
O3
D = 2.83


(S-D)
200
ARG (222)
A
NH2
<>
455
SO4 (1)
E
O4
D = 2.72


(S-D)
224
TRP (246)
A
CZ3
<>
449
ZMA (1)
C
C22
D = 3.72


(S-D)
224
TRP (246)
A
CZ3
<>
449
ZMA (1)
C
C23
D = 3.40


(S-D)
227
LEU (249)
A
CG
<>
449
ZMA (1)
C
C21
D = 3.84


(S-D)
227
LEU (249)
A
CD2
<>
449
ZMA (1)
C
C20
D = 3.51


(S-D)
227
LEU (249)
A
CD2
<>
449
ZMA (1)
C
C21
D = 3.47


(S-D)
227
LEU (249)
A
CD2
<>
449
ZMA (1)
C
C22
D = 3.76


(S-D)
228
HIS (250)
A
CE1
<>
449
ZMA (1)
C
C24
D = 3.40


(S-D)
231
ASN (253)
A
OD1
<>
449
ZMA (1)
C
N15
D = 3.01


(S-D)
231
ASN (253)
A
ND2
<>
449
ZMA (1)
C
N17
D = 3.59


(S-D)
231
ASN (253)
A
ND2
<>
449
ZMA (1)
C
O25
D = 3.30


(S-D)
242
HIS (264)
A
CE1
<>
449
ZMA (1)
C
C5
D = 3.35


(S-D)
245
LEU (267)
A
CD2
<>
449
ZMA (1)
C
C5
D = 3.82


(S-D)
248
MET (270)
A
CG
<>
449
ZMA (1)
C
C6
D = 3.06


(S-D)
248
MET (270)
A
CG
<>
449
ZMA (1)
C
C8
D = 3.83


(S-D)
248
MET (270)
A
SD
<>
449
ZMA (1)
C
C6
D = 3.93


(S-D)
248
MET (270)
A
CE
<>
449
ZMA (1)
C
N15
D = 3.65


(S-D)
264
PHE (286)
A
CD1
<>
454
DRG (5)
D
CAQ
D = 3.81


(S-D)
274
ARG (296)
A
NE
<>
456
SO4 (2)
E
O3
D = 2.99


(S-D)
274
ARG (296)
A
NH2
<>
456
SO4 (2)
E
S
D = 3.88


(S-D)
274
ARG (296)
A
NH2
<>
456
SO4 (2)
E
O4
D = 3.14


(S-D)
275
GLN (297)
A
NE2
<>
456
SO4 (2)
E
O1
D = 2.96


(S-D)
277
PHE (299)
A
CB
<>
454
DRG (5)
D
OAB
D = 2.94


(S-D)
278
ARG (300)
A
NH2
<>
456
SO4 (2)
E
S
D = 3.63


(S-D)
278
ARG (300)
A
NH2
<>
456
SO4 (2)
E
O3
D = 2.72


(B-D)
301
ARG (1014)
A
CA
<>
462
SO4 (9)
E
O2
D = 3.44


(B-D)
301
ARG (1014)
A
C
<>
462
SO4 (9)
E
O2
D = 3.03


(B-D)
302
LEU (1015)
A
N
<>
462
SO4 (9)
E
S
D = 3.34


(B-D)
302
LEU (1015)
A
N
<>
462
SO4 (9)
E
O2
D = 1.92


(B-D)
302
LEU (1015)
A
CA
<>
462
SO4 (9)
E
S
D = 3.99


(B-D)
302
LEU (1015)
A
CA
<>
462
SO4 (9)
E
O2
D = 2.61


(B-D)
302
LEU (1015)
A
C
<>
462
SO4 (9)
E
O2
D = 2.99


(S-D)
302
LEU (1015)
A
CB
<>
462
SO4 (9)
E
S
D = 3.91


(S-D)
302
LEU (1015)
A
CB
<>
462
SO4 (9)
E
O2
D = 2.88


(B-D)
303
LYS (1016)
A
N
<>
462
SO4 (9)
E
S
D = 3.82


(B-D)
303
LYS (1016)
A
N
<>
462
SO4 (9)
E
O2
D = 2.73


(S-D)
303
LYS (1016)
A
CG
<>
462
SO4 (9)
E
S
D = 4.03


(S-D)
363
ARG (1076)
A
NH1
<>
461
SO4 (8)
E
S
D = 3.12


(S-D)
363
ARG (1076)
A
NH1
<>
461
SO4 (8)
E
O2
D = 3.15


(S-D)
363
ARG (1076)
A
NH1
<>
461
SO4 (8)
E
O3
D = 2.89


(S-D)
363
ARG (1076)
A
NH1
<>
461
SO4 (8)
E
O4
D = 2.88


(S-D)
367
ARG (1080)
A
NH1
<>
461
SO4 (8)
E
O4
D = 3.15


(S-D)
367
ARG (1080)
A
NH2
<>
461
SO4 (8)
E
S
D = 3.92


(S-D)
367
ARG (1080)
A
NH2
<>
461
SO4 (8)
E
O2
D = 3.24


(B-D)
401
PHE (1114)
A
CA
<>
460
SO4 (7)
E
S
D = 3.98


(B-D)
401
PHE (1114)
A
CA
<>
460
SO4 (7)
E
O1
D = 3.29


(B-D)
401
PHE (1114)
A
C
<>
460
SO4 (7)
E
O4
D = 3.39


(S-D)
401
PHE (1114)
A
CB
<>
460
SO4 (7)
E
O1
D = 3.43


(S-D)
401
PHE (1114)
A
CD2
<>
460
SO4 (7)
E
O1
D = 3.21


(B-D)
402
THR (1115)
A
N
<>
460
SO4 (7)
E
O4
D = 3.06


(B-D)
403
ASN (1116)
A
N
<>
460
SO4 (7)
E
S
D = 3.83


(B-D)
403
ASN (1116)
A
N
<>
460
SO4 (7)
E
O4
D = 2.69


(S-D)
403
ASN (1116)
A
CB
<>
460
SO4 (7)
E
S
D = 3.91


(S-D)
403
ASN (1116)
A
CB
<>
460
SO4 (7)
E
O3
D = 3.35


(S-D)
403
ASN (1116)
A
CB
<>
460
SO4 (7)
E
O4
D = 3.34


(S-D)
419
ASN (1132)
A
ND2
<>
460
SO4 (7)
E
O3
D = 2.86


(B-D)
429
THR (1142)
A
CA
<>
459
SO4 (6)
E
S
D = 4.03


(B-D)
429
THR (1142)
A
CA
<>
459
SO4 (6)
E
O2
D = 3.24


(B-D)
429
THR (1142)
A
C
<>
459
SO4 (6)
E
O2
D = 3.00


(S-D)
429
THR (1142)
A
CB
<>
459
SO4 (6)
E
S
D = 3.97


(B-D)
430
PRO (1143)
A
N
<>
459
SO4 (6)
E
O2
D = 3.13


(S-D)
430
PRO (1143)
A
CD
<>
459
SO4 (6)
E
O2
D = 3.44


(B-D)
431
ASN (1144)
A
N
<>
459
SO4 (6)
E
O2
D = 2.73


(B-D)
431
ASN (1144)
A
CA
<>
459
SO4 (6)
E
O2
D = 3.38


(S-D)
431
ASN (1144)
A
CB
<>
459
SO4 (6)
E
S
D = 3.74


(S-D)
431
ASN (1144)
A
CB
<>
459
SO4 (6)
E
O2
D = 3.22


(S-D)
431
ASN (1144)
A
CB
<>
459
SO4 (6)
E
O3
D = 3.26


(S-D)
431
ASN (1144)
A
ND2
<>
459
SO4 (6)
E
S
D = 3.93


(S-D)
431
ASN (1144)
A
ND2
<>
459
SO4 (6)
E
O3
D = 2.88


(S-D)
444
THR (1157)
A
CB
<>
455
SO4 (1)
E
S
D = 4.05


(S-D)
444
THR (1157)
A
CB
<>
455
SO4 (1)
E
O3
D = 3.36


(B-D)
445
TRP (1158)
A
N
<>
455
SO4 (1)
E
S
D = 3.81


(B-D)
445
TRP (1158)
A
N
<>
455
SO4 (1)
E
O3
D = 2.87


(S-D)
445
TRP (1158)
A
CD1
<>
455
SO4 (1)
E
S
D = 3.64


(S-D)
445
TRP (1158)
A
CD1
<>
455
SO4 (1)
E
O1
D = 3.39


(S-D)
445
TRP (1158)
A
CD1
<>
455
SO4 (1)
E
O4
D = 3.16










Type: Indicator of the type of contact.


B stands for residue backbone;


S for residue side chain;


C for carbohydrate or sugar;


W for water,


D for ligand, drug, or ion.


DNA, RNA, and amino acids count as residues in this option.


A period is used for atoms that do not fall in any of the previously mentioned categories.
















TABLE 5







Programs for structure superpositioning and RMSD calculations










Name
Description
Author
Year





C-BOP
Coordinate-Based
E. Sandelin
2005



Organization of Proteins




CAALIGN
Cα Align
T. J. Oldfield
2007


CBA
Consistency Based
J. Ebert
2006



Alignment




CE/CE-MC
Combinatorial Extension -
I. Shindyalov
2000



Monte Carlo




CLEMAPS
Conformation-based
W-M. Zheng
2007



alphabet alignments




CTSS
Protein Structure
T. Can
2004



Alignment Using Local





Geometrical Features




CURVE
NA
D. Zhi
2006


DaliLite
Distance Matrix Alignment
L. Holm
1993


DEJAVU
NA
GJ. Kleywegt
1997


EXPRESSO
Fast Multiple Structural
C. Notredame et al.
2007



Alignment using T-Coffee





and Sap




FAST
FAST Alignment and
J. Zhu
2004



Search Tool




FATCAT
Flexible Structure
Y. Ye & A. Godzik
2003



AlignmenT by Chaining





Aligned Fragment Pairs





Allowing Twists




FLASH
Fast aLignment Algorithm
E. S. C. Shih &
2003



for finding Structural
M-J Hwang




Homology of proteins




FlexProt
Flexible Alignment of
M. Shatsky &
2002



Protein Structures
H. Wolfson



GANGSTA
Genetic Algorithm for
B. Kolbeck et al.
2006



Nonsequential and Gapped





STructural Alignment




KENOBI/K2
NA
Z. Weng
2000


LGA
Local-Global Alignment
A. Zemla
2003


LOCK
Hierarchical protein
AP. Singh
1997



structure superposition




LOCK 2
Improvements over LOCK
J. Shapiro
2003


LOVOALIGN
Low Order Value
Andreani et al.
2006



Optimization methods for





Structural Alignment




MALECON
NA
S. Wodak
2004


MAMMOTH
MAtching Molecular
AR. Ortiz
2002



Models Obtained from





Theory




MAMMOTH-
MAMMOTH-based
D. Lupyan
2005


mult
multiple structure





alignment




MASS
Multiple Alignment by
O. Dror &
2003



Secondary Structure
H. Wolfson



MatAlign
Protein Structure
Z. Aung &
2006



Comparison by Matrix
K. L. Tan




Alignment




Matchprot
Comparison of protein
S. Bhattacharya et
2007



structures by growing
al.




neighborhood alignments




Matras
MArkovian TRAnsition of
K. Nishikawa
2000



protein Structure




Matt
Multiple Alignment with
M. Menke
2008



Translations and Twists




MolCom
NA
S. D. O'Hearn
2003


MultiProt
Multiple Alignment of
M. Shatsky &
2004



Protein Structures
H. Wolfson



MUSTANG
MUltiple STructural
A. S. Konagurthu et
2005



AligNment AlGorithm
al.



POSA
Partial Order Structure
Y. Ye & A. Godzik
2005



Alignment




PRIDE
PRobaility of IDEntity
S. Pongor
2002


PrISM
Protein Informatics
B. Honig
2000



Systems for Modeling




ProFit
Protein least-squares
ACR. Martin
1996



Fitting




Protein3Dfit
NA
D. Schomburg
1994


PyMOL
“super” command does
W. L. DeLano
2007



sequence-independent 3D





alignment




RAPIDO
Rapid Alignment of
R. Mosca &
2008



Protein structures In the
T. R. Schneider




presence of Domain





mOvements




SARF2
Spatial ARrangements of
N. Alexandrov
1996



Backbone Fragments




SCALI
Structural Core
C. Bystroff
2004



ALIgnment of proteins




SHEBA
Structural Homology by
B. Lee
2000



Environment-Based





Alignment




SSAP
Sequential Structure
C. Orengo &
1989



Alignment Program
W. Taylor



SSGS
Secondary Structure
G. Wainreb et al.
2006



Guided Superimposition




SSM
Secondary Structure
E. Krissinel
2003



Matching




STAMP
STructural Alignment of
R. Russell &
1992



Multiple Proteins
G. Barton



STRAP
STRucture based
C. Gille
2006



Alignment Program




TALI
Torsion Angle ALIgnment
X. Mioa
2006


TetraDA
Tetrahedral
J. Roach
2005



Decomposition Alignment




TM-align
TM-score based protein
Y. Zhang &
2005



structure alignment
J. Skolnick



TopMatch
Protein structure alignment
M. Sippl &
2008



and visualization of
M. Wiederstein




structural similarities




TOPOFIT
Alignment as a
VA. Ilyin
2004



superimposition of





common volumes at a





topomax point




UCSF
see MatchMaker tool and
E. Meng et al.
2006


Chimera
“matchmaker” command




URMS
Unit-vector RMSD
K. Kedem
2003


VAST
Vector Alignment Search
S. Bryant
1996



Tool




Vorolign
Fast structure alignment
F. Birzele et al.
2007



using Voronoi contacts




YAKUSA
Internal Co-ordinates and
M. Carpentier et al.
2005



BLAST type algorithm
















TABLE 6





HUMAN A2A ADENOSINE STRUCTURE.PDB FILE


(Table 6: discloses SEQ ID NOS 20-27, respectively, in order of appearance.)















Appendix I










HEADER
  MEMBRANE PROTEIN
24-SEP-08
3EML








TITLE
  THE 2.6 A CRYSTAL STRUCTURE OF A HUMAN A2A ADENOSINE


TITLE
 2 RECEPTOR BOUND TO ZM241385.


COMPND
  MOL_ID: 1;


COMPND
 2 MOLECULE: HUMAN ADENOSINE A2A RECEPTOR/T4 LYSOZYME CHIMERA;


COMPND
 3 CHAIN: A;


COMPND
 4 ENGINEERED: YES


SOURCE
  MOL_ID: 1;


SOURCE
 2 ORGANISM_SCIENTIFIC: HOMO SAPIENS, ENTEROBACTERIA PHAGE T4,


SOURCE
 3 HOMO SAPIENS;


SOURCE
 4 EXPRESSION_SYSTEM: SPODOPTERA FRUGIPERDA;


SOURCE
 5 EXPRESSION_SYSTEM_VECTOR_TYPE: PLASMID;


SOURCE
 6 EXPRESSION_SYSTEM_PLASMID: PBAC5B


KEYWDS
  ADENOSINE, CAFFEINE, GPCR, MEMBRANE PROTEIN, RECEPTOR, LCP,


KEYWDS
 2 MESOPHASE


EXPDTA
  X-RAY DIFFRACTION


AUTHOR
  V.-P. JAAKOLA, M. T. GRIFFITH, M. A. HANSON, V. CHEREZOV, E. Y. T. CHIEN,


AUTHOR
 2 J. R. LANE, A. P. IJZERMAN, R. C. STEVENS










JRNL
AUTH

V.-P. JAAKOLA, M. T. GRIFFITH, M. A. HANSON, V. CHEREZOV,


JRNL
AUTH
2
E. Y. T. CHIEN, J. R. LANE, A. P. IJZERMAN, R. C. STEVENS


JRNL
TITL

THE 2.6 A CRYSTAL STRUCTURE OF A HUMAN A2A


JRNL
TITL
2
ADENOSINE RECEPTOR BOUND TO AN ANTAGONIST.


JRNL
REF

TO BE PUBLISHED


JRNL
REFN










REMARK
 1


REMARK
 2


REMARK
 2 RESOLUTION. 2.60 ANGSTROMS.


REMARK
 3


REMARK
 3 REFINEMENT.









REMARK
 3 PROGRAM
: PHENIX (PHENIX.REFINE)


REMARK
 3 AUTHORS
: PAUL ADAMS, PAVEL AFONINE, VICENT CHEN, IAN


REMARK
 3
: DAVIS, KRESHNA GOPAL, RALF GROSSE-


REMARK
 3
: KUNSTLEVE, LI-WEI HUNG, ROBERT IMMORMINO,


REMARK
 3
: TOM IOERGER, AIRLIE MCCOY, ERIK MCKEE, NIGEL


REMARK
 3
: MORIARTY, REETAL PAI, RANDY READ, JANE


REMARK
 3
: RICHARDSON, DAVID RICHARDSON, TOD ROMO, JIM


REMARK
 3
: SACCHETTINI, NICHOLAS SAUTER, JACOB SMITH,


REMARK
 3
: LAURENT STORONI, TOM TERWILLIGER, PETER


REMARK
 3
: ZWART


REMARK
 3










REMARK
 3
REFINEMENT TARGET: ML


REMARK
 3










REMARK
 3
DATA USED IN REFINEMENT.











REMARK
 3
 RESOLUTION RANGE HIGH
(ANGSTROMS)
: 2.60


REMARK
 3
 RESOLUTION RANGE LOW
(ANGSTROMS)
: 19.42


REMARK
 3
 MIN(FOBS/SIGMA_FOBS)

: 2.000


REMARK
 3
 COMPLETENESS FOR RANGE
(%)
: 97.1


REMARK
 3
 NUMBER OF REFLECTIONS

: 18461


REMARK
 3












REMARK
 3
FIT TO DATA USED IN REFINEMENT.











REMARK
 3
 R VALUE
(WORKING + TEST SET)
: 0.198


REMARK
 3
 R VALUE
(WORKING SET)
: 0.196











REMARK
 3
 FREE R VALUE

: 0.231


REMARK
 3
 FREE R VALUE TEST SET SIZE
(%)
: 5.080


REMARK
 3
 FREE R VALUE TEST SET COUNT

: 937


REMARK
 3












REMARK
 3
FIT TO DATA USED IN REFINEMENT (IN BINS).















REMARK
 3
 BIN
RESOLUTION RANGE
COMPL.
NWORK
NFREE
RWORK
RFREE


REMARK
 3
 1
19.4211 - 4.9500
0.98
2595
127
0.1809
0.2180


REMARK
 3
 2
 4.9500 - 3.9397
0.98
2526
120
0.1738
0.2070


REMARK
 3
 3
 3.9397 - 3.4448
0.98
2533
142
0.1794
0.1950


REMARK
 3
 4
 3.4448 - 3.1313
0.97
2477
145
0.2166
0.2329


REMARK
 3
 5
 3.1313 - 2.9077
0.98
2510
143
0.2323
0.3127


REMARK
 3
 6
 2.9077 - 2.7367
0.96
2472
120
0.2490
0.2816


REMARK
 3
 7
 2.7367 - 2.6000
0.94
2411
140
0.2623
0.3054


REMARK
 3
















REMARK
 3
BULK SOLVENT MODELLING.










REMARK
 3
 METHOD USED
: FLAT BULK SOLVENT MODEL


REMARK
 3
 SOLVENT RADIUS
: 1.11


REMARK
 3
 SHRINKAGE RADIUS
: 0.90


REMARK
 3
 K_SOL
: 0.33


REMARK
 3
 B_SOL
: 78.49


REMARK
 3












REMARK
 3
ERROR ESTIMATES.



REMARK
 3
 COORDINATE ERROR (MAXIMUM-LIKELIHOOD BASED)
: 0.430


REMARK
 3
 PHASE ERROR (DEGREES, MAXIMUM-LIKELIHOOD BASED)
: NULL


REMARK
 3




REMARK
 3
B VALUES.












REMARK
 3
 FROM WILSON PLOT
(A**2)
: NULL


REMARK
 3
 MEAN B VALUE
(OVERALL, A**2)
: NULL









REMARK
 3
 OVERALL ANISOTROPIC B VALUE.


REMARK
 3
 B11 (A**2) : NULL


REMARK
 3
 B22 (A**2) : NULL


REMARK
 3
 B33 (A**2) : NULL


REMARK
 3
 B12 (A**2) : NULL


REMARK
 3
 B13 (A**2) : NULL


REMARK
 3
 B23 (A**2) : NULL


REMARK
 3



REMARK
 3
TWINNING INFORMATION.


REMARK
 3
 FRACTION:  NULL


REMARK
 3
 OPERATOR: NULL


REMARK
 3



REMARK
 3
DEVIATIONS FROM IDEAL VALUES.













REMARK
 3


RMSD
COUNT



REMARK
 3
 BOND
:
NULL
NULL



REMARK
 3
 ANGLE
:
NULL
NULL



REMARK
 3
 CHIRALITY
:
NULL
NULL



REMARK
 3
 PLANARITY
:
NULL
NULL



REMARK
 3
 DIHEDRAL
:
NULL
NULL



REMARK
 3














REMARK
 3
TLS DETAILS


REMARK
 3
 NUMBER OF TLS GROUPS : NULL


REMARK
 3



REMARK
 3
NCS DETAILS


REMARK
 3
 NUMBER OF NCS GROUPS : NULL


REMARK
 3



REMARK
 3
OTHER REFINEMENT REMARKS: NULL


REMARK
 4









REMARK
 4 3EML COMPLIES WITH FORMAT V. 3.1, 01-AUG-2007


REMARK
100


REMARK
100 THIS ENTRY HAS BEEN PROCESSED BY RCSB.


REMARK
100 THE RCSB ID CODE IS RCSB049511.


REMARK
200


REMARK
200 EXPERIMENTAL DETAILS










REMARK
200
EXPERIMENT TYPE
: X-RAY DIFFRACTION


REMARK
200
DATE OF DATA COLLECTION
: 28-JUN-2008











REMARK
200
TEMPERATURE
(KELVIN)
: NULL










REMARK
200
PH
: 6.5


REMARK
200
NUMBER OF CRYSTALS USED
: 13


REMARK
200













REMARK
200
SYNCHROTRON
(Y/N)
: Y


REMARK
200
RADIATION SOURCE

: APS


REMARK
200
BEAMLINE

: 23-ID-B


REMARK
200
X-RAY GENERATOR MODEL

: NULL


REMARK
200
MONOCHROMATIC OR LAUE
(M/L)
: M


REMARK
200
WAVELENGTH OR RANGE
(A)
: 1.0332










REMARK
200
MONOCHROMATOR
: DOUBLE CRYSTAL


REMARK
200
OPTICS
: MIRRORS


REMARK
200




REMARK
200
DETECTOR TYPE
: CCD


REMARK
200
DETECTOR MANUFACTURER
: MARMOSAIC 300 MM CCD


REMARK
200
INTENSITY-INTEGRATION SOFTWARE
: XDS


REMARK
200
DATA SCALING SOFTWARE
: XSCALE


REMARK
200




REMARK
200
NUMBER OF UNIQUE REFLECTIONS
: 18465











REMARK
200
RESOLUTION RANGE HIGH
(A)
: 2.600


REMARK
200
RESOLUTION RANGE LOW
(A)
: 20.000











REMARK
200
REJECTION CRITERIA
(SIGMA(I))
: 2.000








REMARK
200


REMARK
200 OVERALL.











REMARK
200
COMPLETENESS FOR RANGE
(%)
: 96.8


REMARK
200
DATA REDUNDANCY

: 3.400


REMARK
200
R MERGE
(I)
: NULL


REMARK
200
R SYM
(I)
: 9.80000










REMARK
200
<I/SIGMA(I)> FOR THE DATA SET
: 7.3500


REMARK
200










REMARK
200 IN THE HIGHEST RESOLUTION SHELL.











REMARK
200
HIGHEST RESOLUTION SHELL, RANGE HIGH
(A)
: 2.60


REMARK
200
HIGHEST RESOLUTION SHELL, RANGE LOW
(A)
: 2.80











REMARK
200
COMPLETENESS FOR SHELL
(%)
: 93.9


REMARK
200
DATA REDUNDANCY IN SHELL

: 2.30


REMARK
200
R MERGE FOR SHELL
(I)
: NULL


REMARK
200
R SYM FOR SHELL
(I)
: 39.80000


REMARK
200
<I/SIGMA(I)> FOR SHELL

: 2.300








REMARK
200


REMARK
200 DIFFRACTION PROTOCOL: SINGLE WAVELENGTH


REMARK
200 METHOD USED TO DETERMINE THE STRUCTURE: MOLECULAR REPLACEMENT


REMARK
200 SOFTWARE USED: PHASER


REMARK
200 STARTING MODEL: PDB ENTRY 2RH1


REMARK
200


REMARK
200 REMARK: NULL


REMARK
280


REMARK
280 CRYSTAL


REMARK
280 SOLVENT CONTENT, VS  (%): 56.79


REMARK
280 MATTHEWS COEFFICIENT, VM (ANGSTROMS**3/DA): 2.85


REMARK
280


REMARK
280 CRYSTALLIZATION CONDITIONS: PEG400 30% V/V, LISO4 185 MM,









REMARK
280
NACITRATE 100 MM, PH 6.5, LIPIDIC MESOPHASE, TEMPERATURE 293 K








REMARK
290


REMARK
290 CRYSTALLOGRAPHIC SYMMETRY


REMARK
290 SYMMETRY OPERATORS FOR SPACE GROUP: P 1 21 1


REMARK
290










REMARK
290
SYMOP
SYMMETRY


REMARK
290
NNNMMM
OPERATOR


REMARK
290
1555
X, Y, Z


REMARK
290
2555
−X, 1//2 + Y, −Z


REMARK
290












REMARK
290
WHERE
NNN -> OPERATOR NUMBER


REMARK
290

MMM -> TRANSLATION VECTOR


REMARK
290










REMARK
290 CRYSTALLOGRAPHIC SYMMETRY TRANSFORMATIONS


REMARK
290 THE FOLLOWING TRANSFORMATIONS OPERATE ON THE ATOM/HETATM


REMARK
290 RECORDS IN THIS ENTRY TO PRODUCE CRYSTALLOGRAPHICALLY


REMARK
290 RELATED MOLECULES.














REMARK
290
 SMTRY1
1
 1.000000
0.000000
 0.000000
 0.00000


REMARK
290
 SMTRY2
1
 0.000000
1.000000
 0.000000
 0.00000


REMARK
290
 SMTRY3
1
 0.000000
0.000000
 1.000000
 0.00000


REMARK
290
 SMTRY1
2
−1.000000
0.000000
 0.000000
 0.00000


REMARK
290
 SMTRY2
2
 0.000000
1.000000
 0.000000
38.46600


REMARK
290
 SMTRY3
2
 0.000000
0.000000
−1.000000
 0.00000








REMARK
290


REMARK
290 REMARK: NULL


REMARK
300


REMARK
300 BIOMOLECULE: 1


REMARK
300 SEE REMARK 350 FOR THE AUTHOR PROVIDED AND/OR PROGRAM


REMARK
300 GENERATED ASSEMBLY INFORMATION FOR THE STRUCTURE IN


REMARK
300 THIS ENTRY. THE REMARK MAY ALSO PROVIDE INFORMATION ON


REMARK
300 BURIED SURFACE AREA.


REMARK
350


REMARK
350 COORDINATES FOR A COMPLETE MULTIMER REPRESENTING THE KNOWN


REMARK
350 BIOLOGICALLY SIGNIFICANT OLIGOMERIZATION STATE OF THE


REMARK
350 MOLECULE CAN BE GENERATED BY APPLYING BIOMT TRANSFORMATIONS


REMARK
350 GIVEN BELOW. BOTH NON-CRYSTALLOGRAPHIC AND


REMARK
350 CRYSTALLOGRAPHIC OPERATIONS ARE GIVEN.


REMARK
350


REMARK
350 BIOMOLECULE: 1


REMARK
350 AUTHOR DETERMINED BIOLOGICAL UNIT: MONOMERIC


REMARK
350 SOFTWARE DETERMINED QUATERNARY STRUCTURE: MONOMERIC


REMARK
350 SOFTWARE USED: PISA


REMARK
350 APPLY THE FOLLOWING TO CHAINS: A














REMARK
350
 BIOMT1
1
1.000000
0.000000
0.000000
0.00000


REMARK
350
 BIOMT2
1
0.000000
1.000000
0.000000
0.00000


REMARK
350
 BIOMT3
1
0.000000
0.000000
1.000000
0.00000








REMARK
465


REMARK
465 MISSING RESIDUES


REMARK
465 THE FOLLOWING RESIDUES WERE NOT LOCATED IN THE


REMARK
465 EXPERIMENT. (M = MODEL NUMBER; RES = RESIDUE NAME; C = CHAIN


REMARK
465 IDENTIFIER; SSEQ = SEQUENCE NUMBER; I = INSERTION CODE.)


REMARK
465













REMARK
465
 M
RES
C
SSEQI



REMARK
465

ASP
A
−14



REMARK
465

TYR
A
−13



REMARK
465

LYS
A
−12



REMARK
465

ASP
A
−11



REMARK
465

ASP
A
−10



REMARK
465

ASP
A
 −9



REMARK
465

ASP
A
 −8



REMARK
465

ALA
A
 −7



REMARK
465

MET
A
 −6



REMARK
465

GLY
A
 −5



REMARK
465

GLN
A
 −4



REMARK
465

PRO
A
 −3



REMARK
465

VAL
A
 −2



REMARK
465

GLY
A
 −1



REMARK
465

ALA
A
 0



REMARK
465

PRO
A
 1



REMARK
465

PRO
A
 2



REMARK
465

PRO
A
149



REMARK
465

LYS
A
150



REMARK
465

GLU
A
151



REMARK
465

GLY
A
152



REMARK
465

LYS
A
153



REMARK
465

ASN
A
154



REMARK
465

HIS
A
155



REMARK
465

GLN
A
311



REMARK
465

GLU
A
312



REMARK
465

PRO
A
313



REMARK
465

PHE
A
314



REMARK
465

LYS
A
315



REMARK
465

ALA
A
316



REMARK
465

HIS
A
317



REMARK
465

HIS
A
318



REMARK
465

HIS
A
319



REMARK
465

HIS
A
320



REMARK
465

HIS
A
321



REMARK
465

HIS
A
322



REMARK
465

HIS
A
323



REMARK
465

HIS
A
324



REMARK
465

HIS
A
325



REMARK
465

HIS
A
326









REMARK
500


REMARK
500 GEOMETRY AND STEREOCHEMISTRY


REMARK
500 SUBTOPIC: CLOSE CONTACTS IN SAME ASYMMETRIC UNIT


REMARK
500


REMARK
500 THE FOLLOWING ATOMS ARE IN CLOSE CONTACT.


REMARK
500


















REMARK
500
ATM1
RES
C
SSEQI
ATM2
RES
C
SSEQI




REMARK
500
 O
HOH
A
564
 O
HOH
A
570

2.10








REMARK
500


REMARK
500 REMARK: NULL


REMARK
500


REMARK
500 GEOMETRY AND STEREOCHEMISTRY


REMARK
500 SUBTOPIC: CLOSE CONTACTS


REMARK
500


REMARK
500 THE FOLLOWING ATOMS THAT ARE RELATED BY CRYSTALLOGRAPHIC


REMARK
500 SYMMETRY ARE IN CLOSE CONTACT. AN ATOM LOCATED WITHIN 0.15


REMARK
500 ANGSTROMS OF A SYMMETRY RELATED ATOM IS ASSUMED TO BE ON A


REMARK
500 SPECIAL POSITION AND IS, THEREFORE, LISTED IN REMARK 375


REMARK
500 INSTEAD OF REMARK 500. ATOMS WITH NON-BLANK ALTERNATE


REMARK
500 LOCATION INDICATORS ARE NOT INCLUDED IN THE CALCULATIONS.


REMARK
500


REMARK
500 DISTANCE CUTOFF:


REMARK
500 2.2 ANGSTROMS FOR CONTACTS NOT INVOLVING HYDROGEN ATOMS


REMARK
500 1.6 ANGSTROMS FOR CONTACTS INVOLVING HYDROGEN ATOMS


REMARK
500



















REMARK
500
ATM1
RES
C
SSEQI
ATM2
RES
C
SSEQI
SSYMOP
DISTANCE



REMARK
500
 O
PHE
A
257
NH2
ARG
A
309
2556
1.99



REMARK
500
 O
PHE
A
257
NH1
ARG
A
309
2556
2.11









REMARK
500


REMARK
500 REMARK: NULL


REMARK
500


REMARK
500 GEOMETRY AND STEREOCHEMISTRY


REMARK
500 SUBTOPIC: TORSION ANGLES


REMARK
500


REMARK
500 TORSION ANGLES OUTSIDE THE EXPECTED RAMACHANDRAN REGIONS:


REMARK
500 (M = MODEL NUMBER; RES = RESIDUE NAME; C = CHAIN IDENTIFIER;


REMARK
500 SSEQ = SEQUENCE NUMBER; I = INSERTION CODE).


REMARK
500


REMARK
500 STANDARD TABLE:


REMARK
500 FORMAT: (10X, I3, 1X, A3, 1X, A1, I4, A1, 4X, F7.2, 3X, F7.2)


REMARK
500


REMARK
500 EXPECTED VALUES: GJ KLEYWEGT AND TA JONES (1996). PHI/PSI-


REMARK
500 CHOLOGY: RAMACHANDRAN REVISITED. STRUCTURE 4, 1395-1400


REMARK
500















REMARK
500
M
RES
CSSEQI
PSI

PHI



REMARK
500

PRO
A1037
32.24

−78.04



REMARK
500

VAL
A 229
−22.06

−141.91









REMARK
500


REMARK
500 REMARK: NULL


REMARK
800


REMARK
800 SITE


REMARK
800 SITE_IDENTIFIER: AC1


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE ZMA A 401


REMARK
800 SITE_IDENTIFIER: AC2


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE STE A 402


REMARK
800 SITE_IDENTIFIER: AC3


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE STE A 403


REMARK
800 SITE_IDENTIFIER: AC4


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE STE A 404


REMARK
800 SITE_IDENTIFIER: AC5


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE STE A 405


REMARK
800 SITE_IDENTIFIER: AC6


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE STE A 406


REMARK
800 SITE_IDENTIFIER: AC7


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE SO4 A 407


REMARK
800 SITE_IDENTIFIER: AC8


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE SO4 A 408


REMARK
800 SITE_IDENTIFIER: AC9


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE SO4 A 409


REMARK
800 SITE_IDENTIFIER: BC1


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE SO4 A 410


REMARK
800 SITE_IDENTIFIER: BC2


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE SO4 A 411


REMARK
800 SITE_IDENTIFIER: BC3


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE SO4 A 412


REMARK
800 SITE_IDENTIFIER: BC4


REMARK
800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE SO4 A 413
















DBREF
3EML
A
  2
 208
UNP
P29274
AA2AR_HUMAN
 2
208


DBREF
3EML
A
1002
1161
UNP
P00720
LYS_BPT4
 2
161


DBREF
3EML
A
 222
 316
UNP
P29274
AA2AR_HUMAN
222
316














SEQADV
3EML
ASP
A
−14
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
TYR
A
−13
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
LYS
A
−12
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
ASP
A
−11
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
ASP
A
−10
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
ASP
A
 −9
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
ASP
A
 −8
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
ALA
A
 −7
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
MET
A
 −6
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
GLY
A
 −5
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
GLN
A
 −4
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
PRO
A
 −3
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
VAL
A
 −2
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
GLY
A
 −1
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
ALA
A
 0
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
PRO
A
 1
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
HIS
A
317
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
HIS
A
318
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
HIS
A
319
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
HIS
A
320
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
HIS
A
321
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
HIS
A
322
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
HIS
A
323
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
HIS
A
324
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
HIS
A
325
UNP
P29274
EXPRESSION TAG


SEQADV
3EML
HIS
A
326
UNP
P29274
EXPRESSION TAG























SEQRES
 1
A
488
ASP
TYR
LYS
ASP
ASP
ASP
ASP
ALA
MET
GLY
GLN
PRO
VAL


SEQRES
 2
A
488
GLY
ALA
PRO
PRO
ILE
MET
GLY
SER
SER
VAL
TYR
ILE
THR


SEQRES
 3
A
488
VAL
GLU
LEU
ALA
ILE
ALA
VAL
LEU
ALA
ILE
LEU
GLY
ASN


SEQRES
 4
A
488
VAL
LEU
VAL
CYS
TRP
ALA
VAL
TRP
LEU
ASN
SER
ASN
LEU


SEQRES
 5
A
488
GLN
ASN
VAL
THR
ASN
TYR
PHE
VAL
VAL
SER
LEU
ALA
ALA


SEQRES
 6
A
488
ALA
ASP
ILE
ALA
VAL
GLY
VAL
LEU
ALA
ILE
PRO
PHE
ALA


SEQRES
 7
A
488
ILE
THR
ILE
SER
THR
GLY
PHE
CYS
ALA
ALA
CYS
HIS
GLY


SEQRES
 8
A
488
CYS
LEU
PHE
ILE
ALA
CYS
PHE
VAL
LEU
VAL
LEU
THR
GLN


SEQRES
 9
A
488
SER
SER
ILE
PHE
SER
LEU
LEU
ALA
ILE
ALA
ILE
ASP
ARG


SEQRES
10
A
488
TYR
ILE
ALA
ILE
ARG
ILE
PRO
LEU
ARG
TYR
ASN
GLY
LEU


SEQRES
11
A
488
VAL
THR
GLY
THR
ARG
ALA
LYS
GLY
ILE
ILE
ALA
ILE
CYS


SEQRES
12
A
488
TRP
VAL
LEU
SER
PHE
ALA
ILE
GLY
LEU
THR
PRO
MET
LEU


SEQRES
13
A
488
GLY
TRP
ASN
ASN
CYS
GLY
GLN
PRO
LYS
GLU
GLY
LYS
ASN


SEQRES
14
A
488
HIS
SER
GLN
GLY
CYS
GLY
GLU
GLY
GLN
VAL
ALA
CYS
LEU


SEQRES
15
A
488
PHE
GLU
ASP
VAL
VAL
PRO
MET
ASN
TYR
MET
VAL
TYR
PHE


SEQRES
16
A
488
ASN
PHE
PHE
ALA
CYS
VAL
LEU
VAL
PRO
LEU
LEU
LEU
MET


SEQRES
17
A
488
LEU
GLY
VAL
TYR
LEU
ARG
ILE
PHE
LEU
ALA
ALA
ARG
ARG


SEQRES
18
A
488
GLN
LEU
ASN
ILE
PHE
GLU
MET
LEU
ARG
ILE
ASP
GLU
GLY


SEQRES
19
A
488
LEU
ARG
LEU
LYS
ILE
TYR
LYS
ASP
THR
GLU
GLY
TYR
TYR


SEQRES
20
A
488
THR
ILE
GLY
ILE
GLY
HIS
LEU
LEU
THR
LYS
SER
PRO
SER


SEQRES
21
A
488
LEU
ASN
ALA
ALA
LYS
SER
GLU
LEU
ASP
LYS
ALA
ILE
GLY


SEQRES
22
A
488
ARG
ASN
THR
ASN
GLY
VAL
ILE
THR
LYS
ASP
GLU
ALA
GLU


SEQRES
23
A
488
LYS
LEU
PHE
ASN
GLN
ASP
VAL
ASP
ALA
ALA
VAL
ARG
GLY


SEQRES
24
A
488
ILE
LEU
ARG
ASN
ALA
LYS
LEU
LYS
PRO
VAL
TYR
ASP
SER


SEQRES
25
A
488
LEU
ASP
ALA
VAL
ARG
ARG
ALA
ALA
LEU
ILE
ASN
MET
VAL


SEQRES
26
A
488
PHE
GLN
MET
GLY
GLU
THR
GLY
VAL
ALA
GLY
PHE
THR
ASN


SEQRES
27
A
488
SER
LEU
ARG
MET
LEU
GLN
GLN
LYS
ARG
TRP
ASP
GLU
ALA


SEQRES
28
A
488
ALA
VAL
ASN
LEU
ALA
LYS
SER
ARG
TRP
TYR
ASN
GLN
THR


SEQRES
29
A
488
PRO
ASN
ARG
ALA
LYS
ARG
VAL
ILE
THR
THR
PHE
ARG
THR


SEQRES
30
A
488
GLY
THR
TRP
ASP
ALA
TYR
ARG
SER
THR
LEU
GLN
LYS
GLU


SEQRES
31
A
488
VAL
HIS
ALA
ALA
LYS
SER
LEU
ALA
ILE
ILE
VAL
GLY
LEU


SEQRES
32
A
488
PHE
ALA
LEU
CYS
TRP
LEU
PRO
LEU
HIS
ILE
ILE
ASN
CYS


SEQRES
33
A
488
PHE
THR
PHE
PHE
CYS
PRO
ASP
CYS
SER
HIS
ALA
PRO
LEU


SEQRES
34
A
488
TRP
LEU
MET
TYR
LEU
ALA
ILE
VAL
LEU
SER
HIS
THR
ASN


SEQRES
35
A
488
SER
VAL
VAL
ASN
PRO
PHE
ILE
TYR
ALA
TYR
ARG
ILE
ARG


SEQRES
36
A
488
GLU
PHE
ARG
GLN
THR
PHE
ARG
LYS
ILE
ILE
ARG
SER
HIS


SEQRES
37
A
488
VAL
LEU
ARG
GLN
GLN
GLU
PRO
PHE
LYS
ALA
HIS
HIS
HIS


SEQRES
38
A
488
HIS
HIS
HIS
HIS
HIS
HIS
HIS

















HET
ZMA
A
401
25


HET
 STE
A
402
20


HET
 STE
A
403
20


HET
 STE
A
404
20


HET
 STE
A
405
20


HET
 STE
A
406
20


HET
 SO4
A
407
 5


HET
 SO4
A
408
 5


HET
 SO4
A
409
 5


HET
 SO4
A
410
 5


HET
 SO4
A
411
 5


HET
 SO4
A
412
 5


HET
 SO4
A
413
 5









HETNAM

ZMA 4-{2-[(7-AMINO-2-FURAN-2-YL[1,2,4]TRIAZOLO[1,5-A][1,3,


HETNAM
 2
ZMA 5]TRIAZIN-5-YL)AMINO]ETHYL}PHENOL


HETNAM

STE STEARIC ACID


HETNAM

SO4 SULFATE ION










FORMUL
 2
ZMA
 C16H15N7O2


FORMUL
 3
 STE
 5(C18H36O2)


FORMUL
 8
 SO4
 7(O4S2−)


FORMUL
 5
HOH
*77(H2O)

















HELIX
 1
 1
SER
A
  6
ASN
A
 34
1
29


HELIX
 2
 2
SER
A
 35
GLN
A
 38
5
 4


HELIX
 3
 3
VAL
A
 40
LEU
A
 58
1
19


HELIX
 4
 4
LEU
A
 58
SER
A
 67
1
10


HELIX
 5
 5
ALA
A
 73
ARG
A
 107
1
35


HELIX
 6
 6
ILE
A
 108
TYR
A
 112
5
 5


HELIX
 7
 7
THR
A
 117
LEU
A
 137
1
21


HELIX
 8
 8
THR
A
 138
GLY
A
 142
5
 5


HELIX
 9
 9
LEU
A
 167
VAL
A
 172
1
 6


HELIX
10
10
PRO
A
 173
TYR
A
 179
1
 7


HELIX
11
11
ASN
A
 181
VAL
A
 186
1
 6


HELIX
12
12
VAL
A
 186
ARG
A
 205
1
20


HELIX
13
13
ASN
A
1002
GLU
A
1011
1
10


HELIX
14
14
SER
A
1038
GLY
A
1051
1
14


HELIX
15
15
THR
A
1059
ASN
A
1081
1
23


HELIX
16
16
LYS
A
1083
LEU
A
1091
1
 9


HELIX
17
17
ASP
A
1092
GLY
A
1107
1
16


HELIX
18
18
GLY
A
1107
ALA
A
1112
1
 6


HELIX
19
19
PHE
A
1114
GLN
A
1123
1
10


HELIX
20
20
ARG
A
1125
ALA
A
1134
1
10


HELIX
21
21
SER
A
1136
THR
A
1142
1
 7


HELIX
22
22
THR
A
1142
GLY
A
1156
1
15


HELIX
23
23
TRP
A
1158
CYS
A
 259
1
42


HELIX
24
24
PRO
A
 266
ILE
A
 292
1
27


HELIX
25
25
ILE
A
 292
HIS
A
 306
1
15





















SHEET
 1
 A
2
CYS
A 71
ALA
A 72
 0








SHEET
 2
 A
2
VAL
A 164
ALA
A 165
−1
O
VAL
A 164
N
ALA
A 72


SHEET
 1
 B
3
ARG
A1014
LYS
A1019
 0








SHEET
 2
 B
3
TYR
A1025
GLY
A1028
−1
O
THR
A1026
N
TYR
A1018


SHEET
 3
 B
3
HIS
A1031
THR
A1034
−1
O
LEU
A1033
N
TYR
A1025

















SSBOND
 1
CYS
A
 71
CYS
A
159
1555
1555
2.03


SSBOND
 2
CYS
A
 74
CYS
A
146
1555
1555
2.03


SSBOND
 3
CYS
A
 77
CYS
A
166
1555
1555
2.03


SSBOND
 4
CYS
A
259
CYS
A
262
1555
1555
2.03


















SITE
 1
AC1
11
PHE
A 168
GLU
A 169
MET
A 177
TRP
A 246


SITE
 2
AC1
11
LEU
A 249
HIS
A 250
ASN
A 253
HIS
A 264


SITE
 3
AC1
11
MET
A 270
HOH
A 519
HOH
A 559




SITE
 1
AC2
 4
VAL
A 57
LEU
A 58
STE
A 405
HOH
A 571


SITE
 1
AC3
 1
VAL
A 46








SITE
 1
AC4
 3
VAL
A 57
PHE
A 62
STE
A 405




SITE
 1
AC5
 4
GLY
A 76
ILE
A 80
STE
A 402
STE
A 404


SITE
 1
AC6
 3
GLY
A 23
PHE
A 299
HOH
A 562




SITE
 1
AC7
 5
ARG
A 222
HOH
A 506
ASN
A1040
THR
A1157


SITE
 2
AC7
 5
TRP
A1158








SITE
 1
AC8
 3
ARG
A 296
GLN
A 297
ARG
A 300




SITE
 1
AC9
 5
ARG
A 107
ALA
A 203
ARG
A 206
HOH
A 530


SITE
 2
AC9
 5
ARG
A1008








SITE
 1
BC1
 3
ALA
A 73
CYS
A 74
HIS
A 75




SITE
 1
BC2
 4
THR
A1142
PRO
A1143
ASN
A1144
ARG
A1145


SITE
 1
BC3
 5
PHE
A1114
THR
A1115
ASN
A1116
SER
A1117


SITE
 2
BC3
 5
ASN
A1132








SITE
 1
BC4
 3
HOH
A 547
ARG
A1076
ARG
A1080

















CRYST1
 47.736
76.932
86.553
90.00
101.32
90.00
P 1 21 1
2











ORIGX1
1.000000
0.000000
0.000000
0.00000


ORIGX2
0.000000
1.000000
0.000000
0.00000


ORIGX3
0.000000
0.000000
1.000000
0.00000


SCALE1
0.020949
0.000000
0.004192
0.00000


SCALE2
0.000000
0.012998
0.000000
0.00000


SCALE3
0.000000
0.000000
0.011783
0.00000


















ATOM
1
N
ILE
A
3
−30.582
−20.763
57.829
1.00
115.32
N


ATOM
2
CA
ILE
A
3
−29.314
−20.499
57.159
1.00
116.02
C


ATOM
3
C
ILE
A
3
−28.389
−19.651
58.027
1.00
113.18
C


ATOM
4
O
ILE
A
3
−28.839
−18.751
58.736
1.00
111.11
O


ATOM
5
CB
ILE
A
3
−29.525
−19.801
55.801
1.00
122.12
C


ATOM
6
CG1
ILE
A
3
−30.369
−18.537
55.975
1.00
127.32
C


ATOM
7
CG2
ILE
A
3
−30.184
−20.750
54.811
1.00
119.11
C


ATOM
8
CD1
ILE
A
3
−30.644
−17.800
54.681
1.00
127.54
C


ATOM
9
N
MET
A
4
−27.095
−19.947
57.964
1.00
114.09
N


ATOM
10
CA
MET
A
4
−26.097
−19.237
58.759
1.00
113.72
C


ATOM
11
C
MET
A
4
−25.637
−17.954
58.075
1.00
111.28
C


ATOM
12
O
MET
A
4
−25.728
−17.821
56.855
1.00
111.47
O


ATOM
13
CB
MET
A
4
−24.892
−20.141
59.029
1.00
114.23
C


ATOM
14
CG
MET
A
4
−25.165
−21.271
60.008
1.00
114.99
C


ATOM
15
SD
MET
A
4
−25.242
−20.704
61.718
1.00
176.57
S


ATOM
16
CE
MET
A
4
−23.568
−20.112
61.954
1.00
112.29
C


ATOM
17
N
GLY
A
5
−25.139
−17.013
58.871
1.00
108.62
N


ATOM
18
CA
GLY
A
5
−24.637
−15.757
58.348
1.00
113.00
C


ATOM
19
C
GLY
A
5
−23.270
−15.907
57.707
1.00
120.15
C


ATOM
20
O
GLY
A
5
−22.728
−14.954
57.146
1.00
122.73
O


ATOM
21
N
SER
A
6
−22.710
−17.110
57.793
1.00
121.00
N


ATOM
22
CA
SER
A
6
−21.405
−17.393
57.205
1.00
112.22
C


ATOM
23
C
SER
A
6
−21.516
−18.439
56.100
1.00
107.46
C


ATOM
24
O
SER
A
6
−20.735
−18.431
55.148
1.00
111.51
O


ATOM
25
CB
SER
A
6
−20.418
−17.860
58.278
1.00
103.57
C


ATOM
26
OG
SER
A
6
−20.834
−19.083
58.859
1.00
100.88
O


ATOM
27
N
SER
A
7
−22.488
−19.337
56.231
1.00
98.15
N


ATOM
28
CA
SER
A
7
−22.729
−20.351
55.212
1.00
92.91
C


ATOM
29
C
SER
A
7
−23.089
−19.692
53.886
1.00
87.40
C


ATOM
30
O
SER
A
7
−22.962
−20.298
52.823
1.00
82.75
O


ATOM
31
CB
SER
A
7
−23.837
−21.309
55.651
1.00
90.04
C


ATOM
32
OG
SER
A
7
−23.450
−22.041
56.801
1.00
91.37
O


ATOM
33
N
VAL
A
8
−23.544
−18.445
53.961
1.00
83.91
N


ATOM
34
CA
VAL
A
8
−23.812
−17.654
52.768
1.00
78.45
C


ATOM
35
C
VAL
A
8
−22.500
−17.121
52.210
1.00
68.73
C


ATOM
36
O
VAL
A
8
−22.235
−17.220
51.011
1.00
65.71
O


ATOM
37
CB
VAL
A
8
−24.746
−16.469
53.071
1.00
79.64
C


ATOM
38
CG1
VAL
A
8
−24.852
−15.553
51.860
1.00
79.22
C


ATOM
39
CG2
VAL
A
8
−26.119
−16.970
53.493
1.00
77.55
C


ATOM
40
N
TYR
A
9
−21.682
−16.557
53.094
1.00
60.14
N


ATOM
41
CA
TYR
A
9
−20.372
−16.044
52.715
1.00
61.91
C


ATOM
42
C
TYR
A
9
−19.552
−17.109
51.995
1.00
67.50
C


ATOM
43
O
TYR
A
9
−18.914
−16.835
50.978
1.00
68.07
O


ATOM
44
CB
TYR
A
9
−19.614
−15.550
53.949
1.00
58.73
C


ATOM
45
CG
TYR
A
9
−18.146
−15.294
53.694
1.00
65.03
C


ATOM
46
CD1
TYR
A
9
−17.730
−14.172
52.991
1.00
68.96
C


ATOM
47
CD2
TYR
A
9
−17.176
−16.176
54.155
1.00
66.40
C


ATOM
48
CE1
TYR
A
9
−16.391
−13.933
52.755
1.00
74.95
C


ATOM
49
CE2
TYR
A
9
−15.832
−15.947
53.922
1.00
65.41
C


ATOM
50
CZ
TYR
A
9
−15.444
−14.824
53.221
1.00
75.65
C


ATOM
51
OH
TYR
A
9
−14.108
−14.589
52.985
1.00
74.15
O


ATOM
52
N
ILE
A
10
−19.579
−18.326
52.528
1.00
68.00
N


ATOM
53
CA
ILE
A
10
−18.808
−19.429
51.967
1.00
63.94
C


ATOM
54
C
ILE
A
10
−19.372
−19.907
50.630
1.00
62.03
C


ATOM
55
O
ILE
A
10
−18.619
−20.204
49.703
1.00
68.15
O


ATOM
56
CB
ILE
A
10
−18.730
−20.611
52.951
1.00
63.47
C


ATOM
57
CG1
ILE
A
10
−18.048
−20.170
54.247
1.00
66.00
C


ATOM
58
CG2
ILE
A
10
−17.982
−21.777
52.327
1.00
65.06
C


ATOM
59
CD1
ILE
A
10
−17.993
−21.246
55.307
1.00
68.16
C


ATOM
60
N
THR
A
11
−20.695
−19.981
50.531
1.00
61.30
N


ATOM
61
CA
THR
A
11
−21.340
−20.389
49.288
1.00
64.10
C


ATOM
62
C
THR
A
11
−21.057
−19.383
48.177
1.00
61.59
C


ATOM
63
O
THR
A
11
−20.570
−19.745
47.106
1.00
54.04
O


ATOM
64
CB
THR
A
11
−22.866
−20.533
49.455
1.00
67.09
C


ATOM
65
OG1
THR
A
11
−23.150
−21.507
50.467
1.00
68.70
O


ATOM
66
CG2
THR
A
11
−23.507
−20.970
48.144
1.00
53.89
C


ATOM
67
N
VAL
A
12
−21.365
−18.118
48.448
1.00
65.58
N


ATOM
68
CA
VAL
A
12
−21.164
−17.040
47.486
1.00
63.91
C


ATOM
69
C
VAL
A
12
−19.753
−17.054
46.912
1.00
67.80
C


ATOM
70
O
VAL
A
12
−19.562
−16.955
45.700
1.00
71.79
O


ATOM
71
CB
VAL
A
12
−21.421
−15.661
48.130
1.00
61.21
C


ATOM
72
CG1
VAL
A
12
−20.973
−14.544
47.199
1.00
53.70
C


ATOM
73
CG2
VAL
A
12
−22.891
−15.505
48.488
1.00
67.26
C


ATOM
74
N
GLU
A
13
−18.767
−17.184
47.792
1.00
66.46
N


ATOM
75
CA
GLU
A
13
−17.369
−17.098
47.389
1.00
69.25
C


ATOM
76
C
GLU
A
13
−16.900
−18.343
46.637
1.00
68.66
C


ATOM
77
O
GLU
A
13
−15.990
−18.271
45.812
1.00
66.95
O


ATOM
78
CB
GLU
A
13
−16.486
−16.837
48.607
1.00
69.29
C


ATOM
79
CG
GLU
A
13
−15.232
−16.053
48.291
1.00
76.14
C


ATOM
80
CD
GLU
A
13
−14.751
−15.258
49.479
1.00
74.21
C


ATOM
81
OE1
GLU
A
13
−15.593
−14.923
50.333
1.00
78.41
O


ATOM
82
OE2
GLU
A
13
−13.540
−14.968
49.560
1.00
78.21
O


ATOM
83
N
LEU
A
14
−17.522
−19.481
46.926
1.00
67.94
N


ATOM
84
CA
LEU
A
14
−17.253
−20.701
46.174
1.00
64.86
C


ATOM
85
C
LEU
A
14
−17.828
−20.588
44.768
1.00
63.34
C


ATOM
86
O
LEU
A
14
−17.233
−21.069
43.804
1.00
67.04
O


ATOM
87
CB
LEU
A
14
−17.832
−21.923
46.888
1.00
66.60
C


ATOM
88
CG
LEU
A
14
−16.872
−22.686
47.803
1.00
68.43
C


ATOM
89
CD1
LEU
A
14
−16.114
−21.728
48.695
1.00
76.17
C


ATOM
90
CD2
LEU
A
14
−17.619
−23.715
48.635
1.00
66.48
C


ATOM
91
N
ALA
A
15
−18.990
−19.951
44.659
1.00
54.24
N


ATOM
92
CA
ALA
A
15
−19.610
−19.714
43.362
1.00
54.16
C


ATOM
93
C
ALA
A
15
−18.732
−18.786
42.533
1.00
53.26
C


ATOM
94
O
ALA
A
15
−18.501
−19.023
41.347
1.00
57.84
O


ATOM
95
CB
ALA
A
15
−20.998
−19.124
43.536
1.00
56.06
C


ATOM
96
N
ILE
A
16
−18.242
−17.729
43.171
1.00
52.04
N


ATOM
97
CA
ILE
A
16
−17.339
−16.787
42.524
1.00
53.28
C


ATOM
98
C
ILE
A
16
−16.086
−17.491
42.013
1.00
53.42
C


ATOM
99
O
ILE
A
16
−15.595
−17.193
40.923
1.00
53.32
O


ATOM
100
CB
ILE
A
16
−16.935
−15.656
43.486
1.00
51.70
C


ATOM
101
CG1
ILE
A
16
−18.140
−14.761
43.782
1.00
56.16
C


ATOM
102
CG2
ILE
A
16
−15.785
−14.844
42.907
1.00
48.96
C


ATOM
103
CD1
ILE
A
16
−17.926
−13.800
44.932
1.00
61.38
C


ATOM
104
N
ALA
A
17
−15.577
−18.431
42.803
1.00
48.45
N


ATOM
105
CA
ALA
A
17
−14.378
−19.178
42.438
1.00
53.75
C


ATOM
106
C
ALA
A
17
−14.587
−20.009
41.172
1.00
63.57
C


ATOM
107
O
ALA
A
17
−13.728
−20.041
40.292
1.00
69.25
O


ATOM
108
CB
ALA
A
17
−13.934
−20.068
43.594
1.00
49.57
C


ATOM
109
N
VAL
A
18
−15.733
−20.679
41.086
1.00
60.60
N


ATOM
110
CA
VAL
A
18
−16.040
−21.525
39.938
1.00
58.67
C


ATOM
111
C
VAL
A
18
−16.102
−20.719
38.642
1.00
60.19
C


ATOM
112
O
VAL
A
18
−15.559
−21.135
37.617
1.00
59.26
O


ATOM
113
CB
VAL
A
18
−17.364
−22.291
40.133
1.00
64.12
C


ATOM
114
CG1
VAL
A
18
−17.721
−23.067
38.873
1.00
63.73
C


ATOM
115
CG2
VAL
A
18
−17.266
−23.224
41.331
1.00
65.66
C


ATOM
116
N
LEU
A
19
−16.764
−19.566
38.689
1.00
56.71
N


ATOM
117
CA
LEU
A
19
−16.861
−18.700
37.517
1.00
58.49
C


ATOM
118
C
LEU
A
19
−15.510
−18.100
37.143
1.00
53.86
C


ATOM
119
O
LEU
A
19
−15.165
−18.018
35.964
1.00
53.92
O


ATOM
120
CB
LEU
A
19
−17.892
−17.590
37.734
1.00
67.30
C


ATOM
121
CG
LEU
A
19
−19.324
−17.907
37.298
1.00
76.63
C


ATOM
122
CD1
LEU
A
19
−19.913
−19.038
38.129
1.00
79.95
C


ATOM
123
CD2
LEU
A
19
−20.196
−16.665
37.381
1.00
75.91
C


ATOM
124
N
ALA
A
20
−14.750
−17.681
38.150
1.00
59.37
N


ATOM
125
CA
ALA
A
20
−13.418
−17.137
37.921
1.00
54.11
C


ATOM
126
C
ALA
A
20
−12.584
−18.117
37.105
1.00
54.81
C


ATOM
127
O
ALA
A
20
−11.968
−17.745
36.107
1.00
53.51
O


ATOM
128
CB
ALA
A
20
−12.735
−16.832
39.244
1.00
53.22
C


ATOM
129
N
ILE
A
21
−12.580
−19.374
37.534
1.00
51.11
N


ATOM
130
CA
ILE
A
21
−11.829
−20.421
36.850
1.00
44.22
C


ATOM
131
C
ILE
A
21
−12.371
−20.707
35.450
1.00
51.90
C


ATOM
132
O
ILE
A
21
−11.644
−20.606
34.463
1.00
62.45
O


ATOM
133
CB
ILE
A
21
−11.822
−21.726
37.668
1.00
51.90
C


ATOM
134
CG1
ILE
A
21
−11.099
−21.513
39.000
1.00
56.33
C


ATOM
135
CG2
ILE
A
21
−11.168
−22.847
36.878
1.00
52.44
C


ATOM
136
CD1
ILE
A
21
−11.218
−22.678
39.961
1.00
53.18
C


ATOM
137
N
LEU
A
22
−13.649
−21.064
35.369
1.00
63.25
N


ATOM
138
CA
LEU
A
22
−14.267
−21.406
34.092
1.00
63.45
C


ATOM
139
C
LEU
A
22
−14.160
−20.273
33.076
1.00
59.45
C


ATOM
140
O
LEU
A
22
−13.798
−20.495
31.920
1.00
60.42
O


ATOM
141
CB
LEU
A
22
−15.734
−21.788
34.292
1.00
61.90
C


ATOM
142
CG
LEU
A
22
−15.984
−23.111
35.014
1.00
63.21
C


ATOM
143
CD1
LEU
A
22
−17.474
−23.393
35.110
1.00
61.60
C


ATOM
144
CD2
LEU
A
22
−15.264
−24.246
34.303
1.00
61.95
C


ATOM
145
N
GLY
A
23
−14.477
−19.060
33.512
1.00
49.29
N


ATOM
146
CA
GLY
A
23
−14.455
−17.910
32.630
1.00
41.16
C


ATOM
147
C
GLY
A
23
−13.080
−17.637
32.058
1.00
47.99
C


ATOM
148
O
GLY
A
23
−12.926
−17.447
30.853
1.00
52.04
O


ATOM
149
N
ASN
A
24
−12.073
−17.628
32.926
1.00
50.22
N


ATOM
150
CA
ASN
A
24
−10.718
−17.270
32.518
1.00
44.51
C


ATOM
151
C
ASN
A
24
−9.942
−18.401
31.843
1.00
50.67
C


ATOM
152
O
ASN
A
24
−8.975
−18.154
31.122
1.00
50.53
O


ATOM
153
CB
ASN
A
24
−9.941
−16.688
33.701
1.00
46.69
C


ATOM
154
CG
ASN
A
24
−10.426
−15.300
34.082
1.00
54.60
C


ATOM
155
OD1
ASN
A
24
−10.253
−14.342
33.328
1.00
51.61
O


ATOM
156
ND2
ASN
A
24
−11.045
−15.188
35.252
1.00
45.15
N


ATOM
157
N
VAL
A
25
−10.363
−19.639
32.076
1.00
45.08
N


ATOM
158
CA
VAL
A
25
−9.825
−20.758
31.316
1.00
47.66
C


ATOM
159
C
VAL
A
25
−10.255
−20.592
29.864
1.00
55.47
C


ATOM
160
O
VAL
A
25
−9.499
−20.884
28.936
1.00
60.83
O


ATOM
161
CB
VAL
A
25
−10.324
−22.116
31.852
1.00
47.32
C


ATOM
162
CG1
VAL
A
25
−10.178
−23.193
30.789
1.00
43.42
C


ATOM
163
CG2
VAL
A
25
−9.559
−22.507
33.109
1.00
38.82
C


ATOM
164
N
LEU
A
26
−11.476
−20.101
29.683
1.00
56.99
N


ATOM
165
CA
LEU
A
26
−12.045
−19.904
28.357
1.00
54.09
C


ATOM
166
C
LEU
A
26
−11.273
−18.847
27.570
1.00
56.51
C


ATOM
167
O
LEU
A
26
−11.094
−18.972
26.359
1.00
61.89
O


ATOM
168
CB
LEU
A
26
−13.519
−19.511
28.472
1.00
61.54
C


ATOM
169
CG
LEU
A
26
−14.357
−19.530
27.193
1.00
71.92
C


ATOM
170
CD1
LEU
A
26
−14.364
−20.919
26.575
1.00
72.32
C


ATOM
171
CD2
LEU
A
26
−15.775
−19.063
27.482
1.00
71.63
C


ATOM
172
N
VAL
A
27
−10.817
−17.807
28.262
1.00
57.29
N


ATOM
173
CA
VAL
A
27
−10.052
−16.742
27.620
1.00
48.64
C


ATOM
174
C
VAL
A
27
−8.740
−17.276
27.057
1.00
48.87
C


ATOM
175
O
VAL
A
27
−8.377
−16.979
25.919
1.00
55.75
O


ATOM
176
CB
VAL
A
27
−9.759
−15.577
28.592
1.00
46.54
C


ATOM
177
CG1
VAL
A
27
−8.709
−14.647
28.004
1.00
43.30
C


ATOM
178
CG2
VAL
A
27
−11.035
−14.813
28.912
1.00
39.25
C


ATOM
179
N
CYS
A
28
−8.034
−18.069
27.858
1.00
48.72
N


ATOM
180
CA
CYS
A
28
−6.770
−18.660
27.430
1.00
57.38
C


ATOM
181
C
CYS
A
28
−6.984
−19.673
26.309
1.00
59.99
C


ATOM
182
O
CYS
A
28
−6.181
−19.764
25.379
1.00
60.57
O


ATOM
183
CB
CYS
A
28
−6.065
−19.333
28.611
1.00
57.82
C


ATOM
184
SG
CYS
A
28
−5.723
−18.241
30.008
1.00
58.82
S


ATOM
185
N
TRP
A
29
−8.071
−20.435
26.411
1.00
57.26
N


ATOM
186
CA
TRP
A
29
−8.408
−21.451
25.419
1.00
57.95
C


ATOM
187
C
TRP
A
29
−8.565
−20.828
24.036
1.00
59.13
C


ATOM
188
O
TRP
A
29
−8.090
−21.373
23.039
1.00
56.47
O


ATOM
189
CB
TRP
A
29
−9.707
−22.157
25.811
1.00
62.93
C


ATOM
190
CG
TRP
A
29
−9.935
−23.460
25.103
1.00
61.45
C


ATOM
191
CD1
TRP
A
29
−9.324
−23.894
23.962
1.00
61.41
C


ATOM
192
CD2
TRP
A
29
−10.861
−24.488
25.478
1.00
61.95
C


ATOM
193
NE1
TRP
A
29
−9.801
−25.134
23.612
1.00
58.38
N


ATOM
194
CE2
TRP
A
29
−10.747
−25.520
24.525
1.00
59.99
C


ATOM
195
CE3
TRP
A
29
−11.771
−24.638
26.528
1.00
65.86
C


ATOM
196
CZ2
TRP
A
29
−11.509
−26.685
24.592
1.00
59.67
C


ATOM
197
CZ3
TRP
A
29
−12.527
−25.796
26.593
1.00
61.08
C


ATOM
198
CH2
TRP
A
29
−12.390
−26.804
25.630
1.00
55.39
C


ATOM
199
N
ALA
A
30
−9.237
−19.682
23.987
1.00
60.75
N


ATOM
200
CA
ALA
A
30
−9.495
−18.988
22.731
1.00
54.63
C


ATOM
201
C
ALA
A
30
−8.209
−18.494
22.078
1.00
53.63
C


ATOM
202
O
ALA
A
30
−8.017
−18.652
20.872
1.00
63.69
O


ATOM
203
CB
ALA
A
30
−10.452
−17.829
22.957
1.00
56.60
C


ATOM
204
N
VAL
A
31
−7.334
−17.892
22.876
1.00
53.18
N


ATOM
205
CA
VAL
A
31
−6.073
−17.364
22.364
1.00
58.61
C


ATOM
206
C
VAL
A
31
−5.201
−18.476
21.785
1.00
60.55
C


ATOM
207
O
VAL
A
31
−4.472
−18.267
20.816
1.00
65.47
O


ATOM
208
CB
VAL
A
31
−5.292
−16.606
23.459
1.00
61.76
C


ATOM
209
CG1
VAL
A
31
−3.897
−16.235
22.968
1.00
60.52
C


ATOM
210
CG2
VAL
A
31
−6.059
−15.364
23.893
1.00
53.64
C


ATOM
211
N
TRP
A
32
−5.288
−19.660
22.381
1.00
61.93
N


ATOM
212
CA
TRP
A
32
−4.516
−20.807
21.921
1.00
67.14
C


ATOM
213
C
TRP
A
32
−5.058
−21.346
20.596
1.00
64.28
C


ATOM
214
O
TRP
A
32
−4.292
−21.737
19.715
1.00
62.55
O


ATOM
215
CB
TRP
A
32
−4.522
−21.906
22.987
1.00
76.54
C


ATOM
216
CG
TRP
A
32
−3.486
−22.967
22.776
1.00
88.88
C


ATOM
217
CD1
TRP
A
32
−2.148
−22.867
23.025
1.00
92.35
C


ATOM
218
CD2
TRP
A
32
−3.704
−24.296
22.283
1.00
99.86
C


ATOM
219
NE1
TRP
A
32
−1.518
−24.047
22.713
1.00
100.27
N


ATOM
220
CE2
TRP
A
32
−2.451
−24.941
22.255
1.00
103.18
C


ATOM
221
CE3
TRP
A
32
−4.836
−25.002
21.860
1.00
101.46
C


ATOM
222
CZ2
TRP
A
32
−2.298
−26.257
21.822
1.00
104.81
C


ATOM
223
CZ3
TRP
A
32
−4.681
−26.308
21.429
1.00
101.91
C


ATOM
224
CH2
TRP
A
32
−3.422
−26.922
21.414
1.00
105.43
C


ATOM
225
N
LEU
A
33
−6.380
−21.355
20.459
1.00
60.82
N


ATOM
226
CA
LEU
A
33
−7.026
−21.875
19.257
1.00
64.06
C


ATOM
227
C
LEU
A
33
−6.970
−20.904
18.082
1.00
64.97
C


ATOM
228
O
LEU
A
33
−6.647
−21.294
16.960
1.00
59.60
O


ATOM
229
CB
LEU
A
33
−8.486
−22.234
19.544
1.00
68.79
C


ATOM
230
CG
LEU
A
33
−8.760
−23.526
20.312
1.00
72.17
C


ATOM
231
CD1
LEU
A
33
−10.256
−23.783
20.379
1.00
73.45
C


ATOM
232
CD2
LEU
A
33
−8.044
−24.696
19.658
1.00
66.75
C


ATOM
233
N
ASN
A
34
−7.293
−19.642
18.343
1.00
66.04
N


ATOM
234
CA
ASN
A
34
−7.421
−18.654
17.278
1.00
63.50
C


ATOM
235
C
ASN
A
34
−6.139
−17.866
17.023
1.00
73.73
C


ATOM
236
O
ASN
A
34
−5.572
−17.268
17.937
1.00
74.49
O


ATOM
237
CB
ASN
A
34
−8.578
−17.699
17.578
1.00
55.71
C


ATOM
238
CG
ASN
A
34
−9.081
−16.990
16.338
1.00
59.31
C


ATOM
239
OD1
ASN
A
34
−8.462
−17.062
15.275
1.00
63.02
O


ATOM
240
ND2
ASN
A
34
−10.211
−16.301
16.465
1.00
56.96
N


ATOM
241
N
SER
A
35
−5.691
−17.870
15.771
1.00
77.82
N


ATOM
242
CA
SER
A
35
−4.483
−17.149
15.380
1.00
75.43
C


ATOM
243
C
SER
A
35
−4.709
−15.641
15.381
1.00
69.77
C


ATOM
244
O
SER
A
35
−3.775
−14.863
15.580
1.00
66.19
O


ATOM
245
CB
SER
A
35
−4.009
−17.607
13.999
1.00
81.27
C


ATOM
246
OG
SER
A
35
−2.862
−16.883
13.586
1.00
89.74
O


ATOM
247
N
ASN
A
36
−5.954
−15.232
15.155
1.00
64.21
N


ATOM
248
CA
ASN
A
36
−6.304
−13.816
15.149
1.00
67.38
C


ATOM
249
C
ASN
A
36
−6.389
−13.231
16.557
1.00
67.33
C


ATOM
250
O
ASN
A
36
−6.767
−12.076
16.739
1.00
70.96
O


ATOM
251
CB
ASN
A
36
−7.615
−13.591
14.396
1.00
72.24
C


ATOM
252
CG
ASN
A
36
−7.500
−13.924
12.922
1.00
86.62
C


ATOM
253
OD1
ASN
A
36
−6.429
−13.795
12.327
1.00
82.67
O


ATOM
254
ND2
ASN
A
36
−8.605
−14.355
12.323
1.00
98.34
N


ATOM
255
N
LEU
A
37
−6.037
−14.041
17.550
1.00
62.99
N


ATOM
256
CA
LEU
A
37
−5.965
−13.579
18.930
1.00
60.03
C


ATOM
257
C
LEU
A
37
−4.558
−13.799
19.468
1.00
62.48
C


ATOM
258
O
LEU
A
37
−4.329
−13.732
20.674
1.00
70.21
O


ATOM
259
CB
LEU
A
37
−6.979
−14.315
19.808
1.00
51.98
C


ATOM
260
CG
LEU
A
37
−8.463
−14.209
19.453
1.00
50.41
C


ATOM
261
CD1
LEU
A
37
−9.273
−15.208
20.263
1.00
45.06
C


ATOM
262
CD2
LEU
A
37
−8.987
−12.797
19.668
1.00
47.06
C


ATOM
263
N
GLN
A
38
−3.618
−14.072
18.567
1.00
55.36
N


ATOM
264
CA
GLN
A
38
−2.243
−14.365
18.965
1.00
59.02
C


ATOM
265
C
GLN
A
38
−1.308
−13.184
18.723
1.00
62.89
C


ATOM
266
O
GLN
A
38
−0.144
−13.354
18.355
1.00
53.79
O


ATOM
267
CB
GLN
A
38
−1.737
−15.632
18.268
1.00
66.47
C


ATOM
268
CG
GLN
A
38
−2.467
−16.890
18.720
1.00
74.55
C


ATOM
269
CD
GLN
A
38
−1.917
−18.154
18.090
1.00
73.77
C


ATOM
270
OE1
GLN
A
38
−1.085
−18.102
17.185
1.00
81.72
O


ATOM
271
NE2
GLN
A
38
−2.384
−19.303
18.569
1.00
61.31
N


ATOM
272
N
ASN
A
39
−1.836
−11.985
18.941
1.00
70.86
N


ATOM
273
CA
ASN
A
39
−1.044
−10.767
18.906
1.00
66.48
C


ATOM
274
C
ASN
A
39
−0.411
−10.501
20.269
1.00
66.69
C


ATOM
275
O
ASN
A
39
−0.720
−11.183
21.246
1.00
64.50
O


ATOM
276
CB
ASN
A
39
−1.918
−9.589
18.482
1.00
65.45
C


ATOM
277
CG
ASN
A
39
−3.222
−9.523
19.255
1.00
69.71
C


ATOM
278
OD1
ASN
A
39
−3.228
−9.332
20.472
1.00
76.47
O


ATOM
279
ND2
ASN
A
39
−4.336
−9.683
18.550
1.00
64.47
N


ATOM
280
N
VAL
A
40
0.468
−9.506
20.332
1.00
66.28
N


ATOM
281
CA
VAL
A
40
1.198
−9.210
21.564
1.00
62.67
C


ATOM
282
C
VAL
A
40
0.282
−8.719
22.684
1.00
57.05
C


ATOM
283
O
VAL
A
40
0.517
−8.999
23.860
1.00
49.86
O


ATOM
284
CB
VAL
A
40
2.304
−8.166
21.326
1.00
68.95
C


ATOM
285
CG1
VAL
A
40
3.115
−7.956
22.595
1.00
61.33
C


ATOM
286
CG2
VAL
A
40
3.204
−8.600
20.181
1.00
73.71
C


ATOM
287
N
THR
A
41
−0.761
−7.984
22.312
1.00
63.28
N


ATOM
288
CA
THR
A
41
−1.683
−7.422
23.291
1.00
65.30
C


ATOM
289
C
THR
A
41
−2.338
−8.506
24.145
1.00
69.65
C


ATOM
290
O
THR
A
41
−2.532
−8.326
25.348
1.00
72.53
O


ATOM
291
CB
THR
A
41
−2.782
−6.586
22.610
1.00
58.97
C


ATOM
292
OG1
THR
A
41
−2.191
−5.719
21.634
1.00
56.89
O


ATOM
293
CG2
THR
A
41
−3.535
−5.754
23.642
1.00
51.51
C


ATOM
294
N
ASN
A
42
−2.675
−9.630
23.519
1.00
59.31
N


ATOM
295
CA
ASN
A
42
−3.326
−10.731
24.226
1.00
54.96
C


ATOM
296
C
ASN
A
42
−2.363
−11.572
25.063
1.00
53.43
C


ATOM
297
O
ASN
A
42
−2.785
−12.466
25.796
1.00
58.46
O


ATOM
298
CB
ASN
A
42
−4.116
−11.609
23.254
1.00
54.51
C


ATOM
299
CG
ASN
A
42
−5.357
−10.916
22.729
1.00
55.48
C


ATOM
300
OD1
ASN
A
42
−5.981
−10.123
23.434
1.00
55.74
O


ATOM
301
ND2
ASN
A
42
−5.721
−11.209
21.486
1.00
60.06
N


ATOM
302
N
TYR
A
43
−1.071
−11.281
24.949
1.00
52.66
N


ATOM
303
CA
TYR
A
43
−0.072
−11.879
25.827
1.00
54.61
C


ATOM
304
C
TYR
A
43
−0.313
−11.417
27.260
1.00
51.58
C


ATOM
305
O
TYR
A
43
−0.136
−12.176
28.212
1.00
51.67
O


ATOM
306
CB
TYR
A
43
1.333
−11.468
25.392
1.00
57.59
C


ATOM
307
CG
TYR
A
43
1.897
−12.269
24.241
1.00
64.19
C


ATOM
308
CD1
TYR
A
43
1.099
−12.642
23.169
1.00
67.89
C


ATOM
309
CD2
TYR
A
43
3.238
−12.632
24.219
1.00
66.57
C


ATOM
310
CE1
TYR
A
43
1.618
−13.369
22.113
1.00
72.72
C


ATOM
311
CE2
TYR
A
43
3.766
−13.355
23.168
1.00
68.15
C


ATOM
312
CZ
TYR
A
43
2.953
−13.722
22.118
1.00
73.46
C


ATOM
313
OH
TYR
A
43
3.479
−14.444
21.072
1.00
75.89
O


ATOM
314
N
PHE
A
44
−0.717
−10.159
27.402
1.00
53.23
N


ATOM
315
CA
PHE
A
44
−0.989
−9.577
28.709
1.00
55.20
C


ATOM
316
C
PHE
A
44
−2.386
−9.941
29.198
1.00
53.59
C


ATOM
317
O
PHE
A
44
−2.628
−10.028
30.401
1.00
49.70
O


ATOM
318
CB
PHE
A
44
−0.822
−8.057
28.659
1.00
57.61
C


ATOM
319
CG
PHE
A
44
0.556
−7.614
28.256
1.00
60.37
C


ATOM
320
CD1
PHE
A
44
0.778
−7.027
27.022
1.00
62.33
C


ATOM
321
CD2
PHE
A
44
1.631
−7.794
29.110
1.00
60.43
C


ATOM
322
CE1
PHE
A
44
2.047
−6.621
26.649
1.00
58.27
C


ATOM
323
CE2
PHE
A
44
2.901
−7.392
28.744
1.00
57.39
C


ATOM
324
CZ
PHE
A
44
3.110
−6.805
27.513
1.00
58.99
C


ATOM
325
N
VAL
A
45
−3.304
−10.150
28.259
1.00
54.14
N


ATOM
326
CA
VAL
A
45
−4.653
−10.587
28.596
1.00
52.45
C


ATOM
327
C
VAL
A
45
−4.613
−11.992
29.190
1.00
51.25
C


ATOM
328
O
VAL
A
45
−5.332
−12.296
30.141
1.00
55.59
O


ATOM
329
CB
VAL
A
45
−5.578
−10.576
27.361
1.00
55.15
C


ATOM
330
CG1
VAL
A
45
−6.931
−11.187
27.698
1.00
58.64
C


ATOM
331
CG2
VAL
A
45
−5.745
−9.158
26.833
1.00
45.21
C


ATOM
332
N
VAL
A
46
−3.760
−12.841
28.625
1.00
51.50
N


ATOM
333
CA
VAL
A
46
−3.592
−14.209
29.107
1.00
54.61
C


ATOM
334
C
VAL
A
46
−2.954
−14.249
30.495
1.00
55.57
C


ATOM
335
O
VAL
A
46
−3.410
−14.980
31.376
1.00
51.94
O


ATOM
336
CB
VAL
A
46
−2.749
−15.050
28.129
1.00
57.81
C


ATOM
337
CG1
VAL
A
46
−2.243
−16.312
28.809
1.00
56.04
C


ATOM
338
CG2
VAL
A
46
−3.561
−15.388
26.884
1.00
51.86
C


ATOM
339
N
SER
A
47
−1.897
−13.465
30.685
1.00
61.87
N


ATOM
340
CA
SER
A
47
−1.249
−13.359
31.988
1.00
54.01
C


ATOM
341
C
SER
A
47
−2.259
−12.892
33.031
1.00
51.38
C


ATOM
342
O
SER
A
47
−2.294
−13.396
34.154
1.00
46.71
O


ATOM
343
CB
SER
A
47
−0.069
−12.387
31.926
1.00
51.97
C


ATOM
344
OG
SER
A
47
0.587
−12.293
33.179
1.00
57.36
O


ATOM
345
N
LEU
A
48
−3.082
−11.924
32.644
1.00
54.76
N


ATOM
346
CA
LEU
A
48
−4.141
−11.421
33.508
1.00
58.61
C


ATOM
347
C
LEU
A
48
−5.146
−12.526
33.825
1.00
59.46
C


ATOM
348
O
LEU
A
48
−5.596
−12.662
34.963
1.00
59.35
O


ATOM
349
CB
LEU
A
48
−4.846
−10.241
32.840
1.00
65.92
C


ATOM
350
CG
LEU
A
48
−5.938
−9.529
33.637
1.00
66.12
C


ATOM
351
CD1
LEU
A
48
−5.381
−8.991
34.944
1.00
56.59
C


ATOM
352
CD2
LEU
A
48
−6.548
−8.411
32.808
1.00
67.97
C


ATOM
353
N
ALA
A
49
−5.491
−13.312
32.810
1.00
60.16
N


ATOM
354
CA
ALA
A
49
−6.419
−14.427
32.978
1.00
58.88
C


ATOM
355
C
ALA
A
49
−5.838
−15.486
33.910
1.00
56.89
C


ATOM
356
O
ALA
A
49
−6.568
−16.141
34.655
1.00
51.14
O


ATOM
357
CB
ALA
A
49
−6.766
−15.038
31.626
1.00
52.59
C


ATOM
358
N
ALA
A
50
−4.520
−15.651
33.859
1.00
50.59
N


ATOM
359
CA
ALA
A
50
−3.834
−16.597
34.729
1.00
49.49
C


ATOM
360
C
ALA
A
50
−3.989
−16.189
36.190
1.00
53.79
C


ATOM
361
O
ALA
A
50
−4.272
−17.020
37.052
1.00
63.67
O


ATOM
362
CB
ALA
A
50
−2.363
−16.690
34.356
1.00
44.53
C


ATOM
363
N
ALA
A
51
−3.806
−14.900
36.457
1.00
55.33
N


ATOM
364
CA
ALA
A
51
−3.927
−14.370
37.810
1.00
47.52
C


ATOM
365
C
ALA
A
51
−5.332
−14.574
38.369
1.00
53.37
C


ATOM
366
O
ALA
A
51
−5.501
−14.870
39.550
1.00
57.64
O


ATOM
367
CB
ALA
A
51
−3.554
−12.898
37.835
1.00
45.14
C


ATOM
368
N
ASP
A
52
−6.338
−14.415
37.514
1.00
57.53
N


ATOM
369
CA
ASP
A
52
−7.728
−14.560
37.933
1.00
50.75
C


ATOM
370
C
ASP
A
52
−8.103
−16.018
38.189
1.00
57.74
C


ATOM
371
O
ASP
A
52
−8.948
−16.308
39.035
1.00
62.76
O


ATOM
372
CB
ASP
A
52
−8.670
−13.933
36.904
1.00
54.25
C


ATOM
373
CG
ASP
A
52
−8.633
−12.416
36.930
1.00
64.00
C


ATOM
374
OD1
ASP
A
52
−8.476
−11.844
38.030
1.00
69.09
O


ATOM
375
OD2
ASP
A
52
−8.761
−11.794
35.856
1.00
57.84
O


ATOM
376
N
ILE
A
53
−7.474
−16.934
37.459
1.00
54.06
N


ATOM
377
CA
ILE
A
53
−7.679
−18.355
37.706
1.00
51.76
C


ATOM
378
C
ILE
A
53
−7.096
−18.723
39.064
1.00
56.19
C


ATOM
379
O
ILE
A
53
−7.707
−19.462
39.836
1.00
58.51
O


ATOM
380
CB
ILE
A
53
−7.020
−19.231
36.621
1.00
56.32
C


ATOM
381
CG1
ILE
A
53
−7.673
−18.981
35.260
1.00
59.33
C


ATOM
382
CG2
ILE
A
53
−7.120
−20.705
36.994
1.00
49.46
C


ATOM
383
CD1
ILE
A
53
−6.988
−19.699
34.114
1.00
60.95
C


ATOM
384
N
ALA
A
54
−5.910
−18.195
39.351
1.00
52.48
N


ATOM
385
CA
ALA
A
54
−5.230
−18.470
40.611
1.00
50.78
C


ATOM
386
C
ALA
A
54
−6.025
−17.934
41.800
1.00
60.72
C


ATOM
387
O
ALA
A
54
−5.917
−18.448
42.913
1.00
60.49
O


ATOM
388
CB
ALA
A
54
−3.824
−17.886
40.594
1.00
44.14
C


ATOM
389
N
VAL
A
55
−6.822
−16.898
41.559
1.00
59.00
N


ATOM
390
CA
VAL
A
55
−7.672
−16.335
42.601
1.00
53.33
C


ATOM
391
C
VAL
A
55
−8.742
−17.337
43.012
1.00
54.00
C


ATOM
392
O
VAL
A
55
−8.991
−17.543
44.200
1.00
60.44
O


ATOM
393
CB
VAL
A
55
−8.356
−15.033
42.140
1.00
55.05
C


ATOM
394
CG1
VAL
A
55
−9.467
−14.646
43.107
1.00
55.08
C


ATOM
395
CG2
VAL
A
55
−7.337
−13.910
42.022
1.00
53.82
C


ATOM
396
N
GLY
A
56
−9.371
−17.960
42.022
1.00
51.21
N


ATOM
397
CA
GLY
A
56
−10.411
−18.936
42.280
1.00
58.11
C


ATOM
398
C
GLY
A
56
−9.869
−20.208
42.902
1.00
63.92
C


ATOM
399
O
GLY
A
56
−10.535
−20.845
43.718
1.00
62.56
O


ATOM
400
N
VAL
A
57
−8.649
−20.572
42.523
1.00
65.66
N


ATOM
401
CA
VAL
A
57
−8.049
−21.820
42.981
1.00
58.18
C


ATOM
402
C
VAL
A
57
−7.416
−21.721
44.370
1.00
58.97
C


ATOM
403
O
VAL
A
57
−7.558
−22.632
45.183
1.00
57.33
O


ATOM
404
CB
VAL
A
57
−6.999
−22.339
41.980
1.00
55.79
C


ATOM
405
CG1
VAL
A
57
−6.325
−23.589
42.519
1.00
64.68
C


ATOM
406
CG2
VAL
A
57
−7.646
−22.617
40.634
1.00
45.08
C


ATOM
407
N
LEU
A
58
−6.723
−20.619
44.645
1.00
58.83
N


ATOM
408
CA
LEU
A
58
−5.983
−20.492
45.900
1.00
60.87
C


ATOM
409
C
LEU
A
58
−6.427
−19.325
46.783
1.00
59.06
C


ATOM
410
O
LEU
A
58
−6.700
−19.507
47.969
1.00
61.62
O


ATOM
411
CB
LEU
A
58
−4.479
−20.389
45.628
1.00
70.55
C


ATOM
412
CG
LEU
A
58
−3.797
−21.628
45.044
1.00
70.44
C


ATOM
413
CD1
LEU
A
58
−2.334
−21.341
44.750
1.00
69.14
C


ATOM
414
CD2
LEU
A
58
−3.933
−22.812
45.987
1.00
73.02
C


ATOM
415
N
ALA
A
59
−6.486
−18.130
46.205
1.00
54.43
N


ATOM
416
CA
ALA
A
59
−6.774
−16.922
46.976
1.00
50.06
C


ATOM
417
C
ALA
A
59
−8.086
−17.009
47.750
1.00
59.55
C


ATOM
418
O
ALA
A
59
−8.144
−16.658
48.928
1.00
56.30
O


ATOM
419
CB
ALA
A
59
−6.771
−15.701
46.072
1.00
52.42
C


ATOM
420
N
ILE
A
60
−9.138
−17.472
47.083
1.00
56.07
N


ATOM
421
CA
ILE
A
60
−10.452
−17.575
47.713
1.00
56.71
C


ATOM
422
C
ILE
A
60
−10.509
−18.638
48.818
1.00
57.72
C


ATOM
423
O
ILE
A
60
−11.054
−18.383
49.893
1.00
51.88
O


ATOM
424
CB
ILE
A
60
−11.567
−17.800
46.673
1.00
60.41
C


ATOM
425
CG1
ILE
A
60
−11.807
−16.512
45.881
1.00
58.94
C


ATOM
426
CG2
ILE
A
60
−12.846
−18.258
47.353
1.00
51.36
C


ATOM
427
CD1
ILE
A
60
−12.829
−16.646
44.774
1.00
52.17
C


ATOM
428
N
PRO
A
61
−9.954
−19.835
48.559
1.00
57.55
N


ATOM
429
CA
PRO
A
61
−9.851
−20.817
49.645
1.00
58.52
C


ATOM
430
C
PRO
A
61
−9.028
−20.281
50.817
1.00
62.38
C


ATOM
431
O
PRO
A
61
−9.351
−20.564
51.973
1.00
55.92
O


ATOM
432
CB
PRO
A
61
−9.131
−21.994
48.982
1.00
48.18
C


ATOM
433
CG
PRO
A
61
−9.495
−21.884
47.544
1.00
55.33
C


ATOM
434
CD
PRO
A
61
−9.564
−20.408
47.259
1.00
57.67
C


ATOM
435
N
PHE
A
62
−7.981
−19.517
50.522
1.00
54.81
N


ATOM
436
CA
PHE
A
62
−7.181
−18.891
51.569
1.00
51.86
C


ATOM
437
C
PHE
A
62
−8.022
−17.905
52.376
1.00
54.22
C


ATOM
438
O
PHE
A
62
−7.931
−17.856
53.603
1.00
62.37
O


ATOM
439
CB
PHE
A
62
−5.961
−18.176
50.981
1.00
61.40
C


ATOM
440
CG
PHE
A
62
−4.856
−19.103
50.554
1.00
65.62
C


ATOM
441
CD1
PHE
A
62
−4.850
−20.429
50.954
1.00
59.06
C


ATOM
442
CD2
PHE
A
62
−3.807
−18.638
49.777
1.00
66.19
C


ATOM
443
CE1
PHE
A
62
−3.829
−21.278
50.568
1.00
54.74
C


ATOM
444
CE2
PHE
A
62
−2.783
−19.482
49.391
1.00
60.74
C


ATOM
445
CZ
PHE
A
62
−2.794
−20.803
49.787
1.00
58.09
C


ATOM
446
N
ALA
A
63
−8.839
−17.122
51.679
1.00
53.63
N


ATOM
447
CA
ALA
A
63
−9.700
−16.141
52.330
1.00
52.19
C


ATOM
448
C
ALA
A
63
−10.624
−16.807
53.346
1.00
58.31
C


ATOM
449
O
ALA
A
63
−10.789
−16.321
54.465
1.00
59.74
O


ATOM
450
CB
ALA
A
63
−10.512
−15.377
51.293
1.00
49.14
C


ATOM
451
N
ILE
A
64
−11.220
−17.924
52.948
1.00
57.19
N


ATOM
452
CA
ILE
A
64
−12.141
−18.655
53.810
1.00
58.02
C


ATOM
453
C
ILE
A
64
−11.425
−19.250
55.017
1.00
53.50
C


ATOM
454
O
ILE
A
64
−11.937
−19.216
56.136
1.00
51.96
O


ATOM
455
CB
ILE
A
64
−12.840
−19.784
53.037
1.00
55.73
C


ATOM
456
CG1
ILE
A
64
−13.527
−19.221
51.793
1.00
58.64
C


ATOM
457
CG2
ILE
A
64
−13.838
−20.505
53.933
1.00
60.85
C


ATOM
458
CD1
ILE
A
64
−14.063
−20.282
50.869
1.00
61.69
C


ATOM
459
N
THR
A
65
−10.239
−19.800
54.780
1.00
52.08
N


ATOM
460
CA
THR
A
65
−9.437
−20.399
55.838
1.00
54.83
C


ATOM
461
C
THR
A
65
−9.094
−19.381
56.918
1.00
63.10
C


ATOM
462
O
THR
A
65
−9.188
−19.669
58.112
1.00
59.03
O


ATOM
463
CB
THR
A
65
−8.124
−20.972
55.275
1.00
53.32
C


ATOM
464
OG1
THR
A
65
−8.418
−22.016
54.338
1.00
54.74
O


ATOM
465
CG2
THR
A
65
−7.259
−21.528
56.394
1.00
56.55
C


ATOM
466
N
ILE
A
66
−8.703
−18.187
56.485
1.00
60.54
N


ATOM
467
CA
ILE
A
66
−8.212
−17.155
57.390
1.00
58.22
C


ATOM
468
C
ILE
A
66
−9.331
−16.468
58.172
1.00
57.21
C


ATOM
469
O
ILE
A
66
−9.077
−15.816
59.186
1.00
63.98
O


ATOM
470
CB
ILE
A
66
−7.388
−16.097
56.624
1.00
67.42
C


ATOM
471
CG1
ILE
A
66
−6.508
−15.298
57.586
1.00
72.00
C


ATOM
472
CG2
ILE
A
66
−8.300
−15.178
55.822
1.00
69.57
C


ATOM
473
CD1
ILE
A
66
−5.644
−14.265
56.900
1.00
73.41
C


ATOM
474
N
SER
A
67
−10.568
−16.616
57.708
1.00
54.77
N


ATOM
475
CA
SER
A
67
−11.709
−15.994
58.375
1.00
57.12
C


ATOM
476
C
SER
A
67
−12.046
−16.690
59.693
1.00
63.98
C


ATOM
477
O
SER
A
67
−12.965
−16.281
60.404
1.00
64.17
O


ATOM
478
CB
SER
A
67
−12.936
−15.987
57.459
1.00
57.32
C


ATOM
479
OG
SER
A
67
−13.478
−17.289
57.319
1.00
54.70
O


ATOM
480
N
THR
A
68
−11.300
−17.742
60.014
1.00
64.00
N


ATOM
481
CA
THR
A
68
−11.515
−18.483
61.251
1.00
53.90
C


ATOM
482
C
THR
A
68
−10.640
−17.944
62.377
1.00
51.40
C


ATOM
483
O
THR
A
68
−10.957
−18.109
63.555
1.00
47.76
O


ATOM
484
CB
THR
A
68
−11.219
−19.981
61.070
1.00
56.20
C


ATOM
485
OG1
THR
A
68
−9.823
−20.166
60.799
1.00
59.42
O


ATOM
486
CG2
THR
A
68
−12.040
−20.551
59.921
1.00
48.56
C


ATOM
487
N
GLY
A
69
−9.535
−17.302
62.009
1.00
55.64
N


ATOM
488
CA
GLY
A
69
−8.605
−16.759
62.984
1.00
58.61
C


ATOM
489
C
GLY
A
69
−7.849
−17.840
63.734
1.00
59.28
C


ATOM
490
O
GLY
A
69
−7.484
−17.665
64.897
1.00
62.11
O


ATOM
491
N
PHE
A
70
−7.608
−18.961
63.061
1.00
60.20
N


ATOM
492
CA
PHE
A
70
−6.950
−20.108
63.679
1.00
59.57
C


ATOM
493
C
PHE
A
70
−5.500
−19.809
64.058
1.00
50.81
C


ATOM
494
O
PHE
A
70
−4.888
−18.877
63.537
1.00
49.57
O


ATOM
495
CB
PHE
A
70
−6.998
−21.310
62.736
1.00
57.73
C


ATOM
496
CG
PHE
A
70
−6.149
−21.148
61.510
1.00
62.68
C


ATOM
497
CD1
PHE
A
70
−6.544
−20.306
60.484
1.00
65.58
C


ATOM
498
CD2
PHE
A
70
−4.954
−21.837
61.383
1.00
66.10
C


ATOM
499
CE1
PHE
A
70
−5.762
−20.153
59.354
1.00
65.37
C


ATOM
500
CE2
PHE
A
70
−4.168
−21.690
60.256
1.00
65.32
C


ATOM
501
CZ
PHE
A
70
−4.573
−20.846
59.240
1.00
61.83
C


ATOM
502
N
CYS
A
71
−4.958
−20.610
64.969
1.00
48.00
N


ATOM
503
CA
CYS
A
71
−3.574
−20.460
65.399
1.00
51.87
C


ATOM
504
C
CYS
A
71
−2.628
−21.022
64.346
1.00
56.16
C


ATOM
505
O
CYS
A
71
−2.803
−22.149
63.884
1.00
66.76
O


ATOM
506
CB
CYS
A
71
−3.345
−21.179
66.730
1.00
48.71
C


ATOM
507
SG
CYS
A
71
−4.342
−20.570
68.109
1.00
63.99
S


ATOM
508
N
ALA
A
72
−1.627
−20.234
63.970
1.00
46.09
N


ATOM
509
CA
ALA
A
72
−0.642
−20.672
62.988
1.00
46.80
C


ATOM
510
C
ALA
A
72
0.710
−20.010
63.220
1.00
52.70
C


ATOM
511
O
ALA
A
72
0.801
−18.982
63.895
1.00
58.22
O


ATOM
512
CB
ALA
A
72
−1.139
−20.382
61.577
1.00
45.85
C


ATOM
513
N
ALA
A
73
1.757
−20.609
62.662
1.00
56.02
N


ATOM
514
CA
ALA
A
73
3.077
−20.002
62.684
1.00
58.90
C


ATOM
515
C
ALA
A
73
3.019
−18.643
61.994
1.00
65.68
C


ATOM
516
O
ALA
A
73
2.163
−18.409
61.140
1.00
67.58
O


ATOM
517
CB
ALA
A
73
4.093
−20.910
61.989
1.00
54.55
C


ATOM
518
N
CYS
A
74
3.922
−17.747
62.375
1.00
67.83
N


ATOM
519
CA
CYS
A
74
3.908
−16.381
61.858
1.00
68.48
C


ATOM
520
C
CYS
A
74
3.949
−16.314
60.332
1.00
61.01
C


ATOM
521
O
CYS
A
74
2.984
−15.896
59.694
1.00
56.11
O


ATOM
522
CB
CYS
A
74
5.069
−15.577
62.443
1.00
73.92
C


ATOM
523
SG
CYS
A
74
5.320
−13.972
61.659
1.00
89.63
S


ATOM
524
N
HIS
A
75
5.070
−16.729
59.753
1.00
60.21
N


ATOM
525
CA
HIS
A
75
5.288
−16.586
58.317
1.00
66.41
C


ATOM
526
C
HIS
A
75
4.308
−17.394
57.469
1.00
68.42
C


ATOM
527
O
HIS
A
75
3.910
−16.960
56.387
1.00
67.47
O


ATOM
528
CB
HIS
A
75
6.735
−16.929
57.959
1.00
70.61
C


ATOM
529
CG
HIS
A
75
7.728
−15.934
58.471
1.00
76.99
C


ATOM
530
ND1
HIS
A
75
8.456
−16.133
59.625
1.00
83.11
N


ATOM
531
CD2
HIS
A
75
8.099
−14.720
57.997
1.00
77.16
C


ATOM
532
CE1
HIS
A
75
9.239
−15.091
59.834
1.00
83.85
C


ATOM
533
NE2
HIS
A
75
9.042
−14.219
58.861
1.00
81.12
N


ATOM
534
N
GLY
A
76
3.922
−18.566
57.961
1.00
69.55
N


ATOM
535
CA
GLY
A
76
2.938
−19.382
57.275
1.00
66.87
C


ATOM
536
C
GLY
A
76
1.598
−18.675
57.206
1.00
68.69
C


ATOM
537
O
GLY
A
76
0.879
−18.773
56.211
1.00
62.20
O


ATOM
538
N
CYS
A
77
1.268
−17.957
58.275
1.00
69.18
N


ATOM
539
CA
CYS
A
77
0.031
−17.190
58.345
1.00
63.36
C


ATOM
540
C
CYS
A
77
0.065
−16.009
57.379
1.00
64.02
C


ATOM
541
O
CYS
A
77
−0.958
−15.633
56.806
1.00
67.01
O


ATOM
542
CB
CYS
A
77
−0.205
−16.692
59.773
1.00
60.54
C


ATOM
543
SG
CYS
A
77
−1.577
−15.528
59.946
1.00
88.66
S


ATOM
544
N
LEU
A
78
1.249
−15.431
57.204
1.00
58.78
N


ATOM
545
CA
LEU
A
78
1.419
−14.275
56.331
1.00
60.78
C


ATOM
546
C
LEU
A
78
1.251
−14.643
54.861
1.00
66.22
C


ATOM
547
O
LEU
A
78
0.702
−13.866
54.079
1.00
62.14
O


ATOM
548
CB
LEU
A
78
2.781
−13.618
56.569
1.00
56.64
C


ATOM
549
CG
LEU
A
78
2.884
−12.806
57.863
1.00
53.72
C


ATOM
550
CD1
LEU
A
78
4.330
−12.472
58.188
1.00
44.99
C


ATOM
551
CD2
LEU
A
78
2.053
−11.538
57.757
1.00
57.25
C


ATOM
552
N
PHE
A
79
1.719
−15.830
54.488
1.00
63.13
N


ATOM
553
CA
PHE
A
79
1.585
−16.296
53.114
1.00
58.43
C


ATOM
554
C
PHE
A
79
0.117
−16.431
52.718
1.00
57.93
C


ATOM
555
O
PHE
A
79
−0.300
−15.941
51.670
1.00
56.59
O


ATOM
556
CB
PHE
A
79
2.310
−17.628
52.918
1.00
55.48
C


ATOM
557
CG
PHE
A
79
2.224
−18.158
51.516
1.00
55.31
C


ATOM
558
CD1
PHE
A
79
3.085
−17.698
50.533
1.00
55.74
C


ATOM
559
CD2
PHE
A
79
1.278
−19.110
51.178
1.00
52.59
C


ATOM
560
CE1
PHE
A
79
3.006
−18.181
49.240
1.00
49.39
C


ATOM
561
CE2
PHE
A
79
1.194
−19.596
49.887
1.00
48.73
C


ATOM
562
CZ
PHE
A
79
2.059
−19.131
48.918
1.00
49.02
C


ATOM
563
N
ILE
A
80
−0.663
−17.100
53.561
1.00
59.34
N


ATOM
564
CA
ILE
A
80
−2.089
−17.273
53.310
1.00
60.27
C


ATOM
565
C
ILE
A
80
−2.792
−15.927
53.181
1.00
57.82
C


ATOM
566
O
ILE
A
80
−3.709
−15.769
52.376
1.00
53.10
O


ATOM
567
CB
ILE
A
80
−2.765
−18.069
54.441
1.00
68.45
C


ATOM
568
CG1
ILE
A
80
−2.159
−19.468
54.550
1.00
76.48
C


ATOM
569
CG2
ILE
A
80
−4.266
−18.156
54.209
1.00
69.15
C


ATOM
570
CD1
ILE
A
80
−2.812
−20.324
55.613
1.00
76.06
C


ATOM
571
N
ALA
A
81
−2.354
−14.960
53.979
1.00
55.94
N


ATOM
572
CA
ALA
A
81
−2.983
−13.645
54.005
1.00
52.18
C


ATOM
573
C
ALA
A
81
−2.508
−12.747
52.867
1.00
54.56
C


ATOM
574
O
ALA
A
81
−3.265
−11.915
52.369
1.00
63.21
O


ATOM
575
CB
ALA
A
81
−2.737
−12.969
55.348
1.00
48.86
C


ATOM
576
N
CYS
A
82
−1.257
−12.924
52.453
1.00
58.95
N


ATOM
577
CA
CYS
A
82
−0.634
−12.009
51.500
1.00
59.75
C


ATOM
578
C
CYS
A
82
−0.597
−12.513
50.058
1.00
62.46
C


ATOM
579
O
CYS
A
82
−0.364
−11.730
49.137
1.00
61.39
O


ATOM
580
CB
CYS
A
82
0.783
−11.648
51.955
1.00
61.48
C


ATOM
581
SG
CYS
A
82
0.851
−10.613
53.436
1.00
66.38
S


ATOM
582
N
PHE
A
83
−0.820
−13.808
49.856
1.00
57.25
N


ATOM
583
CA
PHE
A
83
−0.715
−14.380
48.516
1.00
52.99
C


ATOM
584
C
PHE
A
83
−1.604
−13.658
47.511
1.00
59.19
C


ATOM
585
O
PHE
A
83
−1.219
−13.464
46.357
1.00
55.51
O


ATOM
586
CB
PHE
A
83
−1.041
−15.874
48.519
1.00
53.72
C


ATOM
587
CG
PHE
A
83
−0.966
−16.507
47.158
1.00
55.03
C


ATOM
588
CD1
PHE
A
83
0.253
−16.663
46.520
1.00
50.93
C


ATOM
589
CD2
PHE
A
83
−2.114
−16.940
46.513
1.00
59.91
C


ATOM
590
CE1
PHE
A
83
0.329
−17.238
45.267
1.00
52.19
C


ATOM
591
CE2
PHE
A
83
−2.045
−17.519
45.260
1.00
55.73
C


ATOM
592
CZ
PHE
A
83
−0.822
−17.668
44.636
1.00
47.31
C


ATOM
593
N
VAL
A
84
−2.793
−13.261
47.951
1.00
61.05
N


ATOM
594
CA
VAL
A
84
−3.729
−12.565
47.078
1.00
53.61
C


ATOM
595
C
VAL
A
84
−3.149
−11.229
46.613
1.00
63.88
C


ATOM
596
O
VAL
A
84
−3.468
−10.748
45.525
1.00
62.14
O


ATOM
597
CB
VAL
A
84
−5.093
−12.343
47.768
1.00
49.09
C


ATOM
598
CG1
VAL
A
84
−4.959
−11.353
48.920
1.00
44.32
C


ATOM
599
CG2
VAL
A
84
−6.131
−11.872
46.761
1.00
47.44
C


ATOM
600
N
LEU
A
85
−2.287
−10.640
47.436
1.00
68.54
N


ATOM
601
CA
LEU
A
85
−1.637
−9.382
47.087
1.00
63.38
C


ATOM
602
C
LEU
A
85
−0.692
−9.582
45.907
1.00
65.55
C


ATOM
603
O
LEU
A
85
−0.505
−8.682
45.088
1.00
72.16
O


ATOM
604
CB
LEU
A
85
−0.879
−8.810
48.287
1.00
54.97
C


ATOM
605
CG
LEU
A
85
−1.708
−8.588
49.554
1.00
55.41
C


ATOM
606
CD1
LEU
A
85
−0.861
−7.963
50.654
1.00
51.57
C


ATOM
607
CD2
LEU
A
85
−2.926
−7.727
49.256
1.00
50.92
C


ATOM
608
N
VAL
A
86
−0.098
−10.768
45.828
1.00
59.46
N


ATOM
609
CA
VAL
A
86
0.746
−11.121
44.694
1.00
61.04
C


ATOM
610
C
VAL
A
86
−0.075
−11.091
43.411
1.00
60.72
C


ATOM
611
O
VAL
A
86
0.303
−10.447
42.430
1.00
49.39
O


ATOM
612
CB
VAL
A
86
1.356
−12.524
44.863
1.00
58.19
C


ATOM
613
CG1
VAL
A
86
2.124
−12.922
43.612
1.00
54.26
C


ATOM
614
CG2
VAL
A
86
2.253
−12.571
46.094
1.00
51.92
C


ATOM
615
N
LEU
A
87
−1.207
−11.787
43.431
1.00
63.38
N


ATOM
616
CA
LEU
A
87
−2.095
−11.856
42.277
1.00
54.40
C


ATOM
617
C
LEU
A
87
−2.586
−10.475
41.852
1.00
52.89
C


ATOM
618
O
LEU
A
87
−2.647
−10.168
40.663
1.00
56.74
O


ATOM
619
CB
LEU
A
87
−3.288
−12.765
42.580
1.00
53.50
C


ATOM
620
CG
LEU
A
87
−2.933
−14.195
42.987
1.00
52.31
C


ATOM
621
CD1
LEU
A
87
−4.185
−15.047
43.113
1.00
56.23
C


ATOM
622
CD2
LEU
A
87
−1.963
−14.803
41.988
1.00
50.49
C


ATOM
623
N
THR
A
88
−2.934
−9.646
42.830
1.00
58.36
N


ATOM
624
CA
THR
A
88
−3.443
−8.310
42.549
1.00
64.79
C


ATOM
625
C
THR
A
88
−2.389
−7.442
41.864
1.00
56.17
C


ATOM
626
O
THR
A
88
−2.678
−6.765
40.877
1.00
49.52
O


ATOM
627
CB
THR
A
88
−3.925
−7.610
43.832
1.00
75.77
C


ATOM
628
OG1
THR
A
88
−4.774
−8.497
44.570
1.00
80.09
O


ATOM
629
CG2
THR
A
88
−4.695
−6.343
43.491
1.00
84.70
C


ATOM
630
N
GLN
A
89
−1.168
−7.469
42.389
1.00
52.39
N


ATOM
631
CA
GLN
A
89
−0.081
−6.683
41.818
1.00
54.11
C


ATOM
632
C
GLN
A
89
0.198
−7.093
40.374
1.00
56.00
C


ATOM
633
O
GLN
A
89
0.394
−6.244
39.506
1.00
48.22
O


ATOM
634
CB
GLN
A
89
1.189
−6.822
42.660
1.00
55.84
C


ATOM
635
CG
GLN
A
89
2.188
−5.703
42.432
1.00
52.12
C


ATOM
636
CD
GLN
A
89
1.597
−4.341
42.740
1.00
59.31
C


ATOM
637
OE1
GLN
A
89
0.969
−4.146
43.781
1.00
58.17
O


ATOM
638
NE2
GLN
A
89
1.791
−3.390
41.833
1.00
59.72
N


ATOM
639
N
SER
A
90
0.216
−8.398
40.126
1.00
56.72
N


ATOM
640
CA
SER
A
90
0.411
−8.919
38.779
1.00
50.13
C


ATOM
641
C
SER
A
90
−0.632
−8.344
37.827
1.00
59.38
C


ATOM
642
O
SER
A
90
−0.308
−7.917
36.717
1.00
61.32
O


ATOM
643
CB
SER
A
90
0.335
−10.447
38.781
1.00
46.14
C


ATOM
644
OG
SER
A
90
0.525
−10.968
37.477
1.00
52.69
O


ATOM
645
N
SER
A
91
−1.886
−8.338
38.270
1.00
60.49
N


ATOM
646
CA
SER
A
91
−2.982
−7.787
37.481
1.00
56.57
C


ATOM
647
C
SER
A
91
−2.711
−6.331
37.118
1.00
49.74
C


ATOM
648
O
SER
A
91
−2.876
−5.926
35.967
1.00
50.92
O


ATOM
649
CB
SER
A
91
−4.302
−7.897
38.248
1.00
62.44
C


ATOM
650
OG
SER
A
91
−4.672
−9.251
38.441
1.00
58.92
O


ATOM
651
N
ILE
A
92
−2.298
−5.549
38.111
1.00
46.68
N


ATOM
652
CA
ILE
A
92
−1.950
−4.150
37.891
1.00
52.49
C


ATOM
653
C
ILE
A
92
−0.922
−4.002
36.770
1.00
58.92
C


ATOM
654
O
ILE
A
92
−1.103
−3.199
35.855
1.00
62.73
O


ATOM
655
CB
ILE
A
92
−1.411
−3.494
39.178
1.00
57.59
C


ATOM
656
CG1
ILE
A
92
−2.566
−3.137
40.114
1.00
53.53
C


ATOM
657
CG2
ILE
A
92
−0.607
−2.248
38.848
1.00
61.25
C


ATOM
658
CD1
ILE
A
92
−3.536
−2.141
39.518
1.00
60.92
C


ATOM
659
N
PHE
A
93
0.152
−4.784
36.844
1.00
59.44
N


ATOM
660
CA
PHE
A
93
1.203
−4.738
35.831
1.00
56.88
C


ATOM
661
C
PHE
A
93
0.677
−5.106
34.445
1.00
65.10
C


ATOM
662
O
PHE
A
93
1.081
−4.513
33.444
1.00
66.34
O


ATOM
663
CB
PHE
A
93
2.370
−5.653
36.210
1.00
47.96
C


ATOM
664
CG
PHE
A
93
3.192
−5.146
37.362
1.00
56.43
C


ATOM
665
CD1
PHE
A
93
3.475
−5.965
38.444
1.00
64.13
C


ATOM
666
CD2
PHE
A
93
3.676
−3.848
37.366
1.00
61.60
C


ATOM
667
CE1
PHE
A
93
4.231
−5.501
39.505
1.00
62.69
C


ATOM
668
CE2
PHE
A
93
4.431
−3.377
38.424
1.00
67.20
C


ATOM
669
CZ
PHE
A
93
4.710
−4.205
39.495
1.00
64.16
C


ATOM
670
N
SER
A
94
−0.221
−6.085
34.393
1.00
65.57
N


ATOM
671
CA
SER
A
94
−0.806
−6.519
33.127
1.00
62.19
C


ATOM
672
C
SER
A
94
−1.677
−5.432
32.502
1.00
63.42
C


ATOM
673
O
SER
A
94
−1.594
−5.171
31.301
1.00
60.85
O


ATOM
674
CB
SER
A
94
−1.616
−7.803
33.314
1.00
57.22
C


ATOM
675
OG
SER
A
94
−0.766
−8.934
33.410
1.00
57.89
O


ATOM
676
N
LEU
A
95
−2.512
−4.803
33.324
1.00
60.44
N


ATOM
677
CA
LEU
A
95
−3.386
−3.733
32.857
1.00
57.55
C


ATOM
678
C
LEU
A
95
−2.576
−2.531
32.383
1.00
52.80
C


ATOM
679
O
LEU
A
95
−2.923
−1.886
31.395
1.00
47.83
O


ATOM
680
CB
LEU
A
95
−4.356
−3.312
33.963
1.00
53.01
C


ATOM
681
CG
LEU
A
95
−5.379
−4.362
34.399
1.00
50.87
C


ATOM
682
CD1
LEU
A
95
−6.207
−3.852
35.568
1.00
50.15
C


ATOM
683
CD2
LEU
A
95
−6.276
−4.754
33.232
1.00
40.45
C


ATOM
684
N
LEU
A
96
−1.494
−2.237
33.095
1.00
50.06
N


ATOM
685
CA
LEU
A
96
−0.623
−1.121
32.748
1.00
51.09
C


ATOM
686
C
LEU
A
96
0.064
−1.359
31.404
1.00
56.60
C


ATOM
687
O
LEU
A
96
0.151
−0.455
30.574
1.00
59.24
O


ATOM
688
CB
LEU
A
96
0.415
−0.900
33.852
1.00
51.51
C


ATOM
689
CG
LEU
A
96
1.412
0.251
33.698
1.00
59.36
C


ATOM
690
CD1
LEU
A
96
0.708
1.547
33.329
1.00
57.37
C


ATOM
691
CD2
LEU
A
96
2.212
0.426
34.981
1.00
57.86
C


ATOM
692
N
ALA
A
97
0.541
−2.582
31.194
1.00
54.75
N


ATOM
693
CA
ALA
A
97
1.225
−2.938
29.955
1.00
48.35
C


ATOM
694
C
ALA
A
97
0.286
−2.894
28.753
1.00
53.15
C


ATOM
695
O
ALA
A
97
0.710
−2.599
27.636
1.00
51.29
O


ATOM
696
CB
ALA
A
97
1.864
−4.311
30.080
1.00
48.03
C


ATOM
697
N
ILE
A
98
−0.988
−3.194
28.985
1.00
58.97
N


ATOM
698
CA
ILE
A
98
−1.994
−3.125
27.931
1.00
48.98
C


ATOM
699
C
ILE
A
98
−2.240
−1.678
27.525
1.00
47.93
C


ATOM
700
O
ILE
A
98
−2.339
−1.364
26.338
1.00
54.16
O


ATOM
701
CB
ILE
A
98
−3.324
−3.763
28.374
1.00
55.37
C


ATOM
702
CG1
ILE
A
98
−3.150
−5.268
28.577
1.00
46.49
C


ATOM
703
CG2
ILE
A
98
−4.418
−3.489
27.349
1.00
52.17
C


ATOM
704
CD1
ILE
A
98
−4.388
−5.958
29.102
1.00
46.43
C


ATOM
705
N
ALA
A
99
−2.336
−0.798
28.517
1.00
51.80
N


ATOM
706
CA
ALA
A
99
−2.524
0.626
28.265
1.00
48.61
C


ATOM
707
C
ALA
A
99
−1.404
1.162
27.387
1.00
50.35
C


ATOM
708
O
ALA
A
99
−1.654
1.764
26.343
1.00
51.87
O


ATOM
709
CB
ALA
A
99
−2.581
1.398
29.577
1.00
43.48
C


ATOM
710
N
ILE
A
100
−0.169
0.935
27.821
1.00
57.69
N


ATOM
711
CA
ILE
A
100
1.008
1.386
27.090
1.00
57.90
C


ATOM
712
C
ILE
A
100
1.051
0.801
25.681
1.00
63.11
C


ATOM
713
O
ILE
A
100
1.325
1.512
24.713
1.00
58.89
O


ATOM
714
CB
ILE
A
100
2.301
1.016
27.839
1.00
62.05
C


ATOM
715
CG1
ILE
A
100
2.333
1.706
29.206
1.00
63.82
C


ATOM
716
CG2
ILE
A
100
3.525
1.387
27.013
1.00
59.79
C


ATOM
717
CD1
ILE
A
100
3.489
1.279
30.082
1.00
68.90
C


ATOM
718
N
ASP
A
101
0.776
−0.495
25.572
1.00
64.12
N


ATOM
719
CA
ASP
A
101
0.753
−1.160
24.275
1.00
60.91
C


ATOM
720
C
ASP
A
101
−0.187
−0.438
23.320
1.00
62.05
C


ATOM
721
O
ASP
A
101
0.175
−0.148
22.180
1.00
61.91
O


ATOM
722
CB
ASP
A
101
0.318
−2.619
24.419
1.00
61.47
C


ATOM
723
CG
ASP
A
101
0.215
−3.329
23.081
1.00
67.28
C


ATOM
724
OD1
ASP
A
101
1.262
−3.532
22.432
1.00
69.92
O


ATOM
725
OD2
ASP
A
101
−0.912
−3.686
22.680
1.00
67.78
O


ATOM
726
N
ARG
A
102
−1.395
−0.151
23.793
1.00
55.06
N


ATOM
727
CA
ARG
A
102
−2.387
0.529
22.971
1.00
59.02
C


ATOM
728
C
ARG
A
102
−1.975
1.970
22.694
1.00
70.32
C


ATOM
729
O
ARG
A
102
−2.400
2.566
21.704
1.00
66.53
O


ATOM
730
CB
ARG
A
102
−3.765
0.488
23.636
1.00
62.10
C


ATOM
731
CG
ARG
A
102
−4.398
−0.897
23.693
1.00
66.18
C


ATOM
732
CD
ARG
A
102
−4.608
−1.477
22.302
1.00
60.89
C


ATOM
733
NE
ARG
A
102
−3.372
−2.005
21.733
1.00
65.56
N


ATOM
734
CZ
ARG
A
102
−3.207
−2.306
20.449
1.00
58.92
C


ATOM
735
NH1
ARG
A
102
−4.202
−2.128
19.591
1.00
58.23
N


ATOM
736
NH2
ARG
A
102
−2.046
−2.780
20.023
1.00
53.18
N


ATOM
737
N
TYR
A
103
−1.144
2.524
23.569
1.00
72.91
N


ATOM
738
CA
TYR
A
103
−0.691
3.900
23.406
1.00
71.24
C


ATOM
739
C
TYR
A
103
0.229
4.050
22.200
1.00
68.76
C


ATOM
740
O
TYR
A
103
−0.051
4.825
21.287
1.00
65.89
O


ATOM
741
CB
TYR
A
103
0.018
4.400
24.666
1.00
66.71
C


ATOM
742
CG
TYR
A
103
0.537
5.811
24.526
1.00
70.68
C


ATOM
743
CD1
TYR
A
103
−0.289
6.901
24.768
1.00
73.34
C


ATOM
744
CD2
TYR
A
103
1.847
6.055
24.138
1.00
74.95
C


ATOM
745
CE1
TYR
A
103
0.177
8.194
24.635
1.00
82.14
C


ATOM
746
CE2
TYR
A
103
2.323
7.345
24.002
1.00
84.73
C


ATOM
747
CZ
TYR
A
103
1.484
8.411
24.253
1.00
92.43
C


ATOM
748
OH
TYR
A
103
1.952
9.698
24.119
1.00
101.50
O


ATOM
749
N
ILE
A
104
1.329
3.304
22.201
1.00
67.33
N


ATOM
750
CA
ILE
A
104
2.311
3.403
21.129
1.00
78.83
C


ATOM
751
C
ILE
A
104
1.843
2.710
19.852
1.00
78.61
C


ATOM
752
O
ILE
A
104
2.579
2.642
18.870
1.00
73.74
O


ATOM
753
CB
ILE
A
104
3.676
2.833
21.557
1.00
86.17
C


ATOM
754
CG1
ILE
A
104
3.559
1.347
21.893
1.00
91.16
C


ATOM
755
CG2
ILE
A
104
4.222
3.600
22.750
1.00
86.38
C


ATOM
756
CD1
ILE
A
104
4.852
0.740
22.390
1.00
96.41
C


ATOM
757
N
ALA
A
105
0.615
2.202
19.870
1.00
81.63
N


ATOM
758
CA
ALA
A
105
0.045
1.540
18.702
1.00
83.62
C


ATOM
759
C
ALA
A
105
−0.940
2.455
17.984
1.00
82.08
C


ATOM
760
O
ALA
A
105
−1.337
2.190
16.850
1.00
87.66
O


ATOM
761
CB
ALA
A
105
−0.637
0.242
19.107
1.00
86.61
C


ATOM
762
N
ILE
A
106
−1.325
3.538
18.650
1.00
85.41
N


ATOM
763
CA
ILE
A
106
−2.329
4.446
18.108
1.00
92.73
C


ATOM
764
C
ILE
A
106
−1.768
5.849
17.868
1.00
92.39
C


ATOM
765
O
ILE
A
106
−2.289
6.601
17.044
1.00
90.77
O


ATOM
766
CB
ILE
A
106
−3.571
4.510
19.023
1.00
92.96
C


ATOM
767
CG1
ILE
A
106
−4.165
3.108
19.196
1.00
86.39
C


ATOM
768
CG2
ILE
A
106
−4.610
5.467
18.459
1.00
89.28
C


ATOM
769
CD1
ILE
A
106
−5.219
3.009
20.278
1.00
77.92
C


ATOM
770
N
ARG
A
107
−0.700
6.194
18.579
1.00
94.13
N


ATOM
771
CA
ARG
A
107
−0.072
7.499
18.407
1.00
98.93
C


ATOM
772
C
ARG
A
107
1.235
7.376
17.633
1.00
93.80
C


ATOM
773
O
ARG
A
107
1.663
8.317
16.963
1.00
89.93
O


ATOM
774
CB
ARG
A
107
0.173
8.169
19.760
1.00
113.54
C


ATOM
775
CG
ARG
A
107
0.275
9.685
19.680
1.00
125.24
C


ATOM
776
CD
ARG
A
107
0.731
10.291
20.997
1.00
130.99
C


ATOM
777
NE
ARG
A
107
2.130
9.988
21.281
1.00
135.53
N


ATOM
778
CZ
ARG
A
107
3.158
10.628
20.733
1.00
134.90
C


ATOM
779
NH1
ARG
A
107
2.945
11.608
19.865
1.00
133.69
N


ATOM
780
NH2
ARG
A
107
4.399
10.287
21.049
1.00
132.96
N


ATOM
781
N
ILE
A
108
1.868
6.210
17.726
1.00
93.64
N


ATOM
782
CA
ILE
A
108
3.109
5.944
17.005
1.00
93.45
C


ATOM
783
C
ILE
A
108
3.048
4.608
16.263
1.00
88.02
C


ATOM
784
O
ILE
A
108
3.827
3.696
16.558
1.00
92.18
O


ATOM
785
CB
ILE
A
108
4.317
5.927
17.960
1.00
100.66
C


ATOM
786
CG1
ILE
A
108
4.179
7.020
19.022
1.00
108.02
C


ATOM
787
CG2
ILE
A
108
5.617
6.080
17.183
1.00
98.70
C


ATOM
788
CD1
ILE
A
108
5.235
6.960
20.106
1.00
111.96
C


ATOM
789
N
PRO
A
109
2.129
4.487
15.294
1.00
73.44
N


ATOM
790
CA
PRO
A
109
1.911
3.242
14.552
1.00
73.83
C


ATOM
791
C
PRO
A
109
3.099
2.845
13.678
1.00
92.11
C


ATOM
792
O
PRO
A
109
3.294
1.655
13.431
1.00
92.13
O


ATOM
793
CB
PRO
A
109
0.702
3.583
13.663
1.00
63.67
C


ATOM
794
CG
PRO
A
109
0.777
5.071
13.526
1.00
59.57
C


ATOM
795
CD
PRO
A
109
1.144
5.505
14.907
1.00
64.69
C


ATOM
796
N
LEU
A
110
3.883
3.818
13.224
1.00
104.30
N


ATOM
797
CA
LEU
A
110
4.970
3.547
12.280
1.00
104.62
C


ATOM
798
C
LEU
A
110
6.059
2.622
12.824
1.00
109.43
C


ATOM
799
O
LEU
A
110
6.735
1.941
12.053
1.00
110.68
O


ATOM
800
CB
LEU
A
110
5.585
4.860
11.773
1.00
99.55
C


ATOM
801
CG
LEU
A
110
4.733
5.587
10.723
1.00
97.53
C


ATOM
802
CD1
LEU
A
110
5.432
6.856
10.267
1.00
100.57
C


ATOM
803
CD2
LEU
A
110
4.455
4.660
9.554
1.00
92.50
C


ATOM
804
N
ARG
A
111
6.225
2.592
14.143
1.00
111.95
N


ATOM
805
CA
ARG
A
111
7.278
1.784
14.738
1.00
113.96
C


ATOM
806
C
ARG
A
111
6.756
0.874
15.852
1.00
103.19
C


ATOM
807
O
ARG
A
111
7.484
0.550
16.787
1.00
102.32
O


ATOM
808
CB
ARG
A
111
8.402
2.683
15.259
1.00
127.38
C


ATOM
809
CG
ARG
A
111
9.190
3.384
14.161
1.00
136.53
C


ATOM
810
CD
ARG
A
111
10.425
4.074
14.715
1.00
143.69
C


ATOM
811
NE
ARG
A
111
10.089
5.158
15.635
1.00
153.12
N


ATOM
812
CZ
ARG
A
111
9.812
6.405
15.261
1.00
159.47
C


ATOM
813
NH1
ARG
A
111
9.827
6.743
13.976
1.00
160.35
N


ATOM
814
NH2
ARG
A
111
9.517
7.318
16.178
1.00
161.15
N


ATOM
815
N
TYR
A
112
5.495
0.463
15.747
1.00
95.20
N


ATOM
816
CA
TYR
A
112
4.880
−0.379
16.774
1.00
88.47
C


ATOM
817
C
TYR
A
112
5.393
−1.819
16.742
1.00
89.26
C


ATOM
818
O
TYR
A
112
5.703
−2.396
17.783
1.00
85.67
O


ATOM
819
CB
TYR
A
112
3.354
−0.367
16.652
1.00
83.98
C


ATOM
820
CG
TYR
A
112
2.678
−1.427
17.492
1.00
81.13
C


ATOM
821
CD1
TYR
A
112
2.525
−1.262
18.863
1.00
84.03
C


ATOM
822
CD2
TYR
A
112
2.196
−2.595
16.916
1.00
82.23
C


ATOM
823
CE1
TYR
A
112
1.911
−2.229
19.636
1.00
82.84
C


ATOM
824
CE2
TYR
A
112
1.580
−3.567
17.680
1.00
85.07
C


ATOM
825
CZ
TYR
A
112
1.440
−3.380
19.039
1.00
84.45
C


ATOM
826
OH
TYR
A
112
0.826
−4.347
19.803
1.00
83.19
O


ATOM
827
N
ASN
A
113
5.475
−2.396
15.547
1.00
91.61
N


ATOM
828
CA
ASN
A
113
5.908
−3.784
15.403
1.00
91.99
C


ATOM
829
C
ASN
A
113
7.409
−3.970
15.604
1.00
86.88
C


ATOM
830
O
ASN
A
113
7.868
−5.056
15.957
1.00
83.52
O


ATOM
831
CB
ASN
A
113
5.476
−4.351
14.050
1.00
95.76
C


ATOM
832
CG
ASN
A
113
3.996
−4.679
14.003
1.00
107.24
C


ATOM
833
OD1
ASN
A
113
3.369
−4.915
15.036
1.00
109.02
O


ATOM
834
ND2
ASN
A
113
3.431
−4.699
12.802
1.00
113.64
N


ATOM
835
N
GLY
A
114
8.169
−2.904
15.379
1.00
87.59
N


ATOM
836
CA
GLY
A
114
9.604
−2.939
15.583
1.00
94.18
C


ATOM
837
C
GLY
A
114
9.975
−2.670
17.029
1.00
98.41
C


ATOM
838
O
GLY
A
114
11.121
−2.860
17.436
1.00
100.84
O


ATOM
839
N
LEU
A
115
8.993
−2.228
17.808
1.00
93.62
N


ATOM
840
CA
LEU
A
115
9.209
−1.911
19.214
1.00
87.59
C


ATOM
841
C
LEU
A
115
8.552
−2.959
20.110
1.00
86.78
C


ATOM
842
O
LEU
A
115
9.178
−3.484
21.032
1.00
90.76
O


ATOM
843
CB
LEU
A
115
8.654
−0.521
19.532
1.00
87.19
C


ATOM
844
CG
LEU
A
115
9.218
0.198
20.757
1.00
85.25
C


ATOM
845
CD1
LEU
A
115
10.699
0.477
20.569
1.00
87.46
C


ATOM
846
CD2
LEU
A
115
8.459
1.490
21.013
1.00
84.95
C


ATOM
847
N
VAL
A
116
7.288
−3.260
19.828
1.00
77.94
N


ATOM
848
CA
VAL
A
116
6.538
−4.250
20.592
1.00
76.88
C


ATOM
849
C
VAL
A
116
6.577
−5.611
19.906
1.00
76.54
C


ATOM
850
O
VAL
A
116
5.936
−5.813
18.874
1.00
70.87
O


ATOM
851
CB
VAL
A
116
5.067
−3.827
20.769
1.00
74.85
C


ATOM
852
CG1
VAL
A
116
4.298
−4.887
21.537
1.00
68.42
C


ATOM
853
CG2
VAL
A
116
4.982
−2.486
21.475
1.00
75.76
C


ATOM
854
N
THR
A
117
7.331
−6.541
20.484
1.00
71.30
N


ATOM
855
CA
THR
A
117
7.450
−7.884
19.926
1.00
65.80
C


ATOM
856
C
THR
A
117
7.111
−8.947
20.962
1.00
60.23
C


ATOM
857
O
THR
A
117
7.200
−8.704
22.166
1.00
61.68
O


ATOM
858
CB
THR
A
117
8.864
−8.148
19.380
1.00
64.25
C


ATOM
859
OG1
THR
A
117
9.817
−8.065
20.449
1.00
65.60
O


ATOM
860
CG2
THR
A
117
9.217
−7.132
18.304
1.00
57.57
C


ATOM
861
N
GLY
A
118
6.722
−10.126
20.484
1.00
58.84
N


ATOM
862
CA
GLY
A
118
6.357
−11.227
21.356
1.00
56.83
C


ATOM
863
C
GLY
A
118
7.448
−11.582
22.345
1.00
59.65
C


ATOM
864
O
GLY
A
118
7.172
−11.866
23.511
1.00
65.43
O


ATOM
865
N
THR
A
119
8.693
−11.563
21.878
1.00
60.99
N


ATOM
866
CA
THR
A
119
9.841
−11.877
22.721
1.00
63.61
C


ATOM
867
C
THR
A
119
9.944
−10.928
23.910
1.00
62.11
C


ATOM
868
O
THR
A
119
10.164
−11.357
25.043
1.00
60.57
O


ATOM
869
CB
THR
A
119
11.154
−11.809
21.925
1.00
68.54
C


ATOM
870
OG1
THR
A
119
11.114
−12.758
20.851
1.00
69.43
O


ATOM
871
CG2
THR
A
119
12.343
−12.112
22.828
1.00
68.23
C


ATOM
872
N
ARG
A
120
9.787
−9.636
23.642
1.00
58.16
N


ATOM
873
CA
ARG
A
120
9.893
−8.621
24.683
1.00
65.76
C


ATOM
874
C
ARG
A
120
8.710
−8.667
25.645
1.00
68.43
C


ATOM
875
O
ARG
A
120
8.876
−8.490
26.853
1.00
69.60
O


ATOM
876
CB
ARG
A
120
10.034
−7.230
24.060
1.00
71.97
C


ATOM
877
CG
ARG
A
120
11.309
−7.071
23.250
1.00
78.55
C


ATOM
878
CD
ARG
A
120
11.456
−5.677
22.670
1.00
83.21
C


ATOM
879
NE
ARG
A
120
12.730
−5.531
21.974
1.00
85.78
N


ATOM
880
CZ
ARG
A
120
13.078
−4.465
21.261
1.00
88.12
C


ATOM
881
NH1
ARG
A
120
14.260
−4.424
20.663
1.00
90.28
N


ATOM
882
NH2
ARG
A
120
12.243
−3.442
21.143
1.00
92.85
N


ATOM
883
N
ALA
A
121
7.520
−8.909
25.106
1.00
63.83
N


ATOM
884
CA
ALA
A
121
6.324
−9.029
25.931
1.00
60.03
C


ATOM
885
C
ALA
A
121
6.516
−10.108
26.991
1.00
65.69
C


ATOM
886
O
ALA
A
121
6.301
−9.869
28.180
1.00
65.55
O


ATOM
887
CB
ALA
A
121
5.110
−9.337
25.069
1.00
58.90
C


ATOM
888
N
LYS
A
122
6.926
−11.295
26.552
1.00
65.70
N


ATOM
889
CA
LYS
A
122
7.179
−12.405
27.464
1.00
67.95
C


ATOM
890
C
LYS
A
122
8.228
−12.035
28.508
1.00
68.55
C


ATOM
891
O
LYS
A
122
8.132
−12.437
29.668
1.00
72.17
O


ATOM
892
CB
LYS
A
122
7.623
−13.649
26.690
1.00
71.37
C


ATOM
893
CG
LYS
A
122
6.523
−14.296
25.867
1.00
73.26
C


ATOM
894
CD
LYS
A
122
7.056
−15.466
25.057
1.00
81.69
C


ATOM
895
CE
LYS
A
122
5.954
−16.120
24.240
1.00
94.16
C


ATOM
896
NZ
LYS
A
122
6.467
−17.242
23.405
1.00
98.43
N


ATOM
897
N
GLY
A
123
9.230
−11.267
28.090
1.00
57.35
N


ATOM
898
CA
GLY
A
123
10.271
−10.821
28.997
1.00
59.23
C


ATOM
899
C
GLY
A
123
9.714
−9.933
30.092
1.00
63.70
C


ATOM
900
O
GLY
A
123
9.964
−10.156
31.277
1.00
63.61
O


ATOM
901
N
ILE
A
124
8.951
−8.923
29.690
1.00
63.36
N


ATOM
902
CA
ILE
A
124
8.350
−7.987
30.631
1.00
67.49
C


ATOM
903
C
ILE
A
124
7.402
−8.692
31.601
1.00
70.93
C


ATOM
904
O
ILE
A
124
7.356
−8.363
32.787
1.00
66.42
O


ATOM
905
CB
ILE
A
124
7.594
−6.867
29.890
1.00
64.60
C


ATOM
906
CG1
ILE
A
124
8.578
−6.008
29.091
1.00
59.98
C


ATOM
907
CG2
ILE
A
124
6.796
−6.018
30.870
1.00
57.60
C


ATOM
908
CD1
ILE
A
124
7.918
−5.087
28.085
1.00
56.97
C


ATOM
909
N
ILE
A
125
6.652
−9.663
31.089
1.00
69.67
N


ATOM
910
CA
ILE
A
125
5.711
−10.423
31.906
1.00
66.41
C


ATOM
911
C
ILE
A
125
6.429
−11.197
33.006
1.00
64.69
C


ATOM
912
O
ILE
A
125
6.041
−11.143
34.173
1.00
63.37
O


ATOM
913
CB
ILE
A
125
4.889
−11.405
31.050
1.00
63.12
C


ATOM
914
CG1
ILE
A
125
3.968
−10.635
30.100
1.00
61.63
C


ATOM
915
CG2
ILE
A
125
4.083
−12.342
31.938
1.00
56.10
C


ATOM
916
CD1
ILE
A
125
3.402
−11.476
28.975
1.00
51.66
C


ATOM
917
N
ALA
A
126
7.479
−11.916
32.624
1.00
66.05
N


ATOM
918
CA
ALA
A
126
8.261
−12.697
33.575
1.00
67.52
C


ATOM
919
C
ALA
A
126
8.763
−11.818
34.714
1.00
64.64
C


ATOM
920
O
ALA
A
126
8.674
−12.190
35.884
1.00
67.81
O


ATOM
921
CB
ALA
A
126
9.428
−13.376
32.872
1.00
62.18
C


ATOM
922
N
ILE
A
127
9.288
−10.650
34.361
1.00
63.73
N


ATOM
923
CA
ILE
A
127
9.822
−9.716
35.345
1.00
67.95
C


ATOM
924
C
ILE
A
127
8.728
−9.206
36.280
1.00
66.97
C


ATOM
925
O
ILE
A
127
8.937
−9.082
37.487
1.00
61.28
O


ATOM
926
CB
ILE
A
127
10.510
−8.519
34.661
1.00
70.20
C


ATOM
927
CG1
ILE
A
127
11.572
−9.010
33.677
1.00
68.52
C


ATOM
928
CG2
ILE
A
127
11.130
−7.593
35.696
1.00
74.05
C


ATOM
929
CD1
ILE
A
127
12.282
−7.897
32.940
1.00
72.14
C


ATOM
930
N
CYS
A
128
7.559
−8.918
35.717
1.00
63.06
N


ATOM
931
CA
CYS
A
128
6.446
−8.396
36.500
1.00
54.69
C


ATOM
932
C
CYS
A
128
5.929
−9.405
37.523
1.00
49.73
C


ATOM
933
O
CYS
A
128
5.450
−9.022
38.589
1.00
52.32
O


ATOM
934
CB
CYS
A
128
5.312
−7.932
35.585
1.00
66.50
C


ATOM
935
SG
CYS
A
128
5.681
−6.422
34.666
1.00
74.56
S


ATOM
936
N
TRP
A
129
6.023
−10.691
37.201
1.00
51.13
N


ATOM
937
CA
TRP
A
129
5.634
−11.733
38.147
1.00
52.40
C


ATOM
938
C
TRP
A
129
6.621
−11.815
39.309
1.00
56.96
C


ATOM
939
O
TRP
A
129
6.234
−12.091
40.444
1.00
66.31
O


ATOM
940
CB
TRP
A
129
5.504
−13.092
37.453
1.00
48.49
C


ATOM
941
CG
TRP
A
129
4.171
−13.305
36.794
1.00
51.24
C


ATOM
942
CD1
TRP
A
129
3.890
−13.210
35.462
1.00
59.03
C


ATOM
943
CD2
TRP
A
129
2.937
−13.645
37.441
1.00
43.56
C


ATOM
944
NE1
TRP
A
129
2.559
−13.472
35.240
1.00
57.23
N


ATOM
945
CE2
TRP
A
129
1.953
−13.742
36.438
1.00
49.30
C


ATOM
946
CE3
TRP
A
129
2.571
−13.878
38.770
1.00
49.07
C


ATOM
947
CZ2
TRP
A
129
0.626
−14.061
36.722
1.00
45.75
C


ATOM
948
CZ3
TRP
A
129
1.252
−14.194
39.051
1.00
46.69
C


ATOM
949
CH2
TRP
A
129
0.296
−14.283
38.031
1.00
41.88
C


ATOM
950
N
VAL
A
130
7.896
−11.572
39.022
1.00
52.61
N


ATOM
951
CA
VAL
A
130
8.919
−11.549
40.059
1.00
56.34
C


ATOM
952
C
VAL
A
130
8.679
−10.394
41.025
1.00
64.62
C


ATOM
953
O
VAL
A
130
8.685
−10.579
42.242
1.00
67.44
O


ATOM
954
CB
VAL
A
130
10.330
−11.417
39.461
1.00
60.77
C


ATOM
955
CG1
VAL
A
130
11.360
−11.244
40.568
1.00
56.40
C


ATOM
956
CG2
VAL
A
130
10.656
−12.629
38.604
1.00
63.46
C


ATOM
957
N
LEU
A
131
8.469
−9.201
40.475
1.00
63.64
N


ATOM
958
CA
LEU
A
131
8.192
−8.021
41.287
1.00
62.11
C


ATOM
959
C
LEU
A
131
6.918
−8.208
42.099
1.00
58.39
C


ATOM
960
O
LEU
A
131
6.829
−7.758
43.240
1.00
62.62
O


ATOM
961
CB
LEU
A
131
8.063
−6.776
40.407
1.00
66.71
C


ATOM
962
CG
LEU
A
131
9.301
−6.326
39.633
1.00
67.88
C


ATOM
963
CD1
LEU
A
131
8.978
−5.100
38.796
1.00
68.03
C


ATOM
964
CD2
LEU
A
131
10.451
−6.042
40.584
1.00
73.75
C


ATOM
965
N
SER
A
132
5.933
−8.871
41.501
1.00
54.97
N


ATOM
966
CA
SER
A
132
4.658
−9.114
42.167
1.00
56.03
C


ATOM
967
C
SER
A
132
4.842
−9.945
43.435
1.00
59.03
C


ATOM
968
O
SER
A
132
4.230
−9.663
44.465
1.00
58.03
O


ATOM
969
CB
SER
A
132
3.675
−9.802
41.217
1.00
57.35
C


ATOM
970
OG
SER
A
132
3.337
−8.956
40.130
1.00
56.09
O


ATOM
971
N
PHE
A
133
5.686
−10.969
43.354
1.00
53.41
N


ATOM
972
CA
PHE
A
133
6.003
−11.781
44.524
1.00
57.98
C


ATOM
973
C
PHE
A
133
6.777
−10.967
45.557
1.00
62.28
C


ATOM
974
O
PHE
A
133
6.518
−11.060
46.756
1.00
62.05
O


ATOM
975
CB
PHE
A
133
6.801
−13.025
44.125
1.00
55.72
C


ATOM
976
CG
PHE
A
133
5.944
−14.177
43.686
1.00
59.06
C


ATOM
977
CD1
PHE
A
133
5.632
−14.357
42.348
1.00
60.09
C


ATOM
978
CD2
PHE
A
133
5.445
−15.078
44.613
1.00
63.30
C


ATOM
979
CE1
PHE
A
133
4.839
−15.416
41.943
1.00
62.08
C


ATOM
980
CE2
PHE
A
133
4.651
−16.138
44.216
1.00
64.41
C


ATOM
981
CZ
PHE
A
133
4.348
−16.307
42.879
1.00
64.42
C


ATOM
982
N
ALA
A
134
7.726
−10.168
45.079
1.00
62.65
N


ATOM
983
CA
ALA
A
134
8.536
−9.328
45.953
1.00
58.86
C


ATOM
984
C
ALA
A
134
7.674
−8.318
46.702
1.00
56.08
C


ATOM
985
O
ALA
A
134
7.892
−8.057
47.884
1.00
57.64
O


ATOM
986
CB
ALA
A
134
9.613
−8.614
45.147
1.00
56.23
C


ATOM
987
N
ILE
A
135
6.693
−7.754
46.006
1.00
59.20
N


ATOM
988
CA
ILE
A
135
5.815
−6.748
46.591
1.00
62.08
C


ATOM
989
C
ILE
A
135
4.731
−7.376
47.463
1.00
59.08
C


ATOM
990
O
ILE
A
135
4.510
−6.950
48.597
1.00
65.05
O


ATOM
991
CB
ILE
A
135
5.152
−5.881
45.500
1.00
65.36
C


ATOM
992
CG1
ILE
A
135
6.211
−5.073
44.746
1.00
64.34
C


ATOM
993
CG2
ILE
A
135
4.104
−4.960
46.108
1.00
61.49
C


ATOM
994
CD1
ILE
A
135
5.666
−4.310
43.557
1.00
64.42
C


ATOM
995
N
GLY
A
136
4.060
−8.392
46.931
1.00
47.67
N


ATOM
996
CA
GLY
A
136
2.968
−9.037
47.638
1.00
48.58
C


ATOM
997
C
GLY
A
136
3.391
−9.763
48.902
1.00
57.36
C


ATOM
998
O
GLY
A
136
2.628
−9.840
49.865
1.00
58.29
O


ATOM
999
N
LEU
A
137
4.608
−10.297
48.902
1.00
66.46
N


ATOM
1000
CA
LEU
A
137
5.096
−11.071
50.039
1.00
63.23
C


ATOM
1001
C
LEU
A
137
6.127
−10.304
50.861
1.00
66.91
C


ATOM
1002
O
LEU
A
137
6.957
−10.903
51.544
1.00
64.37
O


ATOM
1003
CB
LEU
A
137
5.681
−12.404
49.569
1.00
63.17
C


ATOM
1004
CG
LEU
A
137
4.679
−13.392
48.968
1.00
64.82
C


ATOM
1005
CD1
LEU
A
137
5.353
−14.717
48.646
1.00
62.63
C


ATOM
1006
CD2
LEU
A
137
3.496
−13.597
49.906
1.00
58.64
C


ATOM
1007
N
THR
A
138
6.067
−8.978
50.794
1.00
72.48
N


ATOM
1008
CA
THR
A
138
6.975
−8.126
51.558
1.00
69.66
C


ATOM
1009
C
THR
A
138
6.856
−8.334
53.071
1.00
61.71
C


ATOM
1010
O
THR
A
138
7.867
−8.362
53.773
1.00
60.72
O


ATOM
1011
CB
THR
A
138
6.783
−6.631
51.218
1.00
65.16
C


ATOM
1012
OG1
THR
A
138
7.358
−6.354
49.935
1.00
63.90
O


ATOM
1013
CG2
THR
A
138
7.456
−5.755
52.261
1.00
64.16
C


ATOM
1014
N
PRO
A
139
5.620
−8.472
53.582
1.00
57.22
N


ATOM
1015
CA
PRO
A
139
5.457
−8.731
55.018
1.00
63.21
C


ATOM
1016
C
PRO
A
139
6.185
−10.000
55.452
1.00
68.08
C


ATOM
1017
O
PRO
A
139
6.656
−10.084
56.586
1.00
67.41
O


ATOM
1018
CB
PRO
A
139
3.945
−8.909
55.170
1.00
52.42
C


ATOM
1019
CG
PRO
A
139
3.364
−8.127
54.046
1.00
55.59
C


ATOM
1020
CD
PRO
A
139
4.323
−8.300
52.904
1.00
49.95
C


ATOM
1021
N
MET
A
140
6.272
−10.974
54.551
1.00
73.20
N


ATOM
1022
CA
MET
A
140
6.982
−12.217
54.829
1.00
76.09
C


ATOM
1023
C
MET
A
140
8.487
−12.004
54.924
1.00
82.03
C


ATOM
1024
O
MET
A
140
9.203
−12.822
55.500
1.00
83.70
O


ATOM
1025
CB
MET
A
140
6.685
−13.262
53.752
1.00
70.94
C


ATOM
1026
CG
MET
A
140
5.535
−14.193
54.080
1.00
69.49
C


ATOM
1027
SD
MET
A
140
5.659
−15.729
53.147
1.00
85.83
S


ATOM
1028
CE
MET
A
140
7.396
−16.107
53.368
1.00
82.79
C


ATOM
1029
N
LEU
A
141
8.963
−10.904
54.350
1.00
83.94
N


ATOM
1030
CA
LEU
A
141
10.393
−10.622
54.313
1.00
84.78
C


ATOM
1031
C
LEU
A
141
10.873
−9.915
55.578
1.00
84.45
C


ATOM
1032
O
LEU
A
141
12.075
−9.742
55.780
1.00
83.38
O


ATOM
1033
CB
LEU
A
141
10.743
−9.794
53.073
1.00
84.57
C


ATOM
1034
CG
LEU
A
141
10.203
−10.324
51.742
1.00
84.86
C


ATOM
1035
CD1
LEU
A
141
10.617
−9.419
50.593
1.00
86.16
C


ATOM
1036
CD2
LEU
A
141
10.668
−11.749
51.497
1.00
86.17
C


ATOM
1037
N
GLY
A
142
9.935
−9.506
56.428
1.00
79.23
N


ATOM
1038
CA
GLY
A
142
10.290
−8.891
57.696
1.00
80.80
C


ATOM
1039
C
GLY
A
142
9.340
−7.814
58.186
1.00
80.96
C


ATOM
1040
O
GLY
A
142
9.326
−7.488
59.374
1.00
78.36
O


ATOM
1041
N
TRP
A
143
8.546
−7.259
57.275
1.00
76.74
N


ATOM
1042
CA
TRP
A
143
7.622
−6.181
57.613
1.00
68.29
C


ATOM
1043
C
TRP
A
143
6.319
−6.726
58.203
1.00
71.50
C


ATOM
1044
O
TRP
A
143
5.253
−6.584
57.602
1.00
72.95
O


ATOM
1045
CB
TRP
A
143
7.314
−5.346
56.368
1.00
64.17
C


ATOM
1046
CG
TRP
A
143
6.819
−3.961
56.662
1.00
62.07
C


ATOM
1047
CD1
TRP
A
143
6.288
−3.511
57.837
1.00
60.98
C


ATOM
1048
CD2
TRP
A
143
6.785
−2.851
55.756
1.00
61.23
C


ATOM
1049
NE1
TRP
A
143
5.940
−2.186
57.722
1.00
64.65
N


ATOM
1050
CE2
TRP
A
143
6.233
−1.758
56.453
1.00
65.50
C


ATOM
1051
CE3
TRP
A
143
7.173
−2.673
54.423
1.00
56.46
C


ATOM
1052
CZ2
TRP
A
143
6.058
−0.506
55.865
1.00
58.65
C


ATOM
1053
CZ3
TRP
A
143
6.999
−1.429
53.841
1.00
56.45
C


ATOM
1054
CH2
TRP
A
143
6.446
−0.363
54.561
1.00
53.43
C


ATOM
1055
N
ASN
A
144
6.403
−7.343
59.379
1.00
66.92
N


ATOM
1056
CA
ASN
A
144
5.231
−7.962
60.000
1.00
75.59
C


ATOM
1057
C
ASN
A
144
5.113
−7.717
61.506
1.00
87.35
C


ATOM
1058
O
ASN
A
144
5.944
−7.030
62.100
1.00
93.88
O


ATOM
1059
CB
ASN
A
144
5.199
−9.463
59.708
1.00
81.45
C


ATOM
1060
CG
ASN
A
144
6.464
−10.170
60.150
1.00
80.28
C


ATOM
1061
OD1
ASN
A
144
7.568
−9.803
59.749
1.00
82.07
O


ATOM
1062
ND2
ASN
A
144
6.308
−11.195
60.977
1.00
79.90
N


ATOM
1063
N
ASN
A
145
4.079
−8.295
62.115
1.00
92.12
N


ATOM
1064
CA
ASN
A
145
3.756
−8.029
63.517
1.00
95.13
C


ATOM
1065
C
ASN
A
145
3.725
−9.256
64.428
1.00
100.95
C


ATOM
1066
O
ASN
A
145
3.019
−9.259
65.435
1.00
97.13
O


ATOM
1067
CB
ASN
A
145
2.407
−7.309
63.620
1.00
91.48
C


ATOM
1068
CG
ASN
A
145
2.509
−5.829
63.319
1.00
87.59
C


ATOM
1069
OD1
ASN
A
145
3.601
−5.297
63.124
1.00
87.87
O


ATOM
1070
ND2
ASN
A
145
1.367
−5.154
63.286
1.00
84.05
N


ATOM
1071
N
CYS
A
146
4.485
−10.291
64.089
1.00
110.01
N


ATOM
1072
CA
CYS
A
146
4.487
−11.502
64.906
1.00
116.37
C


ATOM
1073
C
CYS
A
146
5.882
−11.946
65.346
1.00
118.97
C


ATOM
1074
O
CYS
A
146
6.025
−12.650
66.344
1.00
122.98
O


ATOM
1075
CB
CYS
A
146
3.759
−12.645
64.188
1.00
117.89
C


ATOM
1076
SG
CYS
A
146
3.952
−12.663
62.391
1.00
97.28
S


ATOM
1077
N
GLY
A
147
6.905
−11.521
64.610
1.00
114.76
N


ATOM
1078
CA
GLY
A
147
8.267
−11.965
64.858
1.00
114.32
C


ATOM
1079
C
GLY
A
147
8.875
−11.540
66.189
1.00
115.40
C


ATOM
1080
O
GLY
A
147
10.058
−11.784
66.440
1.00
115.94
O


ATOM
1081
N
GLN
A
148
8.079
−10.902
67.044
1.00
113.07
N


ATOM
1082
CA
GLN
A
148
8.567
−10.430
68.338
1.00
107.89
C


ATOM
1083
C
GLN
A
148
7.638
−10.822
69.482
1.00
106.38
C


ATOM
1084
O
GLN
A
148
7.580
−10.132
70.504
1.00
108.96
O


ATOM
1085
CB
GLN
A
148
8.768
−8.910
68.322
1.00
109.08
C


ATOM
1086
CG
GLN
A
148
9.661
−8.423
67.187
1.00
118.94
C


ATOM
1087
CD
GLN
A
148
9.839
−6.918
67.194
1.00
125.94
C


ATOM
1088
OE1
GLN
A
148
9.347
−6.228
68.091
1.00
126.37
O


ATOM
1089
NE2
GLN
A
148
10.546
−6.398
66.192
1.00
128.16
N


ATOM
1090
N
SER
A
156
0.404
−12.289
72.202
1.00
111.40
N


ATOM
1091
CA
SER
A
156
−0.282
−13.281
71.371
1.00
112.40
C


ATOM
1092
C
SER
A
156
−0.539
−14.545
72.189
1.00
107.10
C


ATOM
1093
O
SER
A
156
0.276
−15.461
72.196
1.00
104.13
O


ATOM
1094
CB
SER
A
156
0.596
−13.645
70.188
1.00
111.11
C


ATOM
1095
OG
SER
A
156
1.652
−14.476
70.673
1.00
112.97
O


ATOM
1096
N
GLN
A
157
−1.667
−14.594
72.888
1.00
100.11
N


ATOM
1097
CA
GLN
A
157
−1.926
−15.727
73.767
1.00
94.42
C


ATOM
1098
C
GLN
A
157
−3.155
−16.519
73.335
1.00
83.00
C


ATOM
1099
O
GLN
A
157
−3.948
−16.067
72.517
1.00
80.27
O


ATOM
1100
CB
GLN
A
157
−2.061
−15.267
75.222
1.00
99.49
C


ATOM
1101
CG
GLN
A
157
−1.568
−16.284
76.241
1.00
102.47
C


ATOM
1102
CD
GLN
A
157
−2.217
−16.109
77.595
1.00
106.85
C


ATOM
1103
OE1
GLN
A
157
−3.440
−16.023
77.703
1.00
105.71
O


ATOM
1104
NE2
GLN
A
157
−1.399
−16.062
78.640
1.00
107.96
N


ATOM
1105
N
GLY
A
158
−3.296
−17.713
73.899
1.00
70.83
N


ATOM
1106
CA
GLY
A
158
−4.361
−18.620
73.510
1.00
66.83
C


ATOM
1107
C
GLY
A
158
−3.947
−19.530
72.372
1.00
62.79
C


ATOM
1108
O
GLY
A
158
−4.712
−20.390
71.938
1.00
57.38
O


ATOM
1109
N
CYS
A
159
−2.720
−19.346
71.894
1.00
60.35
N


ATOM
1110
CA
CYS
A
159
−2.212
−20.099
70.749
1.00
56.16
C


ATOM
1111
C
CYS
A
159
−0.913
−20.843
71.049
1.00
59.17
C


ATOM
1112
O
CYS
A
159
−0.459
−21.661
70.245
1.00
62.23
O


ATOM
1113
CB
CYS
A
159
−2.004
−19.174
69.545
1.00
49.69
C


ATOM
1114
SG
CYS
A
159
−3.513
−18.788
68.628
1.00
72.63
S


ATOM
1115
N
GLY
A
160
−0.317
−20.564
72.203
1.00
66.01
N


ATOM
1116
CA
GLY
A
160
0.970
−21.143
72.543
1.00
65.87
C


ATOM
1117
C
GLY
A
160
2.084
−20.457
71.774
1.00
66.73
C


ATOM
1118
O
GLY
A
160
1.859
−19.944
70.680
1.00
69.74
O


ATOM
1119
N
GLU
A
161
3.286
−20.445
72.340
1.00
65.22
N


ATOM
1120
CA
GLU
A
161
4.407
−19.747
71.717
1.00
68.91
C


ATOM
1121
C
GLU
A
161
4.747
−20.351
70.356
1.00
65.43
C


ATOM
1122
O
GLU
A
161
4.569
−21.549
70.135
1.00
66.94
O


ATOM
1123
CB
GLU
A
161
5.636
−19.772
72.630
1.00
71.19
C


ATOM
1124
CG
GLU
A
161
6.546
−20.964
72.411
1.00
79.99
C


ATOM
1125
CD
GLU
A
161
7.555
−20.737
71.297
1.00
87.71
C


ATOM
1126
OE1
GLU
A
161
7.966
−21.727
70.655
1.00
86.91
O


ATOM
1127
OE2
GLU
A
161
7.935
−19.569
71.062
1.00
81.83
O


ATOM
1128
N
GLY
A
162
5.239
−19.513
69.449
1.00
61.92
N


ATOM
1129
CA
GLY
A
162
5.580
−19.956
68.110
1.00
62.74
C


ATOM
1130
C
GLY
A
162
4.385
−19.899
67.179
1.00
74.95
C


ATOM
1131
O
GLY
A
162
4.497
−20.193
65.989
1.00
82.12
O


ATOM
1132
N
GLN
A
163
3.235
−19.521
67.729
1.00
70.48
N


ATOM
1133
CA
GLN
A
163
2.011
−19.408
66.949
1.00
61.37
C


ATOM
1134
C
GLN
A
163
1.238
−18.150
67.316
1.00
66.77
C


ATOM
1135
O
GLN
A
163
1.364
−17.629
68.423
1.00
66.40
O


ATOM
1136
CB
GLN
A
163
1.124
−20.639
67.149
1.00
56.01
C


ATOM
1137
CG
GLN
A
163
1.701
−21.921
66.569
1.00
57.63
C


ATOM
1138
CD
GLN
A
163
0.712
−23.067
66.591
1.00
63.91
C


ATOM
1139
OE1
GLN
A
163
−0.417
−22.920
67.058
1.00
77.41
O


ATOM
1140
NE2
GLN
A
163
1.131
−24.219
66.083
1.00
65.43
N


ATOM
1141
N
VAL
A
164
0.441
−17.666
66.371
1.00
68.38
N


ATOM
1142
CA
VAL
A
164
−0.407
−16.505
66.599
1.00
64.31
C


ATOM
1143
C
VAL
A
164
−1.750
−16.717
65.915
1.00
62.35
C


ATOM
1144
O
VAL
A
164
−1.836
−17.431
64.911
1.00
59.38
O


ATOM
1145
CB
VAL
A
164
0.248
−15.213
66.062
1.00
64.38
C


ATOM
1146
CG1
VAL
A
164
1.561
−14.941
66.784
1.00
66.59
C


ATOM
1147
CG2
VAL
A
164
0.472
−15.312
64.562
1.00
63.12
C


ATOM
1148
N
ALA
A
165
−2.797
−16.118
66.470
1.00
61.77
N


ATOM
1149
CA
ALA
A
165
−4.095
−16.130
65.820
1.00
56.63
C


ATOM
1150
C
ALA
A
165
−3.971
−15.429
64.470
1.00
63.41
C


ATOM
1151
O
ALA
A
165
−3.533
−14.280
64.394
1.00
57.69
O


ATOM
1152
CB
ALA
A
165
−5.130
−15.433
66.691
1.00
49.04
C


ATOM
1153
N
CYS
A
166
−4.338
−16.132
63.405
1.00
64.32
N


ATOM
1154
CA
CYS
A
166
−4.200
−15.593
62.058
1.00
60.34
C


ATOM
1155
C
CYS
A
166
−5.343
−14.641
61.704
1.00
64.43
C


ATOM
1156
O
CYS
A
166
−6.267
−15.006
60.974
1.00
58.57
O


ATOM
1157
CB
CYS
A
166
−4.111
−16.722
61.027
1.00
60.31
C


ATOM
1158
SG
CYS
A
166
−3.427
−16.200
59.438
1.00
79.30
S


ATOM
1159
N
LEU
A
167
−5.277
−13.425
62.239
1.00
65.97
N


ATOM
1160
CA
LEU
A
167
−6.210
−12.364
61.866
1.00
59.40
C


ATOM
1161
C
LEU
A
167
−5.485
−11.335
61.004
1.00
62.14
C


ATOM
1162
O
LEU
A
167
−4.439
−10.812
61.395
1.00
71.58
O


ATOM
1163
CB
LEU
A
167
−6.805
−11.687
63.105
1.00
65.79
C


ATOM
1164
CG
LEU
A
167
−7.879
−12.449
63.888
1.00
66.75
C


ATOM
1165
CD1
LEU
A
167
−8.728
−13.298
62.950
1.00
67.83
C


ATOM
1166
CD2
LEU
A
167
−7.272
−13.293
64.998
1.00
63.93
C


ATOM
1167
N
PHE
A
168
−6.043
−11.050
59.832
1.00
57.68
N


ATOM
1168
CA
PHE
A
168
−5.392
−10.180
58.855
1.00
61.62
C


ATOM
1169
C
PHE
A
168
−4.815
−8.905
59.469
1.00
64.22
C


ATOM
1170
O
PHE
A
168
−3.625
−8.626
59.329
1.00
63.81
O


ATOM
1171
CB
PHE
A
168
−6.361
−9.824
57.722
1.00
60.06
C


ATOM
1172
CG
PHE
A
168
−5.702
−9.158
56.547
1.00
56.89
C


ATOM
1173
CD1
PHE
A
168
−5.178
−9.912
55.511
1.00
57.97
C


ATOM
1174
CD2
PHE
A
168
−5.604
−7.778
56.481
1.00
50.90
C


ATOM
1175
CE1
PHE
A
168
−4.570
−9.303
54.430
1.00
53.39
C


ATOM
1176
CE2
PHE
A
168
−4.999
−7.164
55.403
1.00
51.56
C


ATOM
1177
CZ
PHE
A
168
−4.481
−7.928
54.376
1.00
55.14
C


ATOM
1178
N
GLU
A
169
−5.658
−8.138
60.152
1.00
63.54
N


ATOM
1179
CA
GLU
A
169
−5.236
−6.854
60.705
1.00
64.21
C


ATOM
1180
C
GLU
A
169
−4.296
−7.006
61.901
1.00
64.27
C


ATOM
1181
O
GLU
A
169
−3.751
−6.020
62.401
1.00
59.89
O


ATOM
1182
CB
GLU
A
169
−6.452
−6.003
61.084
1.00
55.80
C


ATOM
1183
CG
GLU
A
169
−7.340
−5.634
59.902
1.00
58.23
C


ATOM
1184
CD
GLU
A
169
−8.281
−4.483
60.211
1.00
67.89
C


ATOM
1185
OE1
GLU
A
169
−8.210
−3.933
61.331
1.00
75.11
O


ATOM
1186
OE2
GLU
A
169
−9.091
−4.125
59.330
1.00
66.46
O


ATOM
1187
N
ASP
A
170
−4.105
−8.242
62.351
1.00
62.92
N


ATOM
1188
CA
ASP
A
170
−3.244
−8.516
63.497
1.00
59.97
C


ATOM
1189
C
ASP
A
170
−1.823
−8.886
63.083
1.00
65.64
C


ATOM
1190
O
ASP
A
170
−0.885
−8.737
63.865
1.00
69.78
O


ATOM
1191
CB
ASP
A
170
−3.835
−9.636
64.356
1.00
62.46
C


ATOM
1192
CG
ASP
A
170
−5.020
−9.178
65.178
1.00
75.69
C


ATOM
1193
OD1
ASP
A
170
−5.343
−7.972
65.141
1.00
83.95
O


ATOM
1194
OD2
ASP
A
170
−5.627
−10.025
65.866
1.00
79.29
O


ATOM
1195
N
VAL
A
171
−1.667
−9.373
61.856
1.00
60.84
N


ATOM
1196
CA
VAL
A
171
−0.364
−9.830
61.386
1.00
61.36
C


ATOM
1197
C
VAL
A
171
0.179
−8.978
60.242
1.00
65.06
C


ATOM
1198
O
VAL
A
171
1.393
−8.847
60.080
1.00
65.39
O


ATOM
1199
CB
VAL
A
171
−0.404
−11.312
60.954
1.00
62.30
C


ATOM
1200
CG1
VAL
A
171
−0.679
−12.205
62.152
1.00
50.95
C


ATOM
1201
CG2
VAL
A
171
−1.452
−11.527
59.872
1.00
68.11
C


ATOM
1202
N
VAL
A
172
−0.722
−8.402
59.452
1.00
59.35
N


ATOM
1203
CA
VAL
A
172
−0.325
−7.558
58.330
1.00
59.25
C


ATOM
1204
C
VAL
A
172
−0.389
−6.081
58.704
1.00
62.38
C


ATOM
1205
O
VAL
A
172
−1.473
−5.528
58.879
1.00
67.88
O


ATOM
1206
CB
VAL
A
172
−1.216
−7.800
57.096
1.00
59.89
C


ATOM
1207
CG1
VAL
A
172
−0.686
−7.023
55.898
1.00
46.18
C


ATOM
1208
CG2
VAL
A
172
−1.296
−9.288
56.781
1.00
61.29
C


ATOM
1209
N
PRO
A
173
0.783
−5.438
58.826
1.00
60.75
N


ATOM
1210
CA
PRO
A
173
0.900
−4.022
59.193
1.00
54.18
C


ATOM
1211
C
PRO
A
173
0.084
−3.110
58.278
1.00
57.11
C


ATOM
1212
O
PRO
A
173
0.177
−3.217
57.055
1.00
63.59
O


ATOM
1213
CB
PRO
A
173
2.394
−3.740
59.014
1.00
52.86
C


ATOM
1214
CG
PRO
A
173
3.049
−5.061
59.201
1.00
57.54
C


ATOM
1215
CD
PRO
A
173
2.099
−6.068
58.626
1.00
61.28
C


ATOM
1216
N
MET
A
174
−0.700
−2.215
58.873
1.00
55.18
N


ATOM
1217
CA
MET
A
174
−1.556
−1.314
58.107
1.00
54.70
C


ATOM
1218
C
MET
A
174
−0.770
−0.258
57.339
1.00
56.48
C


ATOM
1219
O
MET
A
174
−1.190
0.171
56.264
1.00
63.66
O


ATOM
1220
CB
MET
A
174
−2.594
−0.649
59.010
1.00
64.19
C


ATOM
1221
CG
MET
A
174
−3.827
−1.503
59.263
1.00
80.62
C


ATOM
1222
SD
MET
A
174
−4.686
−1.938
57.736
1.00
83.53
S


ATOM
1223
CE
MET
A
174
−4.860
−0.325
56.985
1.00
73.80
C


ATOM
1224
N
ASN
A
175
0.364
0.165
57.887
1.00
60.71
N


ATOM
1225
CA
ASN
A
175
1.216
1.123
57.191
1.00
66.17
C


ATOM
1226
C
ASN
A
175
1.737
0.544
55.877
1.00
67.79
C


ATOM
1227
O
ASN
A
175
2.000
1.275
54.922
1.00
68.29
O


ATOM
1228
CB
ASN
A
175
2.368
1.605
58.082
1.00
66.08
C


ATOM
1229
CG
ASN
A
175
3.259
0.473
58.556
1.00
69.42
C


ATOM
1230
OD1
ASN
A
175
2.891
−0.698
58.481
1.00
80.66
O


ATOM
1231
ND2
ASN
A
175
4.440
0.822
59.054
1.00
57.73
N


ATOM
1232
N
TYR
A
176
1.873
−0.777
55.835
1.00
64.10
N


ATOM
1233
CA
TYR
A
176
2.216
−1.469
54.602
1.00
57.17
C


ATOM
1234
C
TYR
A
176
1.033
−1.439
53.639
1.00
56.23
C


ATOM
1235
O
TYR
A
176
1.189
−1.150
52.453
1.00
58.62
O


ATOM
1236
CB
TYR
A
176
2.610
−2.921
54.889
1.00
61.45
C


ATOM
1237
CG
TYR
A
176
2.598
−3.802
53.658
1.00
63.69
C


ATOM
1238
CD1
TYR
A
176
1.463
−4.523
53.307
1.00
56.39
C


ATOM
1239
CD2
TYR
A
176
3.717
−3.905
52.842
1.00
61.88
C


ATOM
1240
CE1
TYR
A
176
1.445
−5.323
52.181
1.00
59.28
C


ATOM
1241
CE2
TYR
A
176
3.709
−4.703
51.715
1.00
57.78
C


ATOM
1242
CZ
TYR
A
176
2.571
−5.410
51.389
1.00
65.29
C


ATOM
1243
OH
TYR
A
176
2.558
−6.206
50.267
1.00
76.04
O


ATOM
1244
N
MET
A
177
−0.151
−1.738
54.165
1.00
54.66
N


ATOM
1245
CA
MET
A
177
−1.358
−1.824
53.351
1.00
50.97
C


ATOM
1246
C
MET
A
177
−1.750
−0.485
52.736
1.00
59.97
C


ATOM
1247
O
MET
A
177
−2.261
−0.434
51.618
1.00
59.12
O


ATOM
1248
CB
MET
A
177
−2.520
−2.380
54.177
1.00
45.66
C


ATOM
1249
CG
MET
A
177
−2.387
−3.855
54.509
1.00
45.51
C


ATOM
1250
SD
MET
A
177
−2.208
−4.878
53.030
1.00
60.18
S


ATOM
1251
CE
MET
A
177
−3.760
−4.553
52.203
1.00
62.04
C


ATOM
1252
N
VAL
A
178
−1.508
0.596
53.469
1.00
68.22
N


ATOM
1253
CA
VAL
A
178
−1.914
1.923
53.020
1.00
61.62
C


ATOM
1254
C
VAL
A
178
−0.839
2.623
52.191
1.00
57.36
C


ATOM
1255
O
VAL
A
178
−1.091
3.040
51.062
1.00
55.42
O


ATOM
1256
CB
VAL
A
178
−2.308
2.819
54.208
1.00
61.78
C


ATOM
1257
CG1
VAL
A
178
−2.574
4.239
53.733
1.00
62.82
C


ATOM
1258
CG2
VAL
A
178
−3.529
2.248
54.914
1.00
46.74
C


ATOM
1259
N
TYR
A
179
0.359
2.747
52.755
1.00
59.67
N


ATOM
1260
CA
TYR
A
179
1.442
3.465
52.089
1.00
59.72
C


ATOM
1261
C
TYR
A
179
2.035
2.699
50.912
1.00
60.59
C


ATOM
1262
O
TYR
A
179
2.060
3.195
49.787
1.00
55.02
O


ATOM
1263
CB
TYR
A
179
2.547
3.822
53.085
1.00
63.83
C


ATOM
1264
CG
TYR
A
179
2.148
4.896
54.067
1.00
68.94
C


ATOM
1265
CD1
TYR
A
179
2.201
4.669
55.435
1.00
75.25
C


ATOM
1266
CD2
TYR
A
179
1.705
6.135
53.624
1.00
65.23
C


ATOM
1267
CE1
TYR
A
179
1.833
5.650
56.336
1.00
76.87
C


ATOM
1268
CE2
TYR
A
179
1.334
7.119
54.515
1.00
68.86
C


ATOM
1269
CZ
TYR
A
179
1.400
6.873
55.869
1.00
76.23
C


ATOM
1270
OH
TYR
A
179
1.029
7.854
56.755
1.00
81.33
O


ATOM
1271
N
PHE
A
180
2.517
1.490
51.176
1.00
73.26
N


ATOM
1272
CA
PHE
A
180
3.219
0.722
50.155
1.00
72.52
C


ATOM
1273
C
PHE
A
180
2.264
0.072
49.157
1.00
72.33
C


ATOM
1274
O
PHE
A
180
2.359
0.307
47.953
1.00
72.48
O


ATOM
1275
CB
PHE
A
180
4.126
−0.329
50.798
1.00
59.61
C


ATOM
1276
CG
PHE
A
180
5.168
−0.875
49.869
1.00
63.52
C


ATOM
1277
CD1
PHE
A
180
6.067
−0.027
49.245
1.00
70.73
C


ATOM
1278
CD2
PHE
A
180
5.254
−2.234
49.621
1.00
69.38
C


ATOM
1279
CE1
PHE
A
180
7.030
−0.524
48.387
1.00
73.13
C


ATOM
1280
CE2
PHE
A
180
6.217
−2.738
48.765
1.00
71.19
C


ATOM
1281
CZ
PHE
A
180
7.105
−1.881
48.148
1.00
65.78
C


ATOM
1282
N
ASN
A
181
1.342
−0.741
49.660
1.00
67.41
N


ATOM
1283
CA
ASN
A
181
0.401
−1.434
48.792
1.00
71.02
C


ATOM
1284
C
ASN
A
181
−0.528
−0.479
48.051
1.00
64.24
C


ATOM
1285
O
ASN
A
181
−0.493
−0.397
46.825
1.00
72.23
O


ATOM
1286
CB
ASN
A
181
−0.412
−2.465
49.578
1.00
78.04
C


ATOM
1287
CG
ASN
A
181
−1.188
−3.404
48.675
1.00
78.10
C


ATOM
1288
OD1
ASN
A
181
−2.225
−3.038
48.120
1.00
77.60
O


ATOM
1289
ND2
ASN
A
181
−0.688
−4.626
48.525
1.00
77.14
N


ATOM
1290
N
PHE
A
182
−1.355
0.248
48.795
1.00
57.68
N


ATOM
1291
CA
PHE
A
182
−2.356
1.106
48.172
1.00
61.54
C


ATOM
1292
C
PHE
A
182
−1.764
2.290
47.404
1.00
62.62
C


ATOM
1293
O
PHE
A
182
−1.845
2.338
46.178
1.00
73.99
O


ATOM
1294
CB
PHE
A
182
−3.385
1.593
49.195
1.00
60.03
C


ATOM
1295
CG
PHE
A
182
−4.462
2.457
48.598
1.00
59.95
C


ATOM
1296
CD1
PHE
A
182
−5.027
2.133
47.374
1.00
61.17
C


ATOM
1297
CD2
PHE
A
182
−4.915
3.585
49.260
1.00
59.97
C


ATOM
1298
CE1
PHE
A
182
−6.016
2.922
46.819
1.00
61.56
C


ATOM
1299
CE2
PHE
A
182
−5.906
4.378
48.710
1.00
60.08
C


ATOM
1300
CZ
PHE
A
182
−6.458
4.045
47.488
1.00
60.69
C


ATOM
1301
N
PHE
A
183
−1.170
3.238
48.121
1.00
55.81
N


ATOM
1302
CA
PHE
A
183
−0.698
4.473
47.496
1.00
61.65
C


ATOM
1303
C
PHE
A
183
0.335
4.250
46.393
1.00
61.58
C


ATOM
1304
O
PHE
A
183
0.170
4.735
45.274
1.00
70.29
O


ATOM
1305
CB
PHE
A
183
−0.140
5.445
48.543
1.00
64.59
C


ATOM
1306
CG
PHE
A
183
−1.187
6.043
49.439
1.00
71.80
C


ATOM
1307
CD1
PHE
A
183
−2.462
6.300
48.963
1.00
75.59
C


ATOM
1308
CD2
PHE
A
183
−0.890
6.366
50.753
1.00
70.99
C


ATOM
1309
CE1
PHE
A
183
−3.427
6.855
49.785
1.00
66.70
C


ATOM
1310
CE2
PHE
A
183
−1.850
6.923
51.578
1.00
67.93
C


ATOM
1311
CZ
PHE
A
183
−3.119
7.167
51.093
1.00
62.56
C


ATOM
1312
N
ALA
A
184
1.394
3.514
46.709
1.00
57.06
N


ATOM
1313
CA
ALA
A
184
2.518
3.367
45.789
1.00
58.06
C


ATOM
1314
C
ALA
A
184
2.287
2.334
44.686
1.00
62.96
C


ATOM
1315
O
ALA
A
184
2.670
2.550
43.536
1.00
65.83
O


ATOM
1316
CB
ALA
A
184
3.791
3.040
46.561
1.00
54.29
C


ATOM
1317
N
CYS
A
185
1.661
1.215
45.036
1.00
56.66
N


ATOM
1318
CA
CYS
A
185
1.569
0.082
44.118
1.00
55.19
C


ATOM
1319
C
CYS
A
185
0.235
−0.043
43.378
1.00
59.96
C


ATOM
1320
O
CYS
A
185
0.155
−0.719
42.352
1.00
59.75
O


ATOM
1321
CB
CYS
A
185
1.891
−1.221
44.855
1.00
55.70
C


ATOM
1322
SG
CYS
A
185
3.576
−1.303
45.509
1.00
62.88
S


ATOM
1323
N
VAL
A
186
−0.806
0.605
43.889
1.00
56.67
N


ATOM
1324
CA
VAL
A
186
−2.122
0.523
43.263
1.00
58.12
C


ATOM
1325
C
VAL
A
186
−2.606
1.877
42.747
1.00
60.90
C


ATOM
1326
O
VAL
A
186
−2.959
2.017
41.575
1.00
61.38
O


ATOM
1327
CB
VAL
A
186
−3.173
−0.054
44.231
1.00
52.12
C


ATOM
1328
CG1
VAL
A
186
−4.548
−0.076
43.574
1.00
47.03
C


ATOM
1329
CG2
VAL
A
186
−2.766
−1.448
44.683
1.00
51.28
C


ATOM
1330
N
LEU
A
187
−2.618
2.869
43.629
1.00
54.09
N


ATOM
1331
CA
LEU
A
187
−3.128
4.194
43.294
1.00
63.42
C


ATOM
1332
C
LEU
A
187
−2.351
4.839
42.146
1.00
65.18
C


ATOM
1333
O
LEU
A
187
−2.945
5.354
41.197
1.00
59.97
O


ATOM
1334
CB
LEU
A
187
−3.109
5.097
44.531
1.00
65.01
C


ATOM
1335
CG
LEU
A
187
−3.723
6.494
44.406
1.00
63.23
C


ATOM
1336
CD1
LEU
A
187
−5.079
6.436
43.722
1.00
59.81
C


ATOM
1337
CD2
LEU
A
187
−3.839
7.147
45.775
1.00
61.29
C


ATOM
1338
N
VAL
A
188
−1.025
4.802
42.234
1.00
60.55
N


ATOM
1339
CA
VAL
A
188
−0.168
5.419
41.224
1.00
59.28
C


ATOM
1340
C
VAL
A
188
−0.351
4.819
39.825
1.00
68.51
C


ATOM
1341
O
VAL
A
188
−0.502
5.556
38.851
1.00
74.08
O


ATOM
1342
CB
VAL
A
188
1.322
5.376
41.633
1.00
55.93
C


ATOM
1343
CG1
VAL
A
188
2.210
5.755
40.458
1.00
58.79
C


ATOM
1344
CG2
VAL
A
188
1.571
6.297
42.818
1.00
49.67
C


ATOM
1345
N
PRO
A
189
−0.329
3.479
39.718
1.00
67.42
N


ATOM
1346
CA
PRO
A
189
−0.566
2.835
38.421
1.00
62.87
C


ATOM
1347
C
PRO
A
189
−1.943
3.153
37.838
1.00
63.18
C


ATOM
1348
O
PRO
A
189
−2.050
3.392
36.636
1.00
64.19
O


ATOM
1349
CB
PRO
A
189
−0.467
1.343
38.750
1.00
68.30
C


ATOM
1350
CG
PRO
A
189
0.411
1.285
39.947
1.00
67.94
C


ATOM
1351
CD
PRO
A
189
0.064
2.502
40.749
1.00
67.68
C


ATOM
1352
N
LEU
A
190
−2.976
3.153
38.676
1.00
59.02
N


ATOM
1353
CA
LEU
A
190
−4.333
3.444
38.216
1.00
64.13
C


ATOM
1354
C
LEU
A
190
−4.454
4.841
37.610
1.00
64.10
C


ATOM
1355
O
LEU
A
190
−5.047
5.013
36.546
1.00
62.95
O


ATOM
1356
CB
LEU
A
190
−5.345
3.273
39.352
1.00
66.37
C


ATOM
1357
CG
LEU
A
190
−5.760
1.839
39.684
1.00
66.79
C


ATOM
1358
CD1
LEU
A
190
−6.728
1.818
40.858
1.00
68.63
C


ATOM
1359
CD2
LEU
A
190
−6.377
1.164
38.467
1.00
65.21
C


ATOM
1360
N
LEU
A
191
−3.897
5.836
38.293
1.00
65.09
N


ATOM
1361
CA
LEU
A
191
−3.911
7.204
37.783
1.00
66.12
C


ATOM
1362
C
LEU
A
191
−3.065
7.314
36.521
1.00
64.56
C


ATOM
1363
O
LEU
A
191
−3.392
8.068
35.603
1.00
56.85
O


ATOM
1364
CB
LEU
A
191
−3.414
8.188
38.844
1.00
65.00
C


ATOM
1365
CG
LEU
A
191
−4.337
8.405
40.047
1.00
70.15
C


ATOM
1366
CD1
LEU
A
191
−3.940
9.659
40.809
1.00
70.66
C


ATOM
1367
CD2
LEU
A
191
−5.794
8.478
39.608
1.00
69.85
C


ATOM
1368
N
LEU
A
192
−1.975
6.555
36.483
1.00
66.12
N


ATOM
1369
CA
LEU
A
192
−1.107
6.519
35.315
1.00
62.98
C


ATOM
1370
C
LEU
A
192
−1.847
5.907
34.130
1.00
61.93
C


ATOM
1371
O
LEU
A
192
−1.710
6.367
32.998
1.00
66.81
O


ATOM
1372
CB
LEU
A
192
0.163
5.724
35.617
1.00
68.96
C


ATOM
1373
CG
LEU
A
192
1.253
5.763
34.547
1.00
83.35
C


ATOM
1374
CD1
LEU
A
192
1.642
7.200
34.240
1.00
86.74
C


ATOM
1375
CD2
LEU
A
192
2.466
4.959
34.992
1.00
88.80
C


ATOM
1376
N
MET
A
193
−2.634
4.870
34.401
1.00
62.18
N


ATOM
1377
CA
MET
A
193
−3.447
4.235
33.369
1.00
59.56
C


ATOM
1378
C
MET
A
193
−4.597
5.137
32.935
1.00
59.47
C


ATOM
1379
O
MET
A
193
−5.082
5.041
31.808
1.00
61.31
O


ATOM
1380
CB
MET
A
193
−3.987
2.888
33.854
1.00
61.23
C


ATOM
1381
CG
MET
A
193
−2.996
1.744
33.719
1.00
72.09
C


ATOM
1382
SD
MET
A
193
−3.674
0.150
34.221
1.00
72.44
S


ATOM
1383
CE
MET
A
193
−3.505
0.246
36.002
1.00
49.34
C


ATOM
1384
N
LEU
A
194
−5.032
6.011
33.835
1.00
55.36
N


ATOM
1385
CA
LEU
A
194
−6.098
6.952
33.522
1.00
50.67
C


ATOM
1386
C
LEU
A
194
−5.593
8.018
32.560
1.00
53.56
C


ATOM
1387
O
LEU
A
194
−6.285
8.394
31.614
1.00
60.12
O


ATOM
1388
CB
LEU
A
194
−6.639
7.600
34.797
1.00
57.62
C


ATOM
1389
CG
LEU
A
194
−7.751
8.635
34.613
1.00
64.63
C


ATOM
1390
CD1
LEU
A
194
−8.880
8.074
33.760
1.00
56.30
C


ATOM
1391
CD2
LEU
A
194
−8.278
9.100
35.963
1.00
67.95
C


ATOM
1392
N
GLY
A
195
−4.379
8.499
32.806
1.00
55.54
N


ATOM
1393
CA
GLY
A
195
−3.775
9.507
31.956
1.00
58.98
C


ATOM
1394
C
GLY
A
195
−3.492
8.991
30.559
1.00
58.15
C


ATOM
1395
O
GLY
A
195
−3.694
9.698
29.572
1.00
57.74
O


ATOM
1396
N
VAL
A
196
−3.024
7.750
30.474
1.00
55.91
N


ATOM
1397
CA
VAL
A
196
−2.691
7.143
29.190
1.00
51.58
C


ATOM
1398
C
VAL
A
196
−3.923
6.951
28.310
1.00
51.36
C


ATOM
1399
O
VAL
A
196
−3.912
7.306
27.131
1.00
53.56
O


ATOM
1400
CB
VAL
A
196
−1.985
5.787
29.369
1.00
50.58
C


ATOM
1401
CG1
VAL
A
196
−1.747
5.134
28.018
1.00
50.07
C


ATOM
1402
CG2
VAL
A
196
−0.677
5.969
30.120
1.00
51.69
C


ATOM
1403
N
TYR
A
197
−4.981
6.386
28.882
1.00
48.78
N


ATOM
1404
CA
TYR
A
197
−6.213
6.167
28.133
1.00
53.66
C


ATOM
1405
C
TYR
A
197
−6.853
7.482
27.710
1.00
56.74
C


ATOM
1406
O
TYR
A
197
−7.323
7.614
26.580
1.00
62.83
O


ATOM
1407
CB
TYR
A
197
−7.203
5.313
28.930
1.00
58.80
C


ATOM
1408
CG
TYR
A
197
−7.000
3.826
28.738
1.00
61.57
C


ATOM
1409
CD1
TYR
A
197
−7.207
3.234
27.497
1.00
59.49
C


ATOM
1410
CD2
TYR
A
197
−6.603
3.014
29.793
1.00
53.77
C


ATOM
1411
CE1
TYR
A
197
−7.022
1.876
27.312
1.00
63.51
C


ATOM
1412
CE2
TYR
A
197
−6.416
1.654
29.616
1.00
60.47
C


ATOM
1413
CZ
TYR
A
197
−6.627
1.091
28.373
1.00
64.49
C


ATOM
1414
OH
TYR
A
197
−6.444
−0.260
28.190
1.00
63.18
O


ATOM
1415
N
LEU
A
198
−6.864
8.454
28.616
1.00
54.86
N


ATOM
1416
CA
LEU
A
198
−7.392
9.774
28.300
1.00
59.87
C


ATOM
1417
C
LEU
A
198
−6.676
10.381
27.098
1.00
63.56
C


ATOM
1418
O
LEU
A
198
−7.308
10.977
26.227
1.00
62.39
O


ATOM
1419
CB
LEU
A
198
−7.288
10.707
29.507
1.00
65.95
C


ATOM
1420
CG
LEU
A
198
−8.371
10.534
30.574
1.00
79.11
C


ATOM
1421
CD1
LEU
A
198
−8.174
11.528
31.710
1.00
80.77
C


ATOM
1422
CD2
LEU
A
198
−9.756
10.684
29.958
1.00
75.76
C


ATOM
1423
N
ARG
A
199
−5.356
10.224
27.053
1.00
61.45
N


ATOM
1424
CA
ARG
A
199
−4.567
10.746
25.941
1.00
64.31
C


ATOM
1425
C
ARG
A
199
−4.863
9.997
24.641
1.00
63.00
C


ATOM
1426
O
ARG
A
199
−4.855
10.585
23.559
1.00
57.26
O


ATOM
1427
CB
ARG
A
199
−3.071
10.697
26.262
1.00
67.13
C


ATOM
1428
CG
ARG
A
199
−2.198
11.282
25.165
1.00
81.51
C


ATOM
1429
CD
ARG
A
199
−0.813
11.638
25.674
1.00
96.32
C


ATOM
1430
NE
ARG
A
199
−0.037
12.348
24.661
1.00
108.06
N


ATOM
1431
CZ
ARG
A
199
1.160
12.885
24.875
1.00
115.00
C


ATOM
1432
NH1
ARG
A
199
1.724
12.796
26.072
1.00
113.90
N


ATOM
1433
NH2
ARG
A
199
1.793
13.512
23.892
1.00
118.37
N


ATOM
1434
N
ILE
A
200
−5.127
8.700
24.753
1.00
65.48
N


ATOM
1435
CA
ILE
A
200
−5.502
7.903
23.592
1.00
69.12
C


ATOM
1436
C
ILE
A
200
−6.825
8.399
23.014
1.00
65.45
C


ATOM
1437
O
ILE
A
200
−6.962
8.566
21.802
1.00
54.79
O


ATOM
1438
CB
ILE
A
200
−5.626
6.408
23.946
1.00
76.83
C


ATOM
1439
CG1
ILE
A
200
−4.259
5.829
24.317
1.00
75.54
C


ATOM
1440
CG2
ILE
A
200
−6.231
5.631
22.786
1.00
79.38
C


ATOM
1441
CD1
ILE
A
200
−4.312
4.385
24.772
1.00
65.44
C


ATOM
1442
N
PHE
A
201
−7.793
8.643
23.893
1.00
69.70
N


ATOM
1443
CA
PHE
A
201
−9.119
9.085
23.472
1.00
69.83
C


ATOM
1444
C
PHE
A
201
−9.089
10.482
22.858
1.00
65.70
C


ATOM
1445
O
PHE
A
201
−9.659
10.712
21.792
1.00
72.46
O


ATOM
1446
CB
PHE
A
201
−10.101
9.048
24.646
1.00
72.76
C


ATOM
1447
CG
PHE
A
201
−10.261
7.687
25.260
1.00
78.84
C


ATOM
1448
CD1
PHE
A
201
−10.304
7.531
26.636
1.00
84.18
C


ATOM
1449
CD2
PHE
A
201
−10.360
6.560
24.461
1.00
82.93
C


ATOM
1450
CE1
PHE
A
201
−10.450
6.279
27.203
1.00
83.93
C


ATOM
1451
CE2
PHE
A
201
−10.505
5.305
25.021
1.00
87.07
C


ATOM
1452
CZ
PHE
A
201
−10.549
5.165
26.394
1.00
86.46
C


ATOM
1453
N
LEU
A
202
−8.424
11.411
23.536
1.00
65.99
N


ATOM
1454
CA
LEU
A
202
−8.326
12.787
23.059
1.00
65.94
C


ATOM
1455
C
LEU
A
202
−7.702
12.854
21.668
1.00
65.29
C


ATOM
1456
O
LEU
A
202
−7.996
13.761
20.890
1.00
55.81
O


ATOM
1457
CB
LEU
A
202
−7.519
13.639
24.043
1.00
61.52
C


ATOM
1458
CG
LEU
A
202
−8.162
13.865
25.414
1.00
63.19
C


ATOM
1459
CD1
LEU
A
202
−7.183
14.521
26.378
1.00
54.16
C


ATOM
1460
CD2
LEU
A
202
−9.426
14.699
25.278
1.00
63.22
C


ATOM
1461
N
ALA
A
203
−6.844
11.886
21.360
1.00
66.53
N


ATOM
1462
CA
ALA
A
203
−6.160
11.848
20.073
1.00
67.52
C


ATOM
1463
C
ALA
A
203
−7.101
11.433
18.945
1.00
65.46
C


ATOM
1464
O
ALA
A
203
−6.902
11.807
17.790
1.00
71.44
O


ATOM
1465
CB
ALA
A
203
−4.958
10.915
20.137
1.00
76.22
C


ATOM
1466
N
ALA
A
204
−8.126
10.659
19.285
1.00
63.70
N


ATOM
1467
CA
ALA
A
204
−9.109
10.219
18.302
1.00
62.18
C


ATOM
1468
C
ALA
A
204
−10.167
11.292
18.085
1.00
64.65
C


ATOM
1469
O
ALA
A
204
−11.004
11.184
17.188
1.00
65.71
O


ATOM
1470
CB
ALA
A
204
−9.756
8.917
18.742
1.00
66.97
C


ATOM
1471
N
ARG
A
205
−10.123
12.327
18.916
1.00
65.50
N


ATOM
1472
CA
ARG
A
205
−11.076
13.424
18.825
1.00
64.94
C


ATOM
1473
C
ARG
A
205
−10.382
14.705
18.383
1.00
60.03
C


ATOM
1474
O
ARG
A
205
−10.940
15.795
18.497
1.00
63.90
O


ATOM
1475
CB
ARG
A
205
−11.773
13.633
20.170
1.00
75.01
C


ATOM
1476
CG
ARG
A
205
−12.585
12.434
20.629
1.00
86.23
C


ATOM
1477
CD
ARG
A
205
−13.927
12.370
19.918
1.00
90.41
C


ATOM
1478
NE
ARG
A
205
−14.907
13.251
20.545
1.00
92.87
N


ATOM
1479
CZ
ARG
A
205
−15.865
12.835
21.367
1.00
91.26
C


ATOM
1480
NH1
ARG
A
205
−15.983
11.545
21.652
1.00
90.17
N


ATOM
1481
NH2
ARG
A
205
−16.712
13.707
21.897
1.00
91.03
N


ATOM
1482
N
ARG
A
206
−9.161
14.566
17.875
1.00
53.21
N


ATOM
1483
CA
ARG
A
206
−8.394
15.716
17.415
1.00
58.22
C


ATOM
1484
C
ARG
A
206
−9.059
16.364
16.204
1.00
60.50
C


ATOM
1485
O
ARG
A
206
−9.722
15.694
15.413
1.00
55.35
O


ATOM
1486
CB
ARG
A
206
−6.960
15.308
17.072
1.00
58.28
C


ATOM
1487
CG
ARG
A
206
−6.839
14.476
15.807
1.00
62.04
C


ATOM
1488
CD
ARG
A
206
−5.397
14.393
15.337
1.00
62.69
C


ATOM
1489
NE
ARG
A
206
−4.572
13.595
16.237
1.00
68.82
N


ATOM
1490
CZ
ARG
A
206
−4.200
12.343
15.993
1.00
78.59
C


ATOM
1491
NH1
ARG
A
206
−3.448
11.689
16.868
1.00
84.01
N


ATOM
1492
NH2
ARG
A
206
−4.578
11.745
14.871
1.00
78.81
N


ATOM
1493
N
GLN
A
207
−8.875
17.673
16.070
1.00
65.00
N


ATOM
1494
CA
GLN
A
207
−9.440
18.427
14.957
1.00
61.28
C


ATOM
1495
C
GLN
A
207
−8.716
18.092
13.656
1.00
61.20
C


ATOM
1496
O
GLN
A
207
−7.486
18.114
13.599
1.00
62.58
O


ATOM
1497
CB
GLN
A
207
−9.346
19.924
15.246
1.00
59.32
C


ATOM
1498
CG
GLN
A
207
−10.010
20.811
14.215
1.00
66.69
C


ATOM
1499
CD
GLN
A
207
−9.989
22.270
14.622
1.00
72.68
C


ATOM
1500
OE1
GLN
A
207
−9.229
22.667
15.506
1.00
77.80
O


ATOM
1501
NE2
GLN
A
207
−10.826
23.076
13.982
1.00
73.65
N


ATOM
1502
N
LEU
A
208
−9.480
17.785
12.613
1.00
58.37
N


ATOM
1503
CA
LEU
A
208
−8.898
17.347
11.347
1.00
60.11
C


ATOM
1504
C
LEU
A
208
−8.603
18.497
10.386
1.00
56.35
C


ATOM
1505
O
LEU
A
208
−9.305
19.509
10.368
1.00
56.10
O


ATOM
1506
CB
LEU
A
208
−9.789
16.301
10.668
1.00
54.72
C


ATOM
1507
CG
LEU
A
208
−9.887
14.946
11.375
1.00
52.42
C


ATOM
1508
CD1
LEU
A
208
−10.804
14.004
10.617
1.00
55.68
C


ATOM
1509
CD2
LEU
A
208
−8.509
14.326
11.545
1.00
53.54
C


ATOM
1510
N
ASN
A
1002
−7.552
18.320
9.591
1.00
57.40
N


ATOM
1511
CA
ASN
A
1002
−7.123
19.309
8.611
1.00
50.58
C


ATOM
1512
C
ASN
A
1002
−6.152
18.677
7.620
1.00
52.71
C


ATOM
1513
O
ASN
A
1002
−5.853
17.487
7.712
1.00
62.40
O


ATOM
1514
CB
ASN
A
1002
−6.478
20.513
9.303
1.00
52.37
C


ATOM
1515
CG
ASN
A
1002
−5.353
20.115
10.241
1.00
54.04
C


ATOM
1516
OD1
ASN
A
1002
−4.466
19.342
9.876
1.00
58.56
O


ATOM
1517
ND2
ASN
A
1002
−5.382
20.649
11.457
1.00
43.77
N


ATOM
1518
N
ILE
A
1003
−5.659
19.468
6.674
1.00
55.19
N


ATOM
1519
CA
ILE
A
1003
−4.779
18.940
5.635
1.00
54.09
C


ATOM
1520
C
ILE
A
1003
−3.527
18.273
6.211
1.00
53.49
C


ATOM
1521
O
ILE
A
1003
−3.006
17.320
5.632
1.00
49.31
O


ATOM
1522
CB
ILE
A
1003
−4.386
20.024
4.604
1.00
60.60
C


ATOM
1523
CG1
ILE
A
1003
−3.570
19.408
3.463
1.00
57.53
C


ATOM
1524
CG2
ILE
A
1003
−3.629
21.163
5.277
1.00
52.48
C


ATOM
1525
CD1
ILE
A
1003
−3.351
20.344
2.295
1.00
49.85
C


ATOM
1526
N
PHE
A
1004
−3.053
18.765
7.353
1.00
57.04
N


ATOM
1527
CA
PHE
A
1004
−1.886
18.173
8.005
1.00
58.69
C


ATOM
1528
C
PHE
A
1004
−2.206
16.805
8.602
1.00
60.13
C


ATOM
1529
O
PHE
A
1004
−1.445
15.850
8.434
1.00
59.59
O


ATOM
1530
CB
PHE
A
1004
−1.327
19.098
9.088
1.00
53.02
C


ATOM
1531
CG
PHE
A
1004
−0.257
18.461
9.933
1.00
61.63
C


ATOM
1532
CD1
PHE
A
1004
1.041
18.342
9.460
1.00
58.63
C


ATOM
1533
CD2
PHE
A
1004
−0.550
17.974
11.197
1.00
64.89
C


ATOM
1534
CE1
PHE
A
1004
2.026
17.754
10.234
1.00
59.07
C


ATOM
1535
CE2
PHE
A
1004
0.432
17.383
11.976
1.00
56.22
C


ATOM
1536
CZ
PHE
A
1004
1.721
17.274
11.493
1.00
54.14
C


ATOM
1537
N
GLU
A
1005
−3.332
16.714
9.302
1.00
54.04
N


ATOM
1538
CA
GLU
A
1005
−3.753
15.451
9.895
1.00
50.95
C


ATOM
1539
C
GLU
A
1005
−4.181
14.483
8.799
1.00
49.35
C


ATOM
1540
O
GLU
A
1005
−4.190
13.267
8.994
1.00
60.90
O


ATOM
1541
CB
GLU
A
1005
−4.899
15.672
10.885
1.00
49.68
C


ATOM
1542
CG
GLU
A
1005
−4.648
16.785
11.894
1.00
54.56
C


ATOM
1543
CD
GLU
A
1005
−3.534
16.457
12.876
1.00
67.59
C


ATOM
1544
OE1
GLU
A
1005
−3.226
15.260
13.058
1.00
64.83
O


ATOM
1545
OE2
GLU
A
1005
−2.970
17.399
13.474
1.00
74.63
O


ATOM
1546
N
MET
A
1006
−4.529
15.038
7.643
1.00
46.22
N


ATOM
1547
CA
MET
A
1006
−4.948
14.245
6.494
1.00
50.79
C


ATOM
1548
C
MET
A
1006
−3.789
13.426
5.931
1.00
54.17
C


ATOM
1549
O
MET
A
1006
−3.897
12.212
5.767
1.00
56.71
O


ATOM
1550
CB
MET
A
1006
−5.517
15.155
5.405
1.00
48.87
C


ATOM
1551
CG
MET
A
1006
−6.042
14.419
4.187
1.00
45.14
C


ATOM
1552
SD
MET
A
1006
−6.340
15.533
2.798
1.00
57.45
S


ATOM
1553
CE
MET
A
1006
−7.410
14.520
1.775
1.00
50.85
C


ATOM
1554
N
LEU
A
1007
−2.679
14.095
5.634
1.00
53.46
N


ATOM
1555
CA
LEU
A
1007
−1.511
13.407
5.091
1.00
59.73
C


ATOM
1556
C
LEU
A
1007
−0.693
12.702
6.167
1.00
60.91
C


ATOM
1557
O
LEU
A
1007
0.115
11.825
5.865
1.00
64.13
O


ATOM
1558
CB
LEU
A
1007
−0.631
14.360
4.281
1.00
49.37
C


ATOM
1559
CG
LEU
A
1007
−1.161
14.638
2.874
1.00
50.71
C


ATOM
1560
CD1
LEU
A
1007
−2.169
15.779
2.895
1.00
49.29
C


ATOM
1561
CD2
LEU
A
1007
−0.020
14.947
1.928
1.00
62.29
C


ATOM
1562
N
ARG
A
1008
−0.904
13.085
7.421
1.00
55.54
N


ATOM
1563
CA
ARG
A
1008
−0.285
12.381
8.534
1.00
51.78
C


ATOM
1564
C
ARG
A
1008
−0.785
10.941
8.549
1.00
54.08
C


ATOM
1565
O
ARG
A
1008
−0.087
10.031
8.994
1.00
59.46
O


ATOM
1566
CB
ARG
A
1008
−0.618
13.072
9.856
1.00
55.69
C


ATOM
1567
CG
ARG
A
1008
−0.030
12.395
11.083
1.00
56.42
C


ATOM
1568
CD
ARG
A
1008
−0.378
13.159
12.352
1.00
61.69
C


ATOM
1569
NE
ARG
A
1008
0.066
12.463
13.557
1.00
70.50
N


ATOM
1570
CZ
ARG
A
1008
−0.150
12.899
14.794
1.00
72.61
C


ATOM
1571
NH1
ARG
A
1008
−0.806
14.034
14.995
1.00
71.04
N


ATOM
1572
NH2
ARG
A
1008
0.290
12.201
15.832
1.00
78.23
N


ATOM
1573
N
ILE
A
1009
−2.001
10.748
8.046
1.00
55.91
N


ATOM
1574
CA
ILE
A
1009
−2.625
9.431
7.990
1.00
54.99
C


ATOM
1575
C
ILE
A
1009
−2.272
8.700
6.698
1.00
60.77
C


ATOM
1576
O
ILE
A
1009
−2.126
7.477
6.686
1.00
69.04
O


ATOM
1577
CB
ILE
A
1009
−4.159
9.539
8.101
1.00
59.77
C


ATOM
1578
CG1
ILE
A
1009
−4.562
9.989
9.507
1.00
55.21
C


ATOM
1579
CG2
ILE
A
1009
−4.819
8.214
7.757
1.00
61.35
C


ATOM
1580
CD1
ILE
A
1009
−6.056
10.152
9.689
1.00
58.71
C


ATOM
1581
N
ASP
A
1010
−2.133
9.454
5.612
1.00
58.39
N


ATOM
1582
CA
ASP
A
1010
−1.835
8.870
4.308
1.00
55.69
C


ATOM
1583
C
ASP
A
1010
−0.342
8.629
4.096
1.00
57.23
C


ATOM
1584
O
ASP
A
1010
0.046
7.671
3.427
1.00
55.67
O


ATOM
1585
CB
ASP
A
1010
−2.384
9.752
3.182
1.00
58.24
C


ATOM
1586
CG
ASP
A
1010
−3.879
9.588
2.988
1.00
59.78
C


ATOM
1587
OD1
ASP
A
1010
−4.441
8.590
3.485
1.00
62.57
O


ATOM
1588
OD2
ASP
A
1010
−4.492
10.457
2.334
1.00
62.77
O


ATOM
1589
N
GLU
A
1011
0.490
9.496
4.664
1.00
59.41
N


ATOM
1590
CA
GLU
A
1011
1.934
9.408
4.456
1.00
69.06
C


ATOM
1591
C
GLU
A
1011
2.725
9.165
5.743
1.00
73.98
C


ATOM
1592
O
GLU
A
1011
3.880
8.746
5.696
1.00
87.32
O


ATOM
1593
CB
GLU
A
1011
2.457
10.654
3.736
1.00
74.32
C


ATOM
1594
CG
GLU
A
1011
1.989
10.773
2.293
1.00
79.53
C


ATOM
1595
CD
GLU
A
1011
2.776
11.805
1.507
1.00
84.42
C


ATOM
1596
OE1
GLU
A
1011
3.777
12.324
2.045
1.00
84.07
O


ATOM
1597
OE2
GLU
A
1011
2.396
12.092
0.352
1.00
77.44
O


ATOM
1598
N
GLY
A
1012
2.105
9.433
6.887
1.00
68.52
N


ATOM
1599
CA
GLY
A
1012
2.732
9.162
8.169
1.00
61.41
C


ATOM
1600
C
GLY
A
1012
3.533
10.321
8.731
1.00
66.01
C


ATOM
1601
O
GLY
A
1012
3.872
11.264
8.016
1.00
65.86
O


ATOM
1602
N
LEU
A
1013
3.837
10.247
10.024
1.00
68.92
N


ATOM
1603
CA
LEU
A
1013
4.603
11.291
10.695
1.00
72.70
C


ATOM
1604
C
LEU
A
1013
5.881
10.738
11.325
1.00
75.09
C


ATOM
1605
O
LEU
A
1013
5.849
9.756
12.067
1.00
73.25
O


ATOM
1606
CB
LEU
A
1013
3.750
11.986
11.759
1.00
69.24
C


ATOM
1607
CG
LEU
A
1013
4.437
13.105
12.545
1.00
68.88
C


ATOM
1608
CD1
LEU
A
1013
4.975
14.171
11.604
1.00
59.51
C


ATOM
1609
CD2
LEU
A
1013
3.486
13.716
13.563
1.00
67.50
C


ATOM
1610
N
ARG
A
1014
7.004
11.381
11.021
1.00
79.98
N


ATOM
1611
CA
ARG
A
1014
8.301
10.977
11.550
1.00
75.43
C


ATOM
1612
C
ARG
A
1014
8.993
12.164
12.208
1.00
65.69
C


ATOM
1613
O
ARG
A
1014
9.090
13.238
11.615
1.00
67.46
O


ATOM
1614
CB
ARG
A
1014
9.182
10.430
10.428
1.00
78.94
C


ATOM
1615
CG
ARG
A
1014
8.720
9.103
9.853
1.00
86.38
C


ATOM
1616
CD
ARG
A
1014
9.219
7.941
10.691
1.00
97.21
C


ATOM
1617
NE
ARG
A
1014
9.348
6.721
9.899
1.00
106.77
N


ATOM
1618
CZ
ARG
A
1014
9.987
5.630
10.307
1.00
116.22
C


ATOM
1619
NH1
ARG
A
1014
10.057
4.566
9.517
1.00
120.57
N


ATOM
1620
NH2
ARG
A
1014
10.559
5.601
11.503
1.00
119.85
N


ATOM
1621
N
LEU
A
1015
9.472
11.972
13.432
1.00
60.33
N


ATOM
1622
CA
LEU
A
1015
10.158
13.041
14.149
1.00
70.48
C


ATOM
1623
C
LEU
A
1015
11.665
12.803
14.186
1.00
74.17
C


ATOM
1624
O
LEU
A
1015
12.424
13.633
14.687
1.00
78.22
O


ATOM
1625
CB
LEU
A
1015
9.593
13.198
15.562
1.00
73.22
C


ATOM
1626
CG
LEU
A
1015
8.105
13.551
15.624
1.00
69.50
C


ATOM
1627
CD1
LEU
A
1015
7.699
13.936
17.038
1.00
67.65
C


ATOM
1628
CD2
LEU
A
1015
7.781
14.673
14.651
1.00
65.05
C


ATOM
1629
N
LYS
A
1016
12.086
11.663
13.649
1.00
70.51
N


ATOM
1630
CA
LYS
A
1016
13.502
11.352
13.503
1.00
75.16
C


ATOM
1631
C
LYS
A
1016
13.825
11.125
12.031
1.00
67.66
C


ATOM
1632
O
LYS
A
1016
13.064
10.470
11.317
1.00
65.42
O


ATOM
1633
CB
LYS
A
1016
13.866
10.103
14.306
1.00
88.31
C


ATOM
1634
CG
LYS
A
1016
13.565
10.193
15.791
1.00
96.33
C


ATOM
1635
CD
LYS
A
1016
13.897
8.880
16.487
1.00
105.15
C


ATOM
1636
CE
LYS
A
1016
13.522
8.915
17.959
1.00
110.63
C


ATOM
1637
NZ
LYS
A
1016
13.792
7.611
18.627
1.00
110.59
N


ATOM
1638
N
ILE
A
1017
14.952
11.664
11.579
1.00
65.18
N


ATOM
1639
CA
ILE
A
1017
15.377
11.485
10.195
1.00
67.57
C


ATOM
1640
C
ILE
A
1017
15.390
10.006
9.815
1.00
69.53
C


ATOM
1641
O
ILE
A
1017
15.910
9.171
10.554
1.00
72.59
O


ATOM
1642
CB
ILE
A
1017
16.773
12.086
9.945
1.00
65.22
C


ATOM
1643
CG1
ILE
A
1017
16.789
13.571
10.315
1.00
71.50
C


ATOM
1644
CG2
ILE
A
1017
17.184
11.894
8.494
1.00
55.83
C


ATOM
1645
CD1
ILE
A
1017
18.071
14.281
9.938
1.00
69.99
C


ATOM
1646
N
TYR
A
1018
14.812
9.692
8.659
1.00
69.36
N


ATOM
1647
CA
TYR
A
1018
14.752
8.320
8.171
1.00
68.77
C


ATOM
1648
C
TYR
A
1018
15.037
8.285
6.674
1.00
66.91
C


ATOM
1649
O
TYR
A
1018
15.095
9.327
6.024
1.00
66.87
O


ATOM
1650
CB
TYR
A
1018
13.372
7.718
8.446
1.00
78.58
C


ATOM
1651
CG
TYR
A
1018
12.266
8.325
7.608
1.00
79.77
C


ATOM
1652
CD1
TYR
A
1018
11.863
7.732
6.419
1.00
72.41
C


ATOM
1653
CD2
TYR
A
1018
11.630
9.496
8.004
1.00
76.71
C


ATOM
1654
CE1
TYR
A
1018
10.856
8.285
5.647
1.00
72.69
C


ATOM
1655
CE2
TYR
A
1018
10.621
10.056
7.240
1.00
70.99
C


ATOM
1656
CZ
TYR
A
1018
10.238
9.447
6.063
1.00
75.69
C


ATOM
1657
OH
TYR
A
1018
9.235
10.002
5.300
1.00
76.97
O


ATOM
1658
N
LYS
A
1019
15.213
7.085
6.130
1.00
71.74
N


ATOM
1659
CA
LYS
A
1019
15.422
6.919
4.695
1.00
78.92
C


ATOM
1660
C
LYS
A
1019
14.120
6.531
4.003
1.00
80.68
C


ATOM
1661
O
LYS
A
1019
13.407
5.642
4.466
1.00
87.51
O


ATOM
1662
CB
LYS
A
1019
16.487
5.856
4.421
1.00
83.84
C


ATOM
1663
CG
LYS
A
1019
17.904
6.272
4.774
1.00
82.05
C


ATOM
1664
CD
LYS
A
1019
18.907
5.256
4.248
1.00
88.19
C


ATOM
1665
CE
LYS
A
1019
20.338
5.675
4.544
1.00
93.03
C


ATOM
1666
NZ
LYS
A
1019
21.321
4.738
3.933
1.00
90.39
N


ATOM
1667
N
ASP
A
1020
13.813
7.194
2.892
1.00
79.28
N


ATOM
1668
CA
ASP
A
1020
12.596
6.889
2.148
1.00
84.03
C


ATOM
1669
C
ASP
A
1020
12.754
5.603
1.341
1.00
95.26
C


ATOM
1670
O
ASP
A
1020
13.744
4.887
1.489
1.00
94.50
O


ATOM
1671
CB
ASP
A
1020
12.186
8.060
1.245
1.00
74.92
C


ATOM
1672
CG
ASP
A
1020
13.154
8.290
0.100
1.00
80.06
C


ATOM
1673
OD1
ASP
A
1020
14.103
7.495
−0.057
1.00
85.47
O


ATOM
1674
OD2
ASP
A
1020
12.962
9.271
−0.650
1.00
82.79
O


ATOM
1675
N
THR
A
1021
11.775
5.318
0.488
1.00
100.19
N


ATOM
1676
CA
THR
A
1021
11.778
4.091
−0.303
1.00
100.11
C


ATOM
1677
C
THR
A
1021
12.995
3.986
−1.219
1.00
98.92
C


ATOM
1678
O
THR
A
1021
13.434
2.886
−1.556
1.00
105.20
O


ATOM
1679
CB
THR
A
1021
10.497
3.967
−1.147
1.00
97.91
C


ATOM
1680
OG1
THR
A
1021
10.309
5.166
−1.910
1.00
100.68
O


ATOM
1681
CG2
THR
A
1021
9.290
3.749
−0.248
1.00
91.55
C


ATOM
1682
N
GLU
A
1022
13.538
5.131
−1.619
1.00
93.43
N


ATOM
1683
CA
GLU
A
1022
14.695
5.155
−2.507
1.00
91.02
C


ATOM
1684
C
GLU
A
1022
15.978
5.566
−1.787
1.00
90.06
C


ATOM
1685
O
GLU
A
1022
16.953
5.972
−2.420
1.00
90.21
O


ATOM
1686
CB
GLU
A
1022
14.433
6.063
−3.710
1.00
91.40
C


ATOM
1687
CG
GLU
A
1022
13.601
7.289
−3.390
1.00
99.93
C


ATOM
1688
CD
GLU
A
1022
13.022
7.933
−4.632
1.00
106.60
C


ATOM
1689
OE1
GLU
A
1022
13.657
7.838
−5.704
1.00
102.38
O


ATOM
1690
OE2
GLU
A
1022
11.930
8.532
−4.537
1.00
112.97
O


ATOM
1691
N
GLY
A
1023
15.967
5.458
−0.463
1.00
90.17
N


ATOM
1692
CA
GLY
A
1023
17.157
5.685
0.337
1.00
94.97
C


ATOM
1693
C
GLY
A
1023
17.601
7.131
0.450
1.00
94.39
C


ATOM
1694
O
GLY
A
1023
18.798
7.412
0.522
1.00
94.16
O


ATOM
1695
N
TYR
A
1024
16.641
8.050
0.466
1.00
92.80
N


ATOM
1696
CA
TYR
A
1024
16.945
9.463
0.662
1.00
85.63
C


ATOM
1697
C
TYR
A
1024
16.502
9.923
2.044
1.00
78.14
C


ATOM
1698
O
TYR
A
1024
15.406
9.593
2.495
1.00
79.69
O


ATOM
1699
CB
TYR
A
1024
16.279
10.323
−0.413
1.00
86.57
C


ATOM
1700
CG
TYR
A
1024
16.826
10.100
−1.802
1.00
94.51
C


ATOM
1701
CD1
TYR
A
1024
15.976
9.924
−2.884
1.00
99.25
C


ATOM
1702
CD2
TYR
A
1024
18.195
10.056
−2.030
1.00
100.23
C


ATOM
1703
CE1
TYR
A
1024
16.472
9.718
−4.157
1.00
105.55
C


ATOM
1704
CE2
TYR
A
1024
18.701
9.850
−3.298
1.00
106.10
C


ATOM
1705
CZ
TYR
A
1024
17.835
9.682
−4.358
1.00
109.96
C


ATOM
1706
OH
TYR
A
1024
18.335
9.476
−5.623
1.00
113.27
O


ATOM
1707
N
TYR
A
1025
17.359
10.686
2.713
1.00
72.90
N


ATOM
1708
CA
TYR
A
1025
17.050
11.174
4.050
1.00
69.83
C


ATOM
1709
C
TYR
A
1025
15.827
12.086
4.048
1.00
65.99
C


ATOM
1710
O
TYR
A
1025
15.754
13.051
3.286
1.00
60.39
O


ATOM
1711
CB
TYR
A
1025
18.263
11.873
4.664
1.00
68.72
C


ATOM
1712
CG
TYR
A
1025
19.390
10.919
4.992
1.00
71.48
C


ATOM
1713
CD1
TYR
A
1025
20.561
10.910
4.246
1.00
72.69
C


ATOM
1714
CD2
TYR
A
1025
19.274
10.017
6.041
1.00
70.08
C


ATOM
1715
CE1
TYR
A
1025
21.588
10.034
4.542
1.00
71.64
C


ATOM
1716
CE2
TYR
A
1025
20.295
9.139
6.344
1.00
72.05
C


ATOM
1717
CZ
TYR
A
1025
21.449
9.151
5.592
1.00
79.14
C


ATOM
1718
OH
TYR
A
1025
22.467
8.276
5.894
1.00
90.30
O


ATOM
1719
N
THR
A
1026
14.871
11.761
4.912
1.00
63.11
N


ATOM
1720
CA
THR
A
1026
13.581
12.436
4.953
1.00
63.07
C


ATOM
1721
C
THR
A
1026
13.149
12.624
6.402
1.00
62.42
C


ATOM
1722
O
THR
A
1026
13.626
11.920
7.291
1.00
61.41
O


ATOM
1723
CB
THR
A
1026
12.510
11.597
4.227
1.00
65.22
C


ATOM
1724
OG1
THR
A
1026
12.962
11.277
2.905
1.00
69.47
O


ATOM
1725
CG2
THR
A
1026
11.193
12.351
4.139
1.00
70.50
C


ATOM
1726
N
ILE
A
1027
12.251
13.575
6.641
1.00
67.05
N


ATOM
1727
CA
ILE
A
1027
11.686
13.761
7.975
1.00
65.98
C


ATOM
1728
C
ILE
A
1027
10.305
14.417
7.912
1.00
61.47
C


ATOM
1729
O
ILE
A
1027
9.890
14.907
6.861
1.00
54.44
O


ATOM
1730
CB
ILE
A
1027
12.628
14.573
8.892
1.00
56.72
C


ATOM
1731
CG1
ILE
A
1027
12.312
14.291
10.364
1.00
51.50
C


ATOM
1732
CG2
ILE
A
1027
12.539
16.060
8.573
1.00
45.36
C


ATOM
1733
CD1
ILE
A
1027
13.381
14.761
11.324
1.00
51.60
C


ATOM
1734
N
GLY
A
1028
9.597
14.414
9.039
1.00
57.98
N


ATOM
1735
CA
GLY
A
1028
8.250
14.952
9.099
1.00
55.26
C


ATOM
1736
C
GLY
A
1028
7.290
14.131
8.260
1.00
58.08
C


ATOM
1737
O
GLY
A
1028
7.284
12.903
8.335
1.00
67.01
O


ATOM
1738
N
ILE
A
1029
6.477
14.810
7.457
1.00
55.02
N


ATOM
1739
CA
ILE
A
1029
5.586
14.123
6.529
1.00
56.46
C


ATOM
1740
C
ILE
A
1029
6.159
14.150
5.116
1.00
54.10
C


ATOM
1741
O
ILE
A
1029
5.890
15.068
4.342
1.00
61.26
O


ATOM
1742
CB
ILE
A
1029
4.169
14.738
6.527
1.00
60.32
C


ATOM
1743
CG1
ILE
A
1029
3.541
14.634
7.918
1.00
66.95
C


ATOM
1744
CG2
ILE
A
1029
3.286
14.048
5.494
1.00
52.13
C


ATOM
1745
CD1
ILE
A
1029
2.112
15.123
7.981
1.00
71.18
C


ATOM
1746
N
GLY
A
1030
6.967
13.143
4.797
1.00
54.04
N


ATOM
1747
CA
GLY
A
1030
7.533
12.996
3.468
1.00
45.95
C


ATOM
1748
C
GLY
A
1030
8.373
14.168
2.993
1.00
53.75
C


ATOM
1749
O
GLY
A
1030
8.474
14.416
1.792
1.00
66.78
O


ATOM
1750
N
HIS
A
1031
8.983
14.888
3.930
1.00
53.64
N


ATOM
1751
CA
HIS
A
1031
9.819
16.031
3.579
1.00
62.35
C


ATOM
1752
C
HIS
A
1031
11.274
15.623
3.359
1.00
67.02
C


ATOM
1753
O
HIS
A
1031
12.033
15.457
4.315
1.00
66.73
O


ATOM
1754
CB
HIS
A
1031
9.736
17.113
4.658
1.00
67.56
C


ATOM
1755
CG
HIS
A
1031
10.494
18.359
4.321
1.00
67.34
C


ATOM
1756
ND1
HIS
A
1031
9.888
19.477
3.787
1.00
67.75
N


ATOM
1757
CD2
HIS
A
1031
11.808
18.663
4.436
1.00
65.25
C


ATOM
1758
CE1
HIS
A
1031
10.796
20.416
3.591
1.00
66.66
C


ATOM
1759
NE2
HIS
A
1031
11.969
19.948
3.978
1.00
64.71
N


ATOM
1760
N
LEU
A
1032
11.659
15.467
2.096
1.00
69.19
N


ATOM
1761
CA
LEU
A
1032
13.023
15.077
1.754
1.00
70.04
C


ATOM
1762
C
LEU
A
1032
14.023
16.187
2.071
1.00
68.84
C


ATOM
1763
O
LEU
A
1032
13.802
17.352
1.739
1.00
67.03
O


ATOM
1764
CB
LEU
A
1032
13.117
14.672
0.280
1.00
79.43
C


ATOM
1765
CG
LEU
A
1032
14.511
14.366
−0.278
1.00
86.39
C


ATOM
1766
CD1
LEU
A
1032
14.444
13.291
−1.352
1.00
90.55
C


ATOM
1767
CD2
LEU
A
1032
15.178
15.627
−0.815
1.00
85.41
C


ATOM
1768
N
LEU
A
1033
15.124
15.813
2.714
1.00
65.64
N


ATOM
1769
CA
LEU
A
1033
16.146
16.773
3.114
1.00
65.91
C


ATOM
1770
C
LEU
A
1033
17.253
16.896
2.072
1.00
71.02
C


ATOM
1771
O
LEU
A
1033
17.614
18.000
1.668
1.00
76.14
O


ATOM
1772
CB
LEU
A
1033
16.739
16.381
4.468
1.00
63.46
C


ATOM
1773
CG
LEU
A
1033
15.787
16.482
5.661
1.00
60.37
C


ATOM
1774
CD1
LEU
A
1033
16.412
15.872
6.904
1.00
60.73
C


ATOM
1775
CD2
LEU
A
1033
15.403
17.932
5.909
1.00
65.47
C


ATOM
1776
N
THR
A
1034
17.788
15.758
1.642
1.00
71.63
N


ATOM
1777
CA
THR
A
1034
18.877
15.744
0.672
1.00
68.38
C


ATOM
1778
C
THR
A
1034
19.046
14.362
0.050
1.00
69.57
C


ATOM
1779
O
THR
A
1034
18.684
13.350
0.651
1.00
62.66
O


ATOM
1780
CB
THR
A
1034
20.212
16.173
1.318
1.00
66.96
C


ATOM
1781
OG1
THR
A
1034
21.254
16.159
0.334
1.00
64.01
O


ATOM
1782
CG2
THR
A
1034
20.583
15.231
2.454
1.00
56.21
C


ATOM
1783
N
LYS
A
1035
19.599
14.328
−1.158
1.00
77.67
N


ATOM
1784
CA
LYS
A
1035
19.866
13.070
−1.846
1.00
73.48
C


ATOM
1785
C
LYS
A
1035
21.298
12.615
−1.593
1.00
61.50
C


ATOM
1786
O
LYS
A
1035
21.736
11.589
−2.111
1.00
60.21
O


ATOM
1787
CB
LYS
A
1035
19.611
13.219
−3.346
1.00
77.83
C


ATOM
1788
CG
LYS
A
1035
18.138
13.248
−3.722
1.00
85.90
C


ATOM
1789
CD
LYS
A
1035
17.893
14.172
−4.901
1.00
92.99
C


ATOM
1790
CE
LYS
A
1035
18.228
15.611
−4.534
1.00
99.27
C


ATOM
1791
NZ
LYS
A
1035
18.022
16.546
−5.674
1.00
100.21
N


ATOM
1792
N
SER
A
1036
22.022
13.389
−0.791
1.00
58.80
N


ATOM
1793
CA
SER
A
1036
23.392
13.056
−0.428
1.00
65.52
C


ATOM
1794
C
SER
A
1036
23.420
11.855
0.511
1.00
74.00
C


ATOM
1795
O
SER
A
1036
22.556
11.720
1.377
1.00
81.62
O


ATOM
1796
CB
SER
A
1036
24.076
14.255
0.230
1.00
71.90
C


ATOM
1797
OG
SER
A
1036
25.359
13.907
0.716
1.00
80.84
O


ATOM
1798
N
PRO
A
1037
24.420
10.978
0.340
1.00
74.48
N


ATOM
1799
CA
PRO
A
1037
24.557
9.743
1.120
1.00
72.50
C


ATOM
1800
C
PRO
A
1037
25.121
10.003
2.512
1.00
76.82
C


ATOM
1801
O
PRO
A
1037
25.831
9.155
3.051
1.00
84.85
O


ATOM
1802
CB
PRO
A
1037
25.569
8.921
0.306
1.00
64.80
C


ATOM
1803
CG
PRO
A
1037
25.774
9.674
−0.983
1.00
65.29
C


ATOM
1804
CD
PRO
A
1037
25.472
11.095
−0.679
1.00
67.78
C


ATOM
1805
N
SER
A
1038
24.809
11.160
3.084
1.00
72.80
N


ATOM
1806
CA
SER
A
1038
25.357
11.531
4.383
1.00
68.55
C


ATOM
1807
C
SER
A
1038
24.282
11.962
5.374
1.00
67.20
C


ATOM
1808
O
SER
A
1038
23.650
13.005
5.205
1.00
68.75
O


ATOM
1809
CB
SER
A
1038
26.395
12.645
4.224
1.00
70.73
C


ATOM
1810
OG
SER
A
1038
26.754
13.188
5.483
1.00
69.18
O


ATOM
1811
N
LEU
A
1039
24.085
11.153
6.410
1.00
60.38
N


ATOM
1812
CA
LEU
A
1039
23.189
11.510
7.500
1.00
59.67
C


ATOM
1813
C
LEU
A
1039
23.616
12.848
8.094
1.00
63.11
C


ATOM
1814
O
LEU
A
1039
22.782
13.689
8.430
1.00
66.11
O


ATOM
1815
CB
LEU
A
1039
23.210
10.429
8.579
1.00
57.26
C


ATOM
1816
CG
LEU
A
1039
22.373
10.705
9.828
1.00
64.93
C


ATOM
1817
CD1
LEU
A
1039
20.894
10.777
9.475
1.00
65.26
C


ATOM
1818
CD2
LEU
A
1039
22.625
9.642
10.886
1.00
66.58
C


ATOM
1819
N
ASN
A
1040
24.927
13.029
8.218
1.00
68.07
N


ATOM
1820
CA
ASN
A
1040
25.503
14.274
8.709
1.00
66.58
C


ATOM
1821
C
ASN
A
1040
25.013
15.469
7.898
1.00
65.15
C


ATOM
1822
O
ASN
A
1040
24.574
16.474
8.457
1.00
64.58
O


ATOM
1823
CB
ASN
A
1040
27.033
14.194
8.670
1.00
69.42
C


ATOM
1824
CG
ASN
A
1040
27.702
15.453
9.188
1.00
67.67
C


ATOM
1825
OD1
ASN
A
1040
27.055
16.316
9.779
1.00
69.99
O


ATOM
1826
ND2
ASN
A
1040
29.008
15.562
8.967
1.00
68.91
N


ATOM
1827
N
ALA
A
1041
25.086
15.349
6.575
1.00
68.84
N


ATOM
1828
CA
ALA
A
1041
24.627
16.406
5.680
1.00
71.51
C


ATOM
1829
C
ALA
A
1041
23.125
16.636
5.822
1.00
73.67
C


ATOM
1830
O
ALA
A
1041
22.658
17.775
5.815
1.00
76.45
O


ATOM
1831
CB
ALA
A
1041
24.979
16.072
4.238
1.00
68.72
C


ATOM
1832
N
ALA
A
1042
22.374
15.546
5.950
1.00
69.30
N


ATOM
1833
CA
ALA
A
1042
20.929
15.627
6.122
1.00
67.49
C


ATOM
1834
C
ALA
A
1042
20.571
16.427
7.369
1.00
66.07
C


ATOM
1835
O
ALA
A
1042
19.672
17.267
7.340
1.00
62.31
O


ATOM
1836
CB
ALA
A
1042
20.324
14.235
6.196
1.00
66.75
C


ATOM
1837
N
LYS
A
1043
21.279
16.163
8.462
1.00
58.42
N


ATOM
1838
CA
LYS
A
1043
21.016
16.849
9.721
1.00
64.00
C


ATOM
1839
C
LYS
A
1043
21.312
18.344
9.620
1.00
65.56
C


ATOM
1840
O
LYS
A
1043
20.650
19.162
10.257
1.00
66.25
O


ATOM
1841
CB
LYS
A
1043
21.833
16.228
10.855
1.00
63.36
C


ATOM
1842
CG
LYS
A
1043
21.459
14.797
11.201
1.00
63.17
C


ATOM
1843
CD
LYS
A
1043
22.234
14.314
12.416
1.00
67.07
C


ATOM
1844
CE
LYS
A
1043
21.892
12.874
12.761
1.00
73.16
C


ATOM
1845
NZ
LYS
A
1043
22.570
12.424
14.009
1.00
71.24
N


ATOM
1846
N
SER
A
1044
22.311
18.694
8.817
1.00
66.30
N


ATOM
1847
CA
SER
A
1044
22.686
20.090
8.631
1.00
65.13
C


ATOM
1848
C
SER
A
1044
21.609
20.826
7.846
1.00
70.13
C


ATOM
1849
O
SER
A
1044
21.309
21.986
8.123
1.00
74.77
O


ATOM
1850
CB
SER
A
1044
24.032
20.195
7.914
1.00
69.62
C


ATOM
1851
OG
SER
A
1044
25.024
19.434
8.583
1.00
72.49
O


ATOM
1852
N
GLU
A
1045
21.034
20.141
6.862
1.00
71.24
N


ATOM
1853
CA
GLU
A
1045
19.923
20.693
6.098
1.00
74.35
C


ATOM
1854
C
GLU
A
1045
18.726
20.927
7.010
1.00
69.93
C


ATOM
1855
O
GLU
A
1045
18.011
21.920
6.874
1.00
67.44
O


ATOM
1856
CB
GLU
A
1045
19.534
19.748
4.958
1.00
77.46
C


ATOM
1857
CG
GLU
A
1045
20.571
19.640
3.854
1.00
79.90
C


ATOM
1858
CD
GLU
A
1045
20.689
20.914
3.038
1.00
82.50
C


ATOM
1859
OE1
GLU
A
1045
19.785
21.769
3.135
1.00
85.49
O


ATOM
1860
OE2
GLU
A
1045
21.684
21.057
2.297
1.00
83.20
O


ATOM
1861
N
LEU
A
1046
18.518
20.005
7.944
1.00
68.76
N


ATOM
1862
CA
LEU
A
1046
17.402
20.091
8.877
1.00
72.48
C


ATOM
1863
C
LEU
A
1046
17.539
21.304
9.793
1.00
69.88
C


ATOM
1864
O
LEU
A
1046
16.583
22.052
9.990
1.00
65.23
O


ATOM
1865
CB
LEU
A
1046
17.302
18.809
9.708
1.00
78.23
C


ATOM
1866
CG
LEU
A
1046
16.103
18.686
10.652
1.00
73.85
C


ATOM
1867
CD1
LEU
A
1046
14.797
18.812
9.883
1.00
70.02
C


ATOM
1868
CD2
LEU
A
1046
16.155
17.370
11.411
1.00
73.33
C


ATOM
1869
N
ASP
A
1047
18.734
21.494
10.346
1.00
66.78
N


ATOM
1870
CA
ASP
A
1047
18.993
22.615
11.243
1.00
69.47
C


ATOM
1871
C
ASP
A
1047
18.819
23.960
10.540
1.00
76.57
C


ATOM
1872
O
ASP
A
1047
18.485
24.963
11.172
1.00
78.82
O


ATOM
1873
CB
ASP
A
1047
20.397
22.510
11.842
1.00
75.25
C


ATOM
1874
CG
ASP
A
1047
20.536
21.343
12.799
1.00
83.59
C


ATOM
1875
OD1
ASP
A
1047
19.553
20.590
12.966
1.00
87.38
O


ATOM
1876
OD2
ASP
A
1047
21.627
21.180
13.387
1.00
78.59
O


ATOM
1877
N
LYS
A
1048
19.048
23.974
9.231
1.00
73.83
N


ATOM
1878
CA
LYS
A
1048
18.880
25.186
8.438
1.00
76.01
C


ATOM
1879
C
LYS
A
1048
17.403
25.538
8.288
1.00
80.45
C


ATOM
1880
O
LYS
A
1048
17.022
26.707
8.355
1.00
80.97
O


ATOM
1881
CB
LYS
A
1048
19.523
25.014
7.060
1.00
83.10
C


ATOM
1882
CG
LYS
A
1048
19.306
26.190
6.121
1.00
93.96
C


ATOM
1883
CD
LYS
A
1048
19.865
25.899
4.737
1.00
102.83
C


ATOM
1884
CE
LYS
A
1048
19.643
27.069
3.790
1.00
107.02
C


ATOM
1885
NZ
LYS
A
1048
20.187
26.792
2.431
1.00
109.15
N


ATOM
1886
N
ALA
A
1049
16.574
24.518
8.090
1.00
79.94
N


ATOM
1887
CA
ALA
A
1049
15.140
24.716
7.902
1.00
69.83
C


ATOM
1888
C
ALA
A
1049
14.427
25.015
9.218
1.00
69.42
C


ATOM
1889
O
ALA
A
1049
13.528
25.853
9.269
1.00
60.97
O


ATOM
1890
CB
ALA
A
1049
14.523
23.498
7.229
1.00
61.47
C


ATOM
1891
N
ILE
A
1050
14.831
24.325
10.280
1.00
74.66
N


ATOM
1892
CA
ILE
A
1050
14.196
24.488
11.583
1.00
80.09
C


ATOM
1893
C
ILE
A
1050
14.699
25.736
12.303
1.00
88.48
C


ATOM
1894
O
ILE
A
1050
13.936
26.423
12.982
1.00
96.01
O


ATOM
1895
CB
ILE
A
1050
14.425
23.257
12.481
1.00
77.76
C


ATOM
1896
CG1
ILE
A
1050
14.083
21.971
11.726
1.00
70.73
C


ATOM
1897
CG2
ILE
A
1050
13.603
23.369
13.758
1.00
77.51
C


ATOM
1898
CD1
ILE
A
1050
12.640
21.884
11.284
1.00
60.96
C


ATOM
1899
N
GLY
A
1051
15.987
26.025
12.152
1.00
88.61
N


ATOM
1900
CA
GLY
A
1051
16.583
27.187
12.784
1.00
87.42
C


ATOM
1901
C
GLY
A
1051
17.140
26.887
14.163
1.00
86.47
C


ATOM
1902
O
GLY
A
1051
17.148
27.751
15.041
1.00
86.08
O


ATOM
1903
N
ARG
A
1052
17.606
25.656
14.353
1.00
79.96
N


ATOM
1904
CA
ARG
A
1052
18.213
25.251
15.615
1.00
79.05
C


ATOM
1905
C
ARG
A
1052
18.925
23.912
15.472
1.00
78.75
C


ATOM
1906
O
ARG
A
1052
18.735
23.197
14.490
1.00
85.14
O


ATOM
1907
CB
ARG
A
1052
17.157
25.147
16.716
1.00
73.95
C


ATOM
1908
CG
ARG
A
1052
16.327
23.874
16.653
1.00
66.70
C


ATOM
1909
CD
ARG
A
1052
15.555
23.652
17.944
1.00
64.28
C


ATOM
1910
NE
ARG
A
1052
14.650
22.509
17.850
1.00
68.44
N


ATOM
1911
CZ
ARG
A
1052
14.977
21.265
18.186
1.00
77.48
C


ATOM
1912
NH1
ARG
A
1052
16.194
20.997
18.641
1.00
82.58
N


ATOM
1913
NH2
ARG
A
1052
14.088
20.289
18.066
1.00
75.98
N


ATOM
1914
N
ASN
A
1053
19.746
23.578
16.462
1.00
73.30
N


ATOM
1915
CA
ASN
A
1053
20.421
22.289
16.494
1.00
77.68
C


ATOM
1916
C
ASN
A
1053
19.455
21.184
16.906
1.00
83.86
C


ATOM
1917
O
ASN
A
1053
19.102
21.062
18.079
1.00
89.66
O


ATOM
1918
CB
ASN
A
1053
21.606
22.334
17.457
1.00
84.67
C


ATOM
1919
CG
ASN
A
1053
22.454
21.083
17.393
1.00
95.60
C


ATOM
1920
OD1
ASN
A
1053
22.977
20.728
16.335
1.00
103.08
O


ATOM
1921
ND2
ASN
A
1053
22.602
20.407
18.527
1.00
93.66
N


ATOM
1922
N
THR
A
1054
19.032
20.379
15.937
1.00
82.14
N


ATOM
1923
CA
THR
A
1054
18.020
19.355
16.176
1.00
74.70
C


ATOM
1924
C
THR
A
1054
18.623
18.013
16.574
1.00
70.81
C


ATOM
1925
O
THR
A
1054
17.989
17.225
17.276
1.00
76.52
O


ATOM
1926
CB
THR
A
1054
17.139
19.139
14.931
1.00
72.46
C


ATOM
1927
OG1
THR
A
1054
17.929
18.576
13.875
1.00
78.51
O


ATOM
1928
CG2
THR
A
1054
16.538
20.458
14.466
1.00
65.15
C


ATOM
1929
N
ASN
A
1055
19.845
17.756
16.117
1.00
71.05
N


ATOM
1930
CA
ASN
A
1055
20.501
16.474
16.353
1.00
78.59
C


ATOM
1931
C
ASN
A
1055
19.770
15.327
15.661
1.00
72.00
C


ATOM
1932
O
ASN
A
1055
19.958
14.161
16.004
1.00
72.01
O


ATOM
1933
CB
ASN
A
1055
20.635
16.194
17.853
1.00
91.78
C


ATOM
1934
CG
ASN
A
1055
21.533
17.195
18.557
1.00
94.50
C


ATOM
1935
OD1
ASN
A
1055
22.476
17.722
17.968
1.00
88.19
O


ATOM
1936
ND2
ASN
A
1055
21.246
17.458
19.827
1.00
97.32
N


ATOM
1937
N
GLY
A
1056
18.934
15.670
14.685
1.00
79.23
N


ATOM
1938
CA
GLY
A
1056
18.203
14.680
13.915
1.00
77.94
C


ATOM
1939
C
GLY
A
1056
16.801
14.417
14.432
1.00
76.68
C


ATOM
1940
O
GLY
A
1056
16.134
13.484
13.985
1.00
78.26
O


ATOM
1941
N
VAL
A
1057
16.351
15.242
15.373
1.00
73.54
N


ATOM
1942
CA
VAL
A
1057
15.035
15.065
15.981
1.00
71.81
C


ATOM
1943
C
VAL
A
1057
14.295
16.390
16.142
1.00
74.80
C


ATOM
1944
O
VAL
A
1057
14.836
17.354
16.684
1.00
72.84
O


ATOM
1945
CB
VAL
A
1057
15.140
14.381
17.359
1.00
74.93
C


ATOM
1946
CG1
VAL
A
1057
13.798
14.412
18.074
1.00
75.20
C


ATOM
1947
CG2
VAL
A
1057
15.641
12.952
17.207
1.00
77.14
C


ATOM
1948
N
ILE
A
1058
13.053
16.429
15.669
1.00
78.97
N


ATOM
1949
CA
ILE
A
1058
12.223
17.624
15.782
1.00
78.10
C


ATOM
1950
C
ILE
A
1058
10.928
17.330
16.535
1.00
66.57
C


ATOM
1951
O
ILE
A
1058
10.592
16.171
16.784
1.00
60.95
O


ATOM
1952
CB
ILE
A
1058
11.877
18.202
14.397
1.00
77.66
C


ATOM
1953
CG1
ILE
A
1058
11.229
17.128
13.520
1.00
72.84
C


ATOM
1954
CG2
ILE
A
1058
13.123
18.758
13.725
1.00
72.77
C


ATOM
1955
CD1
ILE
A
1058
10.750
17.639
12.178
1.00
61.77
C


ATOM
1956
N
THR
A
1059
10.203
18.383
16.898
1.00
58.60
N


ATOM
1957
CA
THR
A
1059
8.926
18.227
17.586
1.00
62.26
C


ATOM
1958
C
THR
A
1059
7.780
18.129
16.586
1.00
64.79
C


ATOM
1959
O
THR
A
1059
7.954
18.415
15.401
1.00
64.65
O


ATOM
1960
CB
THR
A
1059
8.650
19.395
18.552
1.00
69.44
C


ATOM
1961
OG1
THR
A
1059
8.545
20.618
17.812
1.00
73.51
O


ATOM
1962
CG2
THR
A
1059
9.770
19.518
19.572
1.00
72.03
C


ATOM
1963
N
LYS
A
1060
6.611
17.717
17.067
1.00
70.45
N


ATOM
1964
CA
LYS
A
1060
5.428
17.637
16.219
1.00
66.59
C


ATOM
1965
C
LYS
A
1060
5.152
18.986
15.576
1.00
66.61
C


ATOM
1966
O
LYS
A
1060
4.941
19.081
14.367
1.00
70.77
O


ATOM
1967
CB
LYS
A
1060
4.208
17.200
17.028
1.00
72.87
C


ATOM
1968
CG
LYS
A
1060
2.888
17.594
16.383
1.00
80.24
C


ATOM
1969
CD
LYS
A
1060
1.711
17.355
17.310
1.00
85.69
C


ATOM
1970
CE
LYS
A
1060
0.509
18.178
16.880
1.00
86.21
C


ATOM
1971
NZ
LYS
A
1060
0.251
18.057
15.419
1.00
86.92
N


ATOM
1972
N
ASP
A
1061
5.155
20.029
16.399
1.00
67.98
N


ATOM
1973
CA
ASP
A
1061
4.915
21.385
15.927
1.00
73.37
C


ATOM
1974
C
ASP
A
1061
5.832
21.731
14.760
1.00
68.27
C


ATOM
1975
O
ASP
A
1061
5.371
22.189
13.715
1.00
66.95
O


ATOM
1976
CB
ASP
A
1061
5.111
22.383
17.071
1.00
88.29
C


ATOM
1977
CG
ASP
A
1061
4.756
23.806
16.677
1.00
101.24
C


ATOM
1978
OD1
ASP
A
1061
5.065
24.212
15.537
1.00
107.74
O


ATOM
1979
OD2
ASP
A
1061
4.172
24.523
17.515
1.00
102.03
O


ATOM
1980
N
GLU
A
1062
7.131
21.507
14.942
1.00
75.41
N


ATOM
1981
CA
GLU
A
1062
8.120
21.839
13.921
1.00
79.87
C


ATOM
1982
C
GLU
A
1062
7.898
21.064
12.626
1.00
74.97
C


ATOM
1983
O
GLU
A
1062
8.163
21.574
11.536
1.00
74.35
O


ATOM
1984
CB
GLU
A
1062
9.536
21.600
14.448
1.00
81.59
C


ATOM
1985
CG
GLU
A
1062
9.965
22.588
15.518
1.00
85.62
C


ATOM
1986
CD
GLU
A
1062
11.292
22.222
16.150
1.00
84.49
C


ATOM
1987
OE1
GLU
A
1062
11.628
21.019
16.177
1.00
86.95
O


ATOM
1988
OE2
GLU
A
1062
11.996
23.137
16.626
1.00
77.53
O


ATOM
1989
N
ALA
A
1063
7.415
19.832
12.749
1.00
64.21
N


ATOM
1990
CA
ALA
A
1063
7.103
19.018
11.581
1.00
65.21
C


ATOM
1991
C
ALA
A
1063
5.929
19.620
10.819
1.00
69.70
C


ATOM
1992
O
ALA
A
1063
5.836
19.493
9.598
1.00
68.56
O


ATOM
1993
CB
ALA
A
1063
6.793
17.587
11.993
1.00
54.62
C


ATOM
1994
N
GLU
A
1064
5.036
20.282
11.549
1.00
66.00
N


ATOM
1995
CA
GLU
A
1064
3.866
20.908
10.949
1.00
69.72
C


ATOM
1996
C
GLU
A
1064
4.249
22.151
10.154
1.00
73.69
C


ATOM
1997
O
GLU
A
1064
3.717
22.392
9.070
1.00
85.44
O


ATOM
1998
CB
GLU
A
1064
2.831
21.258
12.019
1.00
74.07
C


ATOM
1999
CG
GLU
A
1064
1.489
21.702
11.459
1.00
81.92
C


ATOM
2000
CD
GLU
A
1064
0.378
21.647
12.489
1.00
88.62
C


ATOM
2001
OE1
GLU
A
1064
0.688
21.554
13.697
1.00
88.82
O


ATOM
2002
OE2
GLU
A
1064
−0.806
21.694
12.092
1.00
87.09
O


ATOM
2003
N
LYS
A
1065
5.173
22.939
10.693
1.00
64.49
N


ATOM
2004
CA
LYS
A
1065
5.652
24.129
9.998
1.00
64.57
C


ATOM
2005
C
LYS
A
1065
6.322
23.770
8.675
1.00
68.05
C


ATOM
2006
O
LYS
A
1065
6.155
24.471
7.678
1.00
70.67
O


ATOM
2007
CB
LYS
A
1065
6.596
24.942
10.886
1.00
73.97
C


ATOM
2008
CG
LYS
A
1065
5.874
25.898
11.824
1.00
85.47
C


ATOM
2009
CD
LYS
A
1065
6.833
26.606
12.768
1.00
94.02
C


ATOM
2010
CE
LYS
A
1065
7.287
25.686
13.889
1.00
99.46
C


ATOM
2011
NZ
LYS
A
1065
8.041
26.424
14.941
1.00
102.10
N


ATOM
2012
N
LEU
A
1066
7.075
22.675
8.665
1.00
70.04
N


ATOM
2013
CA
LEU
A
1066
7.685
22.191
7.432
1.00
66.35
C


ATOM
2014
C
LEU
A
1066
6.611
21.771
6.434
1.00
63.34
C


ATOM
2015
O
LEU
A
1066
6.706
22.066
5.244
1.00
62.98
O


ATOM
2016
CB
LEU
A
1066
8.625
21.018
7.713
1.00
74.11
C


ATOM
2017
CG
LEU
A
1066
10.007
21.351
8.276
1.00
76.06
C


ATOM
2018
CD1
LEU
A
1066
10.738
20.079
8.678
1.00
76.86
C


ATOM
2019
CD2
LEU
A
1066
10.820
22.147
7.265
1.00
71.32
C


ATOM
2020
N
PHE
A
1067
5.588
21.083
6.931
1.00
66.17
N


ATOM
2021
CA
PHE
A
1067
4.493
20.622
6.085
1.00
65.88
C


ATOM
2022
C
PHE
A
1067
3.721
21.793
5.485
1.00
62.56
C


ATOM
2023
O
PHE
A
1067
3.364
21.774
4.306
1.00
63.34
O


ATOM
2024
CB
PHE
A
1067
3.547
19.712
6.873
1.00
68.68
C


ATOM
2025
CG
PHE
A
1067
2.373
19.224
6.073
1.00
69.93
C


ATOM
2026
CD1
PHE
A
1067
2.497
18.129
5.234
1.00
70.67
C


ATOM
2027
CD2
PHE
A
1067
1.145
19.862
6.159
1.00
71.48
C


ATOM
2028
CE1
PHE
A
1067
1.419
17.678
4.494
1.00
67.93
C


ATOM
2029
CE2
PHE
A
1067
0.063
19.415
5.422
1.00
73.70
C


ATOM
2030
CZ
PHE
A
1067
0.200
18.322
4.589
1.00
68.07
C


ATOM
2031
N
ASN
A
1068
3.465
22.812
6.299
1.00
64.04
N


ATOM
2032
CA
ASN
A
1068
2.779
24.008
5.822
1.00
66.05
C


ATOM
2033
C
ASN
A
1068
3.508
24.641
4.644
1.00
66.08
C


ATOM
2034
O
ASN
A
1068
2.891
24.993
3.638
1.00
71.39
O


ATOM
2035
CB
ASN
A
1068
2.606
25.024
6.952
1.00
71.52
C


ATOM
2036
CG
ASN
A
1068
1.512
24.632
7.922
1.00
78.35
C


ATOM
2037
OD1
ASN
A
1068
0.908
23.565
7.797
1.00
76.98
O


ATOM
2038
ND2
ASN
A
1068
1.247
25.495
8.897
1.00
80.57
N


ATOM
2039
N
GLN
A
1069
4.824
24.779
4.773
1.00
68.06
N


ATOM
2040
CA
GLN
A
1069
5.655
25.292
3.690
1.00
70.50
C


ATOM
2041
C
GLN
A
1069
5.510
24.442
2.431
1.00
66.20
C


ATOM
2042
O
GLN
A
1069
5.408
24.971
1.324
1.00
68.34
O


ATOM
2043
CB
GLN
A
1069
7.123
25.353
4.121
1.00
87.72
C


ATOM
2044
CG
GLN
A
1069
7.618
26.746
4.498
1.00
105.25
C


ATOM
2045
CD
GLN
A
1069
6.863
27.357
5.664
1.00
118.67
C


ATOM
2046
OE1
GLN
A
1069
6.164
26.663
6.401
1.00
125.68
O


ATOM
2047
NE2
GLN
A
1069
7.006
28.666
5.839
1.00
120.47
N


ATOM
2048
N
ASP
A
1070
5.500
23.124
2.606
1.00
63.34
N


ATOM
2049
CA
ASP
A
1070
5.362
22.201
1.484
1.00
61.95
C


ATOM
2050
C
ASP
A
1070
4.026
22.376
0.770
1.00
61.58
C


ATOM
2051
O
ASP
A
1070
3.944
22.246
−0.450
1.00
65.02
O


ATOM
2052
CB
ASP
A
1070
5.519
20.753
1.951
1.00
67.85
C


ATOM
2053
CG
ASP
A
1070
6.966
20.376
2.207
1.00
71.24
C


ATOM
2054
OD1
ASP
A
1070
7.839
21.264
2.112
1.00
66.70
O


ATOM
2055
OD2
ASP
A
1070
7.229
19.190
2.499
1.00
75.17
O


ATOM
2056
N
VAL
A
1071
2.980
22.665
1.536
1.00
61.41
N


ATOM
2057
CA
VAL
A
1071
1.657
22.875
0.964
1.00
56.84
C


ATOM
2058
C
VAL
A
1071
1.626
24.149
0.128
1.00
58.17
C


ATOM
2059
O
VAL
A
1071
1.147
24.146
−1.006
1.00
58.46
O


ATOM
2060
CB
VAL
A
1071
0.572
22.953
2.056
1.00
62.46
C


ATOM
2061
CG1
VAL
A
1071
−0.742
23.436
1.465
1.00
67.79
C


ATOM
2062
CG2
VAL
A
1071
0.395
21.599
2.723
1.00
55.46
C


ATOM
2063
N
ASP
A
1072
2.145
25.235
0.694
1.00
63.22
N


ATOM
2064
CA
ASP
A
1072
2.189
26.519
0.002
1.00
63.71
C


ATOM
2065
C
ASP
A
1072
2.844
26.391
−1.368
1.00
69.86
C


ATOM
2066
O
ASP
A
1072
2.357
26.946
−2.354
1.00
78.53
O


ATOM
2067
CB
ASP
A
1072
2.935
27.558
0.841
1.00
65.50
C


ATOM
2068
CG
ASP
A
1072
2.155
27.985
2.068
1.00
74.41
C


ATOM
2069
OD1
ASP
A
1072
1.000
27.536
2.226
1.00
78.58
O


ATOM
2070
OD2
ASP
A
1072
2.697
28.772
2.873
1.00
79.03
O


ATOM
2071
N
ALA
A
1073
3.951
25.657
−1.422
1.00
62.49
N


ATOM
2072
CA
ALA
A
1073
4.676
25.457
−2.670
1.00
65.69
C


ATOM
2073
C
ALA
A
1073
3.828
24.697
−3.683
1.00
70.18
C


ATOM
2074
O
ALA
A
1073
3.760
25.072
−4.854
1.00
77.10
O


ATOM
2075
CB
ALA
A
1073
5.982
24.722
−2.411
1.00
66.04
C


ATOM
2076
N
ALA
A
1074
3.182
23.629
−3.224
1.00
64.77
N


ATOM
2077
CA
ALA
A
1074
2.332
22.815
−4.085
1.00
58.33
C


ATOM
2078
C
ALA
A
1074
1.184
23.637
−4.661
1.00
58.51
C


ATOM
2079
O
ALA
A
1074
0.842
23.506
−5.835
1.00
52.13
O


ATOM
2080
CB
ALA
A
1074
1.797
21.615
−3.318
1.00
60.57
C


ATOM
2081
N
VAL
A
1075
0.592
24.483
−3.825
1.00
65.54
N


ATOM
2082
CA
VAL
A
1075
−0.501
25.343
−4.259
1.00
65.91
C


ATOM
2083
C
VAL
A
1075
−0.025
26.311
−5.337
1.00
66.58
C


ATOM
2084
O
VAL
A
1075
−0.728
26.555
−6.319
1.00
69.82
O


ATOM
2085
CB
VAL
A
1075
−1.105
26.135
−3.082
1.00
63.54
C


ATOM
2086
CG1
VAL
A
1075
−2.136
27.132
−3.583
1.00
59.94
C


ATOM
2087
CG2
VAL
A
1075
−1.725
25.186
−2.069
1.00
57.71
C


ATOM
2088
N
ARG
A
1076
1.173
26.857
−5.152
1.00
60.22
N


ATOM
2089
CA
ARG
A
1076
1.758
27.757
−6.140
1.00
59.77
C


ATOM
2090
C
ARG
A
1076
2.010
27.038
−7.463
1.00
61.59
C


ATOM
2091
O
ARG
A
1076
1.793
27.601
−8.537
1.00
60.13
O


ATOM
2092
CB
ARG
A
1076
3.049
28.387
−5.611
1.00
65.41
C


ATOM
2093
CG
ARG
A
1076
2.817
29.650
−4.795
1.00
76.36
C


ATOM
2094
CD
ARG
A
1076
4.118
30.364
−4.455
1.00
79.99
C


ATOM
2095
NE
ARG
A
1076
4.744
29.837
−3.245
1.00
86.97
N


ATOM
2096
CZ
ARG
A
1076
5.820
29.057
−3.237
1.00
81.16
C


ATOM
2097
NH1
ARG
A
1076
6.398
28.713
−4.379
1.00
81.38
N


ATOM
2098
NH2
ARG
A
1076
6.320
28.626
−2.087
1.00
67.17
N


ATOM
2099
N
GLY
A
1077
2.463
25.792
−7.379
1.00
60.84
N


ATOM
2100
CA
GLY
A
1077
2.676
24.986
−8.565
1.00
56.43
C


ATOM
2101
C
GLY
A
1077
1.369
24.720
−9.286
1.00
55.73
C


ATOM
2102
O
GLY
A
1077
1.301
24.771
−10.514
1.00
58.21
O


ATOM
2103
N
ILE
A
1078
0.326
24.436
−8.514
1.00
54.99
N


ATOM
2104
CA
ILE
A
1078
−0.992
24.161
−9.071
1.00
62.60
C


ATOM
2105
C
ILE
A
1078
−1.557
25.370
−9.811
1.00
60.35
C


ATOM
2106
O
ILE
A
1078
−2.206
25.228
−10.848
1.00
63.52
O


ATOM
2107
CB
ILE
A
1078
−1.984
23.728
−7.974
1.00
63.43
C


ATOM
2108
CG1
ILE
A
1078
−1.637
22.324
−7.471
1.00
69.61
C


ATOM
2109
CG2
ILE
A
1078
−3.413
23.774
−8.497
1.00
49.86
C


ATOM
2110
CD1
ILE
A
1078
−2.514
21.847
−6.332
1.00
72.57
C


ATOM
2111
N
LEU
A
1079
−1.299
26.560
−9.277
1.00
55.01
N


ATOM
2112
CA
LEU
A
1079
−1.830
27.789
−9.857
1.00
55.86
C


ATOM
2113
C
LEU
A
1079
−1.100
28.216
−11.130
1.00
64.61
C


ATOM
2114
O
LEU
A
1079
−1.632
28.989
−11.925
1.00
78.56
O


ATOM
2115
CB
LEU
A
1079
−1.813
28.917
−8.824
1.00
53.25
C


ATOM
2116
CG
LEU
A
1079
−2.824
28.754
−7.687
1.00
61.68
C


ATOM
2117
CD1
LEU
A
1079
−2.551
29.741
−6.563
1.00
57.50
C


ATOM
2118
CD2
LEU
A
1079
−4.246
28.904
−8.211
1.00
59.69
C


ATOM
2119
N
ARG
A
1080
0.116
27.711
−11.321
1.00
61.54
N


ATOM
2120
CA
ARG
A
1080
0.877
27.998
−12.534
1.00
58.97
C


ATOM
2121
C
ARG
A
1080
0.452
27.082
−13.680
1.00
66.91
C


ATOM
2122
O
ARG
A
1080
0.714
27.370
−14.849
1.00
63.24
O


ATOM
2123
CB
ARG
A
1080
2.380
27.850
−12.282
1.00
55.15
C


ATOM
2124
CG
ARG
A
1080
2.951
28.843
−11.285
1.00
66.50
C


ATOM
2125
CD
ARG
A
1080
4.472
28.797
−11.279
1.00
78.98
C


ATOM
2126
NE
ARG
A
1080
4.986
27.528
−10.772
1.00
91.02
N


ATOM
2127
CZ
ARG
A
1080
5.436
27.345
−9.535
1.00
92.75
C


ATOM
2128
NH1
ARG
A
1080
5.442
28.352
−8.672
1.00
85.53
N


ATOM
2129
NH2
ARG
A
1080
5.885
26.155
−9.159
1.00
95.14
N


ATOM
2130
N
ASN
A
1081
−0.200
25.976
−13.339
1.00
68.55
N


ATOM
2131
CA
ASN
A
1081
−0.651
25.021
−14.343
1.00
67.01
C


ATOM
2132
C
ASN
A
1081
−2.013
25.402
−14.917
1.00
68.88
C


ATOM
2133
O
ASN
A
1081
−2.981
25.586
−14.178
1.00
67.22
O


ATOM
2134
CB
ASN
A
1081
−0.681
23.606
−13.764
1.00
61.04
C


ATOM
2135
CG
ASN
A
1081
−0.871
22.547
−14.828
1.00
62.36
C


ATOM
2136
OD1
ASN
A
1081
−1.890
22.521
−15.518
1.00
66.42
O


ATOM
2137
ND2
ASN
A
1081
0.110
21.662
−14.966
1.00
59.60
N


ATOM
2138
N
ALA
A
1082
−2.078
25.515
−16.240
1.00
73.35
N


ATOM
2139
CA
ALA
A
1082
−3.275
26.003
−16.922
1.00
65.65
C


ATOM
2140
C
ALA
A
1082
−4.461
25.044
−16.830
1.00
66.30
C


ATOM
2141
O
ALA
A
1082
−5.612
25.459
−16.965
1.00
64.14
O


ATOM
2142
CB
ALA
A
1082
−2.959
26.322
−18.379
1.00
59.91
C


ATOM
2143
N
LYS
A
1083
−4.179
23.764
−16.605
1.00
72.58
N


ATOM
2144
CA
LYS
A
1083
−5.238
22.767
−16.484
1.00
76.68
C


ATOM
2145
C
LYS
A
1083
−5.780
22.691
−15.061
1.00
73.64
C


ATOM
2146
O
LYS
A
1083
−6.990
22.600
−14.850
1.00
70.29
O


ATOM
2147
CB
LYS
A
1083
−4.738
21.388
−16.921
1.00
80.21
C


ATOM
2148
CG
LYS
A
1083
−4.428
21.278
−18.403
1.00
88.39
C


ATOM
2149
CD
LYS
A
1083
−4.245
19.827
−18.821
1.00
92.04
C


ATOM
2150
CE
LYS
A
1083
−5.524
19.028
−18.618
1.00
88.61
C


ATOM
2151
NZ
LYS
A
1083
−5.398
17.638
−19.137
1.00
90.29
N


ATOM
2152
N
LEU
A
1084
−4.877
22.736
−14.088
1.00
73.01
N


ATOM
2153
CA
LEU
A
1084
−5.248
22.551
−12.689
1.00
72.81
C


ATOM
2154
C
LEU
A
1084
−5.884
23.788
−12.056
1.00
70.07
C


ATOM
2155
O
LEU
A
1084
−6.763
23.670
−11.203
1.00
73.42
O


ATOM
2156
CB
LEU
A
1084
−4.032
22.103
−11.873
1.00
68.36
C


ATOM
2157
CG
LEU
A
1084
−3.449
20.743
−12.263
1.00
63.16
C


ATOM
2158
CD1
LEU
A
1084
−2.250
20.397
−11.396
1.00
63.56
C


ATOM
2159
CD2
LEU
A
1084
−4.515
19.665
−12.162
1.00
65.73
C


ATOM
2160
N
LYS
A
1085
−5.443
24.970
−12.475
1.00
63.18
N


ATOM
2161
CA
LYS
A
1085
−5.919
26.214
−11.869
1.00
63.63
C


ATOM
2162
C
LYS
A
1085
−7.445
26.368
−11.869
1.00
65.06
C


ATOM
2163
O
LYS
A
1085
−8.039
26.633
−10.823
1.00
66.73
O


ATOM
2164
CB
LYS
A
1085
−5.258
27.435
−12.517
1.00
55.87
C


ATOM
2165
CG
LYS
A
1085
−5.651
28.751
−11.862
1.00
57.59
C


ATOM
2166
CD
LYS
A
1085
−4.742
29.887
−12.291
1.00
69.71
C


ATOM
2167
CE
LYS
A
1085
−5.017
31.140
−11.476
1.00
70.63
C


ATOM
2168
NZ
LYS
A
1085
−6.441
31.564
−11.577
1.00
71.44
N


ATOM
2169
N
PRO
A
1086
−8.086
26.203
−13.038
1.00
65.83
N


ATOM
2170
CA
PRO
A
1086
−9.540
26.394
−13.108
1.00
63.71
C


ATOM
2171
C
PRO
A
1086
−10.284
25.476
−12.144
1.00
64.91
C


ATOM
2172
O
PRO
A
1086
−11.263
25.893
−11.525
1.00
66.12
O


ATOM
2173
CB
PRO
A
1086
−9.875
26.014
−14.555
1.00
54.10
C


ATOM
2174
CG
PRO
A
1086
−8.601
26.190
−15.303
1.00
55.16
C


ATOM
2175
CD
PRO
A
1086
−7.517
25.818
−14.341
1.00
61.12
C


ATOM
2176
N
VAL
A
1087
−9.815
24.239
−12.023
1.00
58.50
N


ATOM
2177
CA
VAL
A
1087
−10.452
23.253
−11.159
1.00
59.96
C


ATOM
2178
C
VAL
A
1087
−10.213
23.573
−9.686
1.00
62.37
C


ATOM
2179
O
VAL
A
1087
−11.143
23.563
−8.880
1.00
67.88
O


ATOM
2180
CB
VAL
A
1087
−9.941
21.831
−11.457
1.00
57.84
C


ATOM
2181
CG1
VAL
A
1087
−10.628
20.820
−10.554
1.00
61.27
C


ATOM
2182
CG2
VAL
A
1087
−10.165
21.483
−12.921
1.00
56.50
C


ATOM
2183
N
TYR
A
1088
−8.961
23.856
−9.342
1.00
54.70
N


ATOM
2184
CA
TYR
A
1088
−8.602
24.173
−7.966
1.00
60.12
C


ATOM
2185
C
TYR
A
1088
−9.402
25.361
−7.440
1.00
61.96
C


ATOM
2186
O
TYR
A
1088
−9.913
25.333
−6.320
1.00
66.10
O


ATOM
2187
CB
TYR
A
1088
−7.101
24.457
−7.855
1.00
59.30
C


ATOM
2188
CG
TYR
A
1088
−6.655
24.833
−6.461
1.00
58.53
C


ATOM
2189
CD1
TYR
A
1088
−6.388
23.858
−5.508
1.00
53.91
C


ATOM
2190
CD2
TYR
A
1088
−6.504
26.165
−6.095
1.00
62.09
C


ATOM
2191
CE1
TYR
A
1088
−5.981
24.198
−4.230
1.00
56.16
C


ATOM
2192
CE2
TYR
A
1088
−6.098
26.514
−4.819
1.00
60.36
C


ATOM
2193
CZ
TYR
A
1088
−5.838
25.528
−3.892
1.00
63.20
C


ATOM
2194
OH
TYR
A
1088
−5.434
25.874
−2.622
1.00
70.94
O


ATOM
2195
N
ASP
A
1089
−9.510
26.402
−8.258
1.00
59.15
N


ATOM
2196
CA
ASP
A
1089
−10.205
27.621
−7.860
1.00
62.19
C


ATOM
2197
C
ASP
A
1089
−11.694
27.399
−7.608
1.00
62.05
C


ATOM
2198
O
ASP
A
1089
−12.310
28.126
−6.832
1.00
63.54
O


ATOM
2199
CB
ASP
A
1089
−10.008
28.718
−8.910
1.00
71.62
C


ATOM
2200
CG
ASP
A
1089
−8.624
29.337
−8.854
1.00
81.19
C


ATOM
2201
OD1
ASP
A
1089
−7.876
29.038
−7.900
1.00
76.32
O


ATOM
2202
OD2
ASP
A
1089
−8.286
30.127
−9.761
1.00
87.61
O


ATOM
2203
N
SER
A
1090
−12.268
26.391
−8.259
1.00
62.45
N


ATOM
2204
CA
SER
A
1090
−13.703
26.138
−8.154
1.00
60.96
C


ATOM
2205
C
SER
A
1090
−14.061
25.261
−6.957
1.00
70.82
C


ATOM
2206
O
SER
A
1090
−15.232
25.135
−6.600
1.00
75.14
O


ATOM
2207
CB
SER
A
1090
−14.231
25.497
−9.439
1.00
64.89
C


ATOM
2208
OG
SER
A
1090
−13.832
24.140
−9.536
1.00
72.06
O


ATOM
2209
N
LEU
A
1091
−13.050
24.657
−6.340
1.00
71.49
N


ATOM
2210
CA
LEU
A
1091
−13.278
23.728
−5.237
1.00
64.87
C


ATOM
2211
C
LEU
A
1091
−13.365
24.431
−3.886
1.00
59.56
C


ATOM
2212
O
LEU
A
1091
−12.867
25.544
−3.718
1.00
63.51
O


ATOM
2213
CB
LEU
A
1091
−12.175
22.669
−5.196
1.00
61.09
C


ATOM
2214
CG
LEU
A
1091
−12.068
21.740
−6.406
1.00
56.62
C


ATOM
2215
CD1
LEU
A
1091
−10.853
20.832
−6.278
1.00
58.23
C


ATOM
2216
CD2
LEU
A
1091
−13.339
20.922
−6.572
1.00
54.13
C


ATOM
2217
N
ASP
A
1092
−14.006
23.770
−2.927
1.00
58.90
N


ATOM
2218
CA
ASP
A
1092
−14.045
24.257
−1.554
1.00
58.25
C


ATOM
2219
C
ASP
A
1092
−12.768
23.847
−0.826
1.00
51.70
C


ATOM
2220
O
ASP
A
1092
−11.955
23.098
−1.366
1.00
59.19
O


ATOM
2221
CB
ASP
A
1092
−15.276
23.723
−0.818
1.00
65.12
C


ATOM
2222
CG
ASP
A
1092
−15.416
22.216
−0.928
1.00
79.92
C


ATOM
2223
OD1
ASP
A
1092
−15.686
21.723
−2.043
1.00
85.35
O


ATOM
2224
OD2
ASP
A
1092
−15.271
21.526
0.104
1.00
86.82
O


ATOM
2225
N
ALA
A
1093
−12.600
24.334
0.399
1.00
47.80
N


ATOM
2226
CA
ALA
A
1093
−11.363
24.127
1.150
1.00
56.35
C


ATOM
2227
C
ALA
A
1093
−11.005
22.653
1.338
1.00
64.43
C


ATOM
2228
O
ALA
A
1093
−9.847
22.264
1.177
1.00
70.72
O


ATOM
2229
CB
ALA
A
1093
−11.436
24.833
2.498
1.00
54.20
C


ATOM
2230
N
VAL
A
1094
−11.996
21.839
1.681
1.00
59.12
N


ATOM
2231
CA
VAL
A
1094
−11.757
20.423
1.945
1.00
59.35
C


ATOM
2232
C
VAL
A
1094
−11.419
19.652
0.670
1.00
61.16
C


ATOM
2233
O
VAL
A
1094
−10.522
18.809
0.667
1.00
62.93
O


ATOM
2234
CB
VAL
A
1094
−12.955
19.766
2.668
1.00
53.78
C


ATOM
2235
CG1
VAL
A
1094
−12.835
18.251
2.639
1.00
52.45
C


ATOM
2236
CG2
VAL
A
1094
−13.044
20.266
4.102
1.00
46.27
C


ATOM
2237
N
ARG
A
1095
−12.133
19.946
−0.412
1.00
60.52
N


ATOM
2238
CA
ARG
A
1095
−11.884
19.276
−1.685
1.00
54.77
C


ATOM
2239
C
ARG
A
1095
−10.543
19.697
−2.282
1.00
49.77
C


ATOM
2240
O
ARG
A
1095
−9.923
18.943
−3.032
1.00
53.54
O


ATOM
2241
CB
ARG
A
1095
−13.026
19.532
−2.672
1.00
49.27
C


ATOM
2242
CG
ARG
A
1095
−14.321
18.823
−2.302
1.00
53.82
C


ATOM
2243
CD
ARG
A
1095
−15.376
18.974
−3.386
1.00
56.86
C


ATOM
2244
NE
ARG
A
1095
−16.539
18.124
−3.139
1.00
56.74
N


ATOM
2245
CZ
ARG
A
1095
−17.651
18.530
−2.533
1.00
53.19
C


ATOM
2246
NH1
ARG
A
1095
−17.761
19.782
−2.111
1.00
47.16
N


ATOM
2247
NH2
ARG
A
1095
−18.656
17.685
−2.351
1.00
52.18
N


ATOM
2248
N
ARG
A
1096
−10.097
20.901
−1.943
1.00
49.25
N


ATOM
2249
CA
ARG
A
1096
−8.783
21.370
−2.370
1.00
57.10
C


ATOM
2250
C
ARG
A
1096
−7.685
20.530
−1.726
1.00
60.70
C


ATOM
2251
O
ARG
A
1096
−6.678
20.212
−2.360
1.00
58.87
O


ATOM
2252
CB
ARG
A
1096
−8.597
22.850
−2.024
1.00
52.82
C


ATOM
2253
CG
ARG
A
1096
−9.406
23.792
−2.900
1.00
52.13
C


ATOM
2254
CD
ARG
A
1096
−9.190
25.245
−2.515
1.00
53.26
C


ATOM
2255
NE
ARG
A
1096
−9.801
26.150
−3.485
1.00
57.97
N


ATOM
2256
CZ
ARG
A
1096
−9.704
27.474
−3.438
1.00
67.10
C


ATOM
2257
NH1
ARG
A
1096
−9.019
28.057
−2.464
1.00
71.95
N


ATOM
2258
NH2
ARG
A
1096
−10.292
28.216
−4.366
1.00
70.27
N


ATOM
2259
N
ALA
A
1097
−7.891
20.168
−0.465
1.00
55.05
N


ATOM
2260
CA
ALA
A
1097
−6.936
19.342
0.261
1.00
55.29
C


ATOM
2261
C
ALA
A
1097
−6.781
17.974
−0.402
1.00
57.91
C


ATOM
2262
O
ALA
A
1097
−5.687
17.406
−0.431
1.00
51.38
O


ATOM
2263
CB
ALA
A
1097
−7.363
19.191
1.716
1.00
48.61
C


ATOM
2264
N
ALA
A
1098
−7.881
17.452
−0.935
1.00
54.42
N


ATOM
2265
CA
ALA
A
1098
−7.861
16.170
−1.630
1.00
54.61
C


ATOM
2266
C
ALA
A
1098
−7.103
16.268
−2.953
1.00
62.12
C


ATOM
2267
O
ALA
A
1098
−6.486
15.300
−3.399
1.00
59.64
O


ATOM
2268
CB
ALA
A
1098
−9.278
15.670
−1.861
1.00
49.88
C


ATOM
2269
N
LEU
A
1099
−7.152
17.440
−3.580
1.00
60.87
N


ATOM
2270
CA
LEU
A
1099
−6.424
17.665
−4.823
1.00
62.58
C


ATOM
2271
C
LEU
A
1099
−4.938
17.859
−4.537
1.00
57.55
C


ATOM
2272
O
LEU
A
1099
−4.084
17.378
−5.283
1.00
55.25
O


ATOM
2273
CB
LEU
A
1099
−6.983
18.877
−5.571
1.00
65.42
C


ATOM
2274
CG
LEU
A
1099
−6.433
19.099
−6.982
1.00
61.85
C


ATOM
2275
CD1
LEU
A
1099
−6.831
17.954
−7.898
1.00
49.29
C


ATOM
2276
CD2
LEU
A
1099
−6.913
20.428
−7.543
1.00
68.36
C


ATOM
2277
N
ILE
A
1100
−4.636
18.567
−3.454
1.00
51.77
N


ATOM
2278
CA
ILE
A
1100
−3.259
18.750
−3.016
1.00
61.30
C


ATOM
2279
C
ILE
A
1100
−2.667
17.410
−2.583
1.00
70.54
C


ATOM
2280
O
ILE
A
1100
−1.484
17.140
−2.798
1.00
63.42
O


ATOM
2281
CB
ILE
A
1100
−3.168
19.763
−1.860
1.00
61.75
C


ATOM
2282
CG1
ILE
A
1100
−3.610
21.149
−2.336
1.00
54.02
C


ATOM
2283
CG2
ILE
A
1100
−1.753
19.819
−1.305
1.00
61.84
C


ATOM
2284
CD1
ILE
A
1100
−3.812
22.147
−1.216
1.00
45.45
C


ATOM
2285
N
ASN
A
1101
−3.504
16.573
−1.978
1.00
67.91
N


ATOM
2286
CA
ASN
A
1101
−3.103
15.225
−1.593
1.00
60.85
C


ATOM
2287
C
ASN
A
1101
−2.599
14.433
−2.796
1.00
53.19
C


ATOM
2288
O
ASN
A
1101
−1.566
13.768
−2.726
1.00
53.45
O


ATOM
2289
CB
ASN
A
1101
−4.274
14.496
−0.926
1.00
60.93
C


ATOM
2290
CG
ASN
A
1101
−3.875
13.158
−0.327
1.00
55.99
C


ATOM
2291
OD1
ASN
A
1101
−3.113
12.397
−0.923
1.00
58.87
O


ATOM
2292
ND2
ASN
A
1101
−4.402
12.861
0.855
1.00
49.68
N


ATOM
2293
N
MET
A
1102
−3.330
14.515
−3.904
1.00
52.46
N


ATOM
2294
CA
MET
A
1102
−2.955
13.805
−5.123
1.00
54.25
C


ATOM
2295
C
MET
A
1102
−1.652
14.331
−5.722
1.00
55.65
C


ATOM
2296
O
MET
A
1102
−0.833
13.558
−6.218
1.00
52.94
O


ATOM
2297
CB
MET
A
1102
−4.079
13.878
−6.155
1.00
48.69
C


ATOM
2298
CG
MET
A
1102
−5.332
13.123
−5.752
1.00
48.99
C


ATOM
2299
SD
MET
A
1102
−6.631
13.212
−6.999
1.00
72.28
S


ATOM
2300
CE
MET
A
1102
−5.804
12.472
−8.405
1.00
60.39
C


ATOM
2301
N
VAL
A
1103
−1.463
15.646
−5.676
1.00
57.59
N


ATOM
2302
CA
VAL
A
1103
−0.237
16.254
−6.182
1.00
63.01
C


ATOM
2303
C
VAL
A
1103
0.974
15.820
−5.357
1.00
61.51
C


ATOM
2304
O
VAL
A
1103
2.060
15.609
−5.898
1.00
56.54
O


ATOM
2305
CB
VAL
A
1103
−0.327
17.796
−6.206
1.00
57.23
C


ATOM
2306
CG1
VAL
A
1103
1.026
18.404
−6.546
1.00
49.64
C


ATOM
2307
CG2
VAL
A
1103
−1.386
18.251
−7.199
1.00
43.12
C


ATOM
2308
N
PHE
A
1104
0.781
15.684
−4.048
1.00
61.65
N


ATOM
2309
CA
PHE
A
1104
1.851
15.234
−3.160
1.00
62.20
C


ATOM
2310
C
PHE
A
1104
2.295
13.810
−3.480
1.00
67.68
C


ATOM
2311
O
PHE
A
1104
3.414
13.412
−3.155
1.00
69.60
O


ATOM
2312
CB
PHE
A
1104
1.419
15.319
−1.694
1.00
59.39
C


ATOM
2313
CG
PHE
A
1104
1.712
16.644
−1.049
1.00
70.31
C


ATOM
2314
CD1
PHE
A
1104
0.767
17.267
−0.250
1.00
71.41
C


ATOM
2315
CD2
PHE
A
1104
2.933
17.268
−1.243
1.00
73.47
C


ATOM
2316
CE1
PHE
A
1104
1.036
18.484
0.347
1.00
70.55
C


ATOM
2317
CE2
PHE
A
1104
3.207
18.486
−0.652
1.00
74.84
C


ATOM
2318
CZ
PHE
A
1104
2.257
19.095
0.145
1.00
72.20
C


ATOM
2319
N
GLN
A
1105
1.414
13.048
−4.120
1.00
58.94
N


ATOM
2320
CA
GLN
A
1105
1.682
11.642
−4.397
1.00
59.40
C


ATOM
2321
C
GLN
A
1105
2.139
11.389
−5.834
1.00
68.82
C


ATOM
2322
O
GLN
A
1105
3.074
10.622
−6.068
1.00
71.56
O


ATOM
2323
CB
GLN
A
1105
0.444
10.798
−4.087
1.00
57.92
C


ATOM
2324
CG
GLN
A
1105
0.624
9.313
−4.343
1.00
61.43
C


ATOM
2325
CD
GLN
A
1105
−0.620
8.511
−4.018
1.00
67.01
C


ATOM
2326
OE1
GLN
A
1105
−1.583
9.037
−3.460
1.00
76.19
O


ATOM
2327
NE2
GLN
A
1105
−0.606
7.230
−4.366
1.00
63.30
N


ATOM
2328
N
MET
A
1106
1.483
12.037
−6.792
1.00
66.24
N


ATOM
2329
CA
MET
A
1106
1.725
11.750
−8.204
1.00
62.03
C


ATOM
2330
C
MET
A
1106
2.453
12.875
−8.934
1.00
65.48
C


ATOM
2331
O
MET
A
1106
3.003
12.667
−10.015
1.00
74.98
O


ATOM
2332
CB
MET
A
1106
0.404
11.455
−8.916
1.00
67.53
C


ATOM
2333
CG
MET
A
1106
−0.543
10.570
−8.127
1.00
77.13
C


ATOM
2334
SD
MET
A
1106
−2.033
10.192
−9.062
1.00
102.30
S


ATOM
2335
CE
MET
A
1106
−2.364
11.786
−9.804
1.00
87.58
C


ATOM
2336
N
GLY
A
1107
2.450
14.066
−8.347
1.00
65.36
N


ATOM
2337
CA
GLY
A
1107
3.044
15.221
−8.990
1.00
61.19
C


ATOM
2338
C
GLY
A
1107
2.018
15.983
−9.805
1.00
59.33
C


ATOM
2339
O
GLY
A
1107
0.970
15.444
−10.162
1.00
61.28
O


ATOM
2340
N
GLU
A
1108
2.327
17.237
−10.111
1.00
61.54
N


ATOM
2341
CA
GLU
A
1108
1.379
18.126
−10.775
1.00
64.65
C


ATOM
2342
C
GLU
A
1108
1.094
17.713
−12.215
1.00
61.24
C


ATOM
2343
O
GLU
A
1108
−0.026
17.865
−12.704
1.00
64.27
O


ATOM
2344
CB
GLU
A
1108
1.887
19.565
−10.714
1.00
67.92
C


ATOM
2345
CG
GLU
A
1108
2.636
19.866
−9.427
1.00
79.36
C


ATOM
2346
CD
GLU
A
1108
2.476
21.299
−8.979
1.00
91.71
C


ATOM
2347
OE1
GLU
A
1108
1.811
22.070
−9.700
1.00
102.95
O


ATOM
2348
OE2
GLU
A
1108
3.009
21.652
−7.905
1.00
85.96
O


ATOM
2349
N
THR
A
1109
2.111
17.190
−12.891
1.00
64.73
N


ATOM
2350
CA
THR
A
1109
1.942
16.690
−14.249
1.00
65.31
C


ATOM
2351
C
THR
A
1109
1.096
15.421
−14.240
1.00
68.01
C


ATOM
2352
O
THR
A
1109
0.330
15.164
−15.170
1.00
73.32
O


ATOM
2353
CB
THR
A
1109
3.299
16.400
−14.916
1.00
64.81
C


ATOM
2354
OG1
THR
A
1109
4.024
17.625
−15.079
1.00
63.14
O


ATOM
2355
CG2
THR
A
1109
3.100
15.751
−16.276
1.00
62.62
C


ATOM
2356
N
GLY
A
1110
1.235
14.636
−13.177
1.00
60.00
N


ATOM
2357
CA
GLY
A
1110
0.473
13.411
−13.027
1.00
54.91
C


ATOM
2358
C
GLY
A
1110
−1.015
13.665
−12.877
1.00
62.39
C


ATOM
2359
O
GLY
A
1110
−1.832
13.032
−13.546
1.00
69.38
O


ATOM
2360
N
VAL
A
1111
−1.369
14.596
−11.997
1.00
65.76
N


ATOM
2361
CA
VAL
A
1111
−2.769
14.923
−11.759
1.00
67.26
C


ATOM
2362
C
VAL
A
1111
−3.397
15.554
−12.997
1.00
66.07
C


ATOM
2363
O
VAL
A
1111
−4.560
15.301
−13.314
1.00
60.96
O


ATOM
2364
CB
VAL
A
1111
−2.935
15.880
−10.563
1.00
59.99
C


ATOM
2365
CG1
VAL
A
1111
−4.410
16.085
−10.249
1.00
57.17
C


ATOM
2366
CG2
VAL
A
1111
−2.202
15.339
−9.349
1.00
55.73
C


ATOM
2367
N
ALA
A
1112
−2.615
16.372
−13.696
1.00
67.42
N


ATOM
2368
CA
ALA
A
1112
−3.090
17.066
−14.889
1.00
66.27
C


ATOM
2369
C
ALA
A
1112
−3.486
16.096
−16.001
1.00
69.14
C


ATOM
2370
O
ALA
A
1112
−4.085
16.495
−16.999
1.00
65.25
O


ATOM
2371
CB
ALA
A
1112
−2.038
18.047
−15.387
1.00
59.35
C


ATOM
2372
N
GLY
A
1113
−3.148
14.823
−15.822
1.00
79.96
N


ATOM
2373
CA
GLY
A
1113
−3.483
13.799
−16.795
1.00
77.36
C


ATOM
2374
C
GLY
A
1113
−4.925
13.335
−16.692
1.00
83.69
C


ATOM
2375
O
GLY
A
1113
−5.461
12.742
−17.628
1.00
87.05
O


ATOM
2376
N
PHE
A
1114
−5.552
13.601
−15.550
1.00
82.49
N


ATOM
2377
CA
PHE
A
1114
−6.952
13.246
−15.340
1.00
75.42
C


ATOM
2378
C
PHE
A
1114
−7.875
14.272
−15.987
1.00
72.67
C


ATOM
2379
O
PHE
A
1114
−8.647
14.941
−15.300
1.00
71.62
O


ATOM
2380
CB
PHE
A
1114
−7.263
13.149
−13.844
1.00
76.33
C


ATOM
2381
CG
PHE
A
1114
−6.618
11.979
−13.162
1.00
76.97
C


ATOM
2382
CD1
PHE
A
1114
−7.296
10.778
−13.030
1.00
79.65
C


ATOM
2383
CD2
PHE
A
1114
−5.334
12.078
−12.652
1.00
70.64
C


ATOM
2384
CE1
PHE
A
1114
−6.707
9.698
−12.401
1.00
74.39
C


ATOM
2385
CE2
PHE
A
1114
−4.739
11.000
−12.024
1.00
70.90
C


ATOM
2386
CZ
PHE
A
1114
−5.427
9.809
−11.898
1.00
70.81
C


ATOM
2387
N
THR
A
1115
−7.804
14.384
−17.310
1.00
68.40
N


ATOM
2388
CA
THR
A
1115
−8.569
15.392
−18.040
1.00
69.79
C


ATOM
2389
C
THR
A
1115
−10.074
15.321
−17.777
1.00
68.85
C


ATOM
2390
O
THR
A
1115
−10.717
16.340
−17.524
1.00
72.68
O


ATOM
2391
CB
THR
A
1115
−8.320
15.291
−19.560
1.00
73.52
C


ATOM
2392
OG1
THR
A
1115
−6.922
15.454
−19.830
1.00
68.56
O


ATOM
2393
CG2
THR
A
1115
−9.102
16.366
−20.299
1.00
73.33
C


ATOM
2394
N
ASN
A
1116
−10.634
14.118
−17.842
1.00
68.27
N


ATOM
2395
CA
ASN
A
1116
−12.075
13.937
−17.689
1.00
69.21
C


ATOM
2396
C
ASN
A
1116
−12.567
14.060
−16.249
1.00
66.93
C


ATOM
2397
O
ASN
A
1116
−13.571
14.722
−15.987
1.00
73.12
O


ATOM
2398
CB
ASN
A
1116
−12.520
12.603
−18.295
1.00
78.40
C


ATOM
2399
CG
ASN
A
1116
−12.571
12.643
−19.812
1.00
82.74
C


ATOM
2400
OD1
ASN
A
1116
−12.940
13.659
−20.406
1.00
77.44
O


ATOM
2401
ND2
ASN
A
1116
−12.205
11.536
−20.447
1.00
84.64
N


ATOM
2402
N
SER
A
1117
−11.864
13.420
−15.319
1.00
70.09
N


ATOM
2403
CA
SER
A
1117
−12.235
13.488
−13.909
1.00
67.37
C


ATOM
2404
C
SER
A
1117
−12.169
14.921
−13.390
1.00
67.38
C


ATOM
2405
O
SER
A
1117
−13.051
15.362
−12.651
1.00
70.95
O


ATOM
2406
CB
SER
A
1117
−11.342
12.575
−13.065
1.00
69.45
C


ATOM
2407
OG
SER
A
1117
−11.642
11.209
−13.299
1.00
74.98
O


ATOM
2408
N
LEU
A
1118
−11.122
15.644
−13.779
1.00
63.57
N


ATOM
2409
CA
LEU
A
1118
−10.974
17.043
−13.393
1.00
64.09
C


ATOM
2410
C
LEU
A
1118
−12.187
17.852
−13.839
1.00
70.05
C


ATOM
2411
O
LEU
A
1118
−12.769
18.603
−13.058
1.00
74.96
O


ATOM
2412
CB
LEU
A
1118
−9.699
17.638
−13.995
1.00
65.91
C


ATOM
2413
CG
LEU
A
1118
−8.356
17.167
−13.428
1.00
67.56
C


ATOM
2414
CD1
LEU
A
1118
−7.206
17.659
−14.297
1.00
62.29
C


ATOM
2415
CD2
LEU
A
1118
−8.178
17.620
−11.985
1.00
57.62
C


ATOM
2416
N
ARG
A
1119
−12.560
17.684
−15.104
1.00
73.71
N


ATOM
2417
CA
ARG
A
1119
−13.696
18.392
−15.685
1.00
70.74
C


ATOM
2418
C
ARG
A
1119
−14.976
18.205
−14.873
1.00
70.08
C


ATOM
2419
O
ARG
A
1119
−15.683
19.172
−14.582
1.00
73.09
O


ATOM
2420
CB
ARG
A
1119
−13.902
17.945
−17.134
1.00
72.88
C


ATOM
2421
CG
ARG
A
1119
−15.312
18.122
−17.665
1.00
80.58
C


ATOM
2422
CD
ARG
A
1119
−15.339
17.934
−19.174
1.00
88.70
C


ATOM
2423
NE
ARG
A
1119
−16.569
17.295
−19.630
1.00
97.97
N


ATOM
2424
CZ
ARG
A
1119
−16.673
16.000
−19.915
1.00
102.54
C


ATOM
2425
NH1
ARG
A
1119
−17.831
15.502
−20.324
1.00
105.15
N


ATOM
2426
NH2
ARG
A
1119
−15.618
15.204
−19.795
1.00
94.37
N


ATOM
2427
N
MET
A
1120
−15.267
16.962
−14.504
1.00
68.79
N


ATOM
2428
CA
MET
A
1120
−16.442
16.665
−13.694
1.00
67.28
C


ATOM
2429
C
MET
A
1120
−16.357
17.367
−12.344
1.00
70.93
C


ATOM
2430
O
MET
A
1120
−17.359
17.855
−11.821
1.00
72.23
O


ATOM
2431
CB
MET
A
1120
−16.587
15.157
−13.491
1.00
62.61
C


ATOM
2432
CG
MET
A
1120
−16.637
14.365
−14.783
1.00
60.63
C


ATOM
2433
SD
MET
A
1120
−16.686
12.587
−14.497
1.00
109.64
S


ATOM
2434
CE
MET
A
1120
−16.539
11.973
−16.173
1.00
272.52
C


ATOM
2435
N
LEU
A
1121
−15.153
17.414
−11.784
1.00
71.12
N


ATOM
2436
CA
LEU
A
1121
−14.935
18.065
−10.498
1.00
66.74
C


ATOM
2437
C
LEU
A
1121
−15.293
19.546
−10.558
1.00
67.05
C


ATOM
2438
O
LEU
A
1121
−15.886
20.084
−9.622
1.00
72.61
O


ATOM
2439
CB
LEU
A
1121
−13.489
17.879
−10.035
1.00
68.01
C


ATOM
2440
CG
LEU
A
1121
−13.137
16.487
−9.504
1.00
64.05
C


ATOM
2441
CD1
LEU
A
1121
−11.635
16.332
−9.323
1.00
59.67
C


ATOM
2442
CD2
LEU
A
1121
−13.864
16.214
−8.197
1.00
70.14
C


ATOM
2443
N
GLN
A
1122
−14.937
20.202
−11.659
1.00
61.58
N


ATOM
2444
CA
GLN
A
1122
−15.258
21.615
−11.829
1.00
68.03
C


ATOM
2445
C
GLN
A
1122
−16.740
21.815
−12.135
1.00
68.74
C


ATOM
2446
O
GLN
A
1122
−17.304
22.873
−11.858
1.00
61.30
O


ATOM
2447
CB
GLN
A
1122
−14.399
22.253
−12.920
1.00
73.07
C


ATOM
2448
CG
GLN
A
1122
−14.663
23.740
−13.098
1.00
79.50
C


ATOM
2449
CD
GLN
A
1122
−13.583
24.440
−13.895
1.00
87.39
C


ATOM
2450
OE1
GLN
A
1122
−12.909
23.828
−14.723
1.00
89.22
O


ATOM
2451
NE2
GLN
A
1122
−13.415
25.735
−13.649
1.00
92.14
N


ATOM
2452
N
GLN
A
1123
−17.366
20.792
−12.707
1.00
73.35
N


ATOM
2453
CA
GLN
A
1123
−18.801
20.825
−12.958
1.00
82.05
C


ATOM
2454
C
GLN
A
1123
−19.562
20.393
−11.710
1.00
83.17
C


ATOM
2455
O
GLN
A
1123
−20.784
20.249
−11.732
1.00
88.88
O


ATOM
2456
CB
GLN
A
1123
−19.163
19.929
−14.144
1.00
83.42
C


ATOM
2457
CG
GLN
A
1123
−18.787
20.511
−15.497
1.00
87.16
C


ATOM
2458
CD
GLN
A
1123
−19.068
19.556
−16.642
1.00
95.91
C


ATOM
2459
OE1
GLN
A
1123
−18.946
18.341
−16.495
1.00
100.47
O


ATOM
2460
NE2
GLN
A
1123
−19.442
20.105
−17.793
1.00
98.85
N


ATOM
2461
N
LYS
A
1124
−18.823
20.191
−10.623
1.00
74.22
N


ATOM
2462
CA
LYS
A
1124
−19.401
19.772
−9.349
1.00
71.30
C


ATOM
2463
C
LYS
A
1124
−20.210
18.482
−9.475
1.00
69.02
C


ATOM
2464
O
LYS
A
1124
−21.147
18.245
−8.712
1.00
68.45
O


ATOM
2465
CB
LYS
A
1124
−20.257
20.890
−8.747
1.00
67.75
C


ATOM
2466
CG
LYS
A
1124
−19.491
22.179
−8.512
1.00
68.73
C


ATOM
2467
CD
LYS
A
1124
−20.238
23.108
−7.571
1.00
75.88
C


ATOM
2468
CE
LYS
A
1124
−19.508
24.434
−7.424
1.00
85.73
C


ATOM
2469
NZ
LYS
A
1124
−18.068
24.238
−7.097
1.00
90.75
N


ATOM
2470
N
ARG
A
1125
−19.840
17.656
−10.447
1.00
65.31
N


ATOM
2471
CA
ARG
A
1125
−20.449
16.345
−10.612
1.00
70.08
C


ATOM
2472
C
ARG
A
1125
−19.680
15.342
−9.760
1.00
76.69
C


ATOM
2473
O
ARG
A
1125
−19.014
14.444
−10.278
1.00
83.98
O


ATOM
2474
CB
ARG
A
1125
−20.435
15.937
−12.086
1.00
69.85
C


ATOM
2475
CG
ARG
A
1125
−21.117
16.948
−12.997
1.00
75.17
C


ATOM
2476
CD
ARG
A
1125
−20.701
16.784
−14.451
1.00
78.01
C


ATOM
2477
NE
ARG
A
1125
−21.343
15.642
−15.094
1.00
82.50
N


ATOM
2478
CZ
ARG
A
1125
−21.239
15.362
−16.390
1.00
91.10
C


ATOM
2479
NH1
ARG
A
1125
−21.857
14.303
−16.894
1.00
94.57
N


ATOM
2480
NH2
ARG
A
1125
−20.518
16.142
−17.183
1.00
91.49
N


ATOM
2481
N
TRP
A
1126
−19.779
15.515
−8.446
1.00
75.05
N


ATOM
2482
CA
TRP
A
1126
−18.982
14.753
−7.489
1.00
71.36
C


ATOM
2483
C
TRP
A
1126
−19.069
13.243
−7.691
1.00
71.60
C


ATOM
2484
O
TRP
A
1126
−18.049
12.556
−7.714
1.00
76.93
O


ATOM
2485
CB
TRP
A
1126
−19.388
15.111
−6.056
1.00
62.81
C


ATOM
2486
CG
TRP
A
1126
−19.553
16.586
−5.823
1.00
56.10
C


ATOM
2487
CD1
TRP
A
1126
−20.665
17.221
−5.349
1.00
52.22
C


ATOM
2488
CD2
TRP
A
1126
−18.578
17.610
−6.061
1.00
54.90
C


ATOM
2489
NE1
TRP
A
1126
−20.440
18.575
−5.271
1.00
50.72
N


ATOM
2490
CE2
TRP
A
1126
−19.167
18.840
−5.703
1.00
58.29
C


ATOM
2491
CE3
TRP
A
1126
−17.263
17.606
−6.540
1.00
51.51
C


ATOM
2492
CZ2
TRP
A
1126
−18.488
20.053
−5.807
1.00
53.26
C


ATOM
2493
CZ3
TRP
A
1126
−16.591
18.811
−6.645
1.00
54.02
C


ATOM
2494
CH2
TRP
A
1126
−17.204
20.018
−6.280
1.00
56.66
C


ATOM
2495
N
ASP
A
1127
−20.287
12.731
−7.833
1.00
73.28
N


ATOM
2496
CA
ASP
A
1127
−20.495
11.292
−7.960
1.00
78.32
C


ATOM
2497
C
ASP
A
1127
−19.901
10.727
−9.248
1.00
74.61
C


ATOM
2498
O
ASP
A
1127
−19.312
9.644
−9.245
1.00
62.79
O


ATOM
2499
CB
ASP
A
1127
−21.982
10.947
−7.853
1.00
82.22
C


ATOM
2500
CG
ASP
A
1127
−22.507
11.078
−6.436
1.00
91.84
C


ATOM
2501
OD1
ASP
A
1127
−21.683
11.120
−5.497
1.00
88.14
O


ATOM
2502
OD2
ASP
A
1127
−23.741
11.139
−6.258
1.00
100.36
O


ATOM
2503
N
GLU
A
1128
−20.056
11.459
−10.346
1.00
80.14
N


ATOM
2504
CA
GLU
A
1128
−19.481
11.037
−11.618
1.00
87.94
C


ATOM
2505
C
GLU
A
1128
−17.960
11.010
−11.535
1.00
87.34
C


ATOM
2506
O
GLU
A
1128
−17.323
10.042
−11.949
1.00
88.16
O


ATOM
2507
CB
GLU
A
1128
−19.927
11.960
−12.751
1.00
103.85
C


ATOM
2508
CG
GLU
A
1128
−21.400
11.856
−13.098
1.00
114.47
C


ATOM
2509
CD
GLU
A
1128
−21.693
12.315
−14.512
1.00
125.25
C


ATOM
2510
OE1
GLU
A
1128
−22.802
12.836
−14.752
1.00
131.49
O


ATOM
2511
OE2
GLU
A
1128
−20.811
12.156
−15.383
1.00
126.90
O


ATOM
2512
N
ALA
A
1129
−17.387
12.083
−10.998
1.00
81.99
N


ATOM
2513
CA
ALA
A
1129
−15.943
12.173
−10.819
1.00
70.31
C


ATOM
2514
C
ALA
A
1129
−15.428
10.978
−10.031
1.00
64.42
C


ATOM
2515
O
ALA
A
1129
−14.402
10.392
−10.374
1.00
71.73
O


ATOM
2516
CB
ALA
A
1129
−15.579
13.469
−10.112
1.00
70.98
C


ATOM
2517
N
ALA
A
1130
−16.153
10.621
−8.975
1.00
66.81
N


ATOM
2518
CA
ALA
A
1130
−15.771
9.508
−8.113
1.00
67.03
C


ATOM
2519
C
ALA
A
1130
−15.667
8.205
−8.896
1.00
72.79
C


ATOM
2520
O
ALA
A
1130
−14.662
7.497
−8.809
1.00
76.61
O


ATOM
2521
CB
ALA
A
1130
−16.763
9.362
−6.967
1.00
64.32
C


ATOM
2522
N
VAL
A
1131
−16.711
7.894
−9.657
1.00
74.95
N


ATOM
2523
CA
VAL
A
1131
−16.737
6.681
−10.466
1.00
74.08
C


ATOM
2524
C
VAL
A
1131
−15.550
6.637
−11.421
1.00
72.71
C


ATOM
2525
O
VAL
A
1131
−14.905
5.601
−11.582
1.00
78.08
O


ATOM
2526
CB
VAL
A
1131
−18.037
6.580
−11.284
1.00
71.59
C


ATOM
2527
CG1
VAL
A
1131
−18.046
5.305
−12.114
1.00
66.62
C


ATOM
2528
CG2
VAL
A
1131
−19.247
6.635
−10.367
1.00
72.99
C


ATOM
2529
N
ASN
A
1132
−15.267
7.774
−12.047
1.00
70.07
N


ATOM
2530
CA
ASN
A
1132
−14.192
7.869
−13.025
1.00
70.36
C


ATOM
2531
C
ASN
A
1132
−12.819
7.689
−12.382
1.00
72.11
C


ATOM
2532
O
ASN
A
1132
−11.981
6.938
−12.882
1.00
66.71
O


ATOM
2533
CB
ASN
A
1132
−14.262
9.211
−13.756
1.00
73.01
C


ATOM
2534
CG
ASN
A
1132
−13.852
9.105
−15.209
1.00
84.01
C


ATOM
2535
OD1
ASN
A
1132
−14.049
8.071
−15.847
1.00
90.19
O


ATOM
2536
ND2
ASN
A
1132
−13.286
10.180
−15.744
1.00
89.81
N


ATOM
2537
N
LEU
A
1133
−12.598
8.382
−11.268
1.00
67.08
N


ATOM
2538
CA
LEU
A
1133
−11.345
8.276
−10.530
1.00
61.37
C


ATOM
2539
C
LEU
A
1133
−11.093
6.844
−10.073
1.00
72.18
C


ATOM
2540
O
LEU
A
1133
−9.946
6.428
−9.911
1.00
68.43
O


ATOM
2541
CB
LEU
A
1133
−11.360
9.209
−9.318
1.00
56.95
C


ATOM
2542
CG
LEU
A
1133
−11.175
10.702
−9.592
1.00
58.68
C


ATOM
2543
CD1
LEU
A
1133
−11.617
11.522
−8.391
1.00
58.98
C


ATOM
2544
CD2
LEU
A
1133
−9.727
11.006
−9.958
1.00
57.03
C


ATOM
2545
N
ALA
A
1134
−12.173
6.097
−9.865
1.00
79.13
N


ATOM
2546
CA
ALA
A
1134
−12.078
4.721
−9.388
1.00
78.45
C


ATOM
2547
C
ALA
A
1134
−11.562
3.778
−10.472
1.00
80.63
C


ATOM
2548
O
ALA
A
1134
−11.103
2.674
−10.179
1.00
78.78
O


ATOM
2549
CB
ALA
A
1134
−13.428
4.248
−8.870
1.00
77.07
C


ATOM
2550
N
LYS
A
1135
−11.638
4.222
−11.723
1.00
82.35
N


ATOM
2551
CA
LYS
A
1135
−11.201
3.411
−12.853
1.00
84.56
C


ATOM
2552
C
LYS
A
1135
−9.736
3.663
−13.200
1.00
85.69
C


ATOM
2553
O
LYS
A
1135
−9.228
3.138
−14.190
1.00
88.49
O


ATOM
2554
CB
LYS
A
1135
−12.066
3.701
−14.082
1.00
88.73
C


ATOM
2555
CG
LYS
A
1135
−13.563
3.599
−13.845
1.00
92.67
C


ATOM
2556
CD
LYS
A
1135
−14.330
3.968
−15.106
1.00
97.36
C


ATOM
2557
CE
LYS
A
1135
−15.832
3.889
−14.892
1.00
107.44
C


ATOM
2558
NZ
LYS
A
1135
−16.582
4.239
−16.130
1.00
113.83
N


ATOM
2559
N
SER
A
1136
−9.061
4.465
−12.384
1.00
79.73
N


ATOM
2560
CA
SER
A
1136
−7.692
4.877
−12.683
1.00
80.17
C


ATOM
2561
C
SER
A
1136
−6.652
3.844
−12.257
1.00
79.95
C


ATOM
2562
O
SER
A
1136
−6.946
2.926
−11.491
1.00
75.26
O


ATOM
2563
CB
SER
A
1136
−7.383
6.229
−12.031
1.00
76.43
C


ATOM
2564
OG
SER
A
1136
−7.331
6.119
−10.619
1.00
74.25
O


ATOM
2565
N
ARG
A
1137
−5.435
4.005
−12.769
1.00
80.53
N


ATOM
2566
CA
ARG
A
1137
−4.314
3.161
−12.377
1.00
79.92
C


ATOM
2567
C
ARG
A
1137
−3.818
3.582
−11.000
1.00
75.95
C


ATOM
2568
O
ARG
A
1137
−3.226
2.790
−10.268
1.00
80.00
O


ATOM
2569
CB
ARG
A
1137
−3.182
3.266
−13.401
1.00
89.43
C


ATOM
2570
CG
ARG
A
1137
−1.940
2.463
−13.042
1.00
103.96
C


ATOM
2571
CD
ARG
A
1137
−2.237
0.972
−12.997
1.00
117.47
C


ATOM
2572
NE
ARG
A
1137
−1.085
0.194
−12.544
1.00
124.93
N


ATOM
2573
CZ
ARG
A
1137
−0.924
−0.251
−11.302
1.00
129.57
C


ATOM
2574
NH1
ARG
A
1137
0.156
−0.951
−10.981
1.00
129.25
N


ATOM
2575
NH2
ARG
A
1137
−1.843
0.000
−10.379
1.00
132.12
N


ATOM
2576
N
TRP
A
1138
−4.065
4.842
−10.657
1.00
73.47
N


ATOM
2577
CA
TRP
A
1138
−3.722
5.365
−9.341
1.00
65.21
C


ATOM
2578
C
TRP
A
1138
−4.509
4.635
−8.260
1.00
68.50
C


ATOM
2579
O
TRP
A
1138
−3.954
4.231
−7.236
1.00
66.19
O


ATOM
2580
CB
TRP
A
1138
−3.995
6.870
−9.286
1.00
58.78
C


ATOM
2581
CG
TRP
A
1138
−4.172
7.420
−7.901
1.00
66.32
C


ATOM
2582
CD1
TRP
A
1138
−3.254
7.412
−6.890
1.00
66.55
C


ATOM
2583
CD2
TRP
A
1138
−5.334
8.081
−7.381
1.00
66.73
C


ATOM
2584
NE1
TRP
A
1138
−3.777
8.017
−5.771
1.00
67.36
N


ATOM
2585
CE2
TRP
A
1138
−5.052
8.436
−6.047
1.00
63.72
C


ATOM
2586
CE3
TRP
A
1138
−6.587
8.401
−7.914
1.00
62.36
C


ATOM
2587
CZ2
TRP
A
1138
−5.976
9.097
−5.238
1.00
59.13
C


ATOM
2588
CZ3
TRP
A
1138
−7.503
9.057
−7.109
1.00
58.68
C


ATOM
2589
CH2
TRP
A
1138
−7.193
9.397
−5.787
1.00
55.75
C


ATOM
2590
N
TYR
A
1139
−5.805
4.461
−8.498
1.00
69.54
N


ATOM
2591
CA
TYR
A
1139
−6.667
3.755
−7.560
1.00
72.07
C


ATOM
2592
C
TYR
A
1139
−6.254
2.294
−7.437
1.00
77.48
C


ATOM
2593
O
TYR
A
1139
−6.181
1.749
−6.336
1.00
87.38
O


ATOM
2594
CB
TYR
A
1139
−8.129
3.850
−8.001
1.00
77.29
C


ATOM
2595
CG
TYR
A
1139
−9.083
3.105
−7.097
1.00
83.46
C


ATOM
2596
CD1
TYR
A
1139
−9.593
3.703
−5.953
1.00
84.09
C


ATOM
2597
CD2
TYR
A
1139
−9.470
1.804
−7.384
1.00
91.59
C


ATOM
2598
CE1
TYR
A
1139
−10.464
3.025
−5.121
1.00
92.44
C


ATOM
2599
CE2
TYR
A
1139
−10.340
1.118
−6.558
1.00
96.30
C


ATOM
2600
CZ
TYR
A
1139
−10.834
1.734
−5.428
1.00
97.54
C


ATOM
2601
OH
TYR
A
1139
−11.701
1.056
−4.601
1.00
101.62
O


ATOM
2602
N
ASN
A
1140
−5.985
1.666
−8.576
1.00
80.11
N


ATOM
2603
CA
ASN
A
1140
−5.578
0.268
−8.607
1.00
83.43
C


ATOM
2604
C
ASN
A
1140
−4.304
0.018
−7.805
1.00
86.62
C


ATOM
2605
O
ASN
A
1140
−4.093
−1.075
−7.278
1.00
88.68
O


ATOM
2606
CB
ASN
A
1140
−5.378
−0.188
−10.054
1.00
88.68
C


ATOM
2607
CG
ASN
A
1140
−5.097
−1.672
−10.162
1.00
98.33
C


ATOM
2608
OD1
ASN
A
1140
−5.874
−2.499
−9.686
1.00
105.29
O


ATOM
2609
ND2
ASN
A
1140
−3.984
−2.018
−10.799
1.00
100.64
N


ATOM
2610
N
GLN
A
1141
−3.461
1.041
−7.713
1.00
84.80
N


ATOM
2611
CA
GLN
A
1141
−2.164
0.912
−7.058
1.00
81.98
C


ATOM
2612
C
GLN
A
1141
−2.263
1.099
−5.545
1.00
83.07
C


ATOM
2613
O
GLN
A
1141
−1.714
0.306
−4.779
1.00
92.44
O


ATOM
2614
CB
GLN
A
1141
−1.169
1.906
−7.659
1.00
91.77
C


ATOM
2615
CG
GLN
A
1141
0.284
1.612
−7.333
1.00
102.05
C


ATOM
2616
CD
GLN
A
1141
1.241
2.309
−8.281
1.00
108.23
C


ATOM
2617
OE1
GLN
A
1141
0.853
2.742
−9.366
1.00
105.17
O


ATOM
2618
NE2
GLN
A
1141
2.501
2.417
−7.876
1.00
113.29
N


ATOM
2619
N
THR
A
1142
−2.961
2.147
−5.119
1.00
74.16
N


ATOM
2620
CA
THR
A
1142
−3.159
2.409
−3.695
1.00
70.75
C


ATOM
2621
C
THR
A
1142
−4.636
2.636
−3.382
1.00
78.63
C


ATOM
2622
O
THR
A
1142
−5.064
3.770
−3.176
1.00
84.80
O


ATOM
2623
CB
THR
A
1142
−2.344
3.629
−3.219
1.00
66.58
C


ATOM
2624
OG1
THR
A
1142
−2.717
4.785
−3.978
1.00
66.56
O


ATOM
2625
CG2
THR
A
1142
−0.852
3.376
−3.388
1.00
56.52
C


ATOM
2626
N
PRO
A
1143
−5.418
1.545
−3.341
1.00
81.27
N


ATOM
2627
CA
PRO
A
1143
−6.876
1.577
−3.172
1.00
75.67
C


ATOM
2628
C
PRO
A
1143
−7.329
2.239
−1.874
1.00
68.97
C


ATOM
2629
O
PRO
A
1143
−8.319
2.967
−1.876
1.00
72.77
O


ATOM
2630
CB
PRO
A
1143
−7.258
0.092
−3.161
1.00
78.86
C


ATOM
2631
CG
PRO
A
1143
−6.143
−0.595
−3.869
1.00
81.26
C


ATOM
2632
CD
PRO
A
1143
−4.914
0.171
−3.493
1.00
82.87
C


ATOM
2633
N
ASN
A
1144
−6.618
1.984
−0.781
1.00
64.01
N


ATOM
2634
CA
ASN
A
1144
−6.994
2.537
0.516
1.00
68.96
C


ATOM
2635
C
ASN
A
1144
−6.842
4.056
0.585
1.00
69.73
C


ATOM
2636
O
ASN
A
1144
−7.751
4.759
1.027
1.00
73.42
O


ATOM
2637
CB
ASN
A
1144
−6.198
1.865
1.636
1.00
66.22
C


ATOM
2638
CG
ASN
A
1144
−6.504
0.386
1.758
1.00
69.32
C


ATOM
2639
OD1
ASN
A
1144
−7.648
−0.040
1.589
1.00
70.95
O


ATOM
2640
ND2
ASN
A
1144
−5.483
−0.408
2.055
1.00
74.92
N


ATOM
2641
N
ARG
A
1145
−5.691
4.557
0.149
1.00
64.15
N


ATOM
2642
CA
ARG
A
1145
−5.449
5.994
0.133
1.00
57.15
C


ATOM
2643
C
ARG
A
1145
−6.384
6.687
−0.853
1.00
55.27
C


ATOM
2644
O
ARG
A
1145
−7.016
7.692
−0.524
1.00
54.09
O


ATOM
2645
CB
ARG
A
1145
−3.990
6.293
−0.221
1.00
55.30
C


ATOM
2646
CG
ARG
A
1145
−3.679
7.777
−0.354
1.00
54.05
C


ATOM
2647
CD
ARG
A
1145
−2.181
8.034
−0.430
1.00
52.51
C


ATOM
2648
NE
ARG
A
1145
−1.878
9.463
−0.416
1.00
62.37
N


ATOM
2649
CZ
ARG
A
1145
−0.648
9.968
−0.409
1.00
64.77
C


ATOM
2650
NH1
ARG
A
1145
0.404
9.160
−0.412
1.00
75.79
N


ATOM
2651
NH2
ARG
A
1145
−0.469
11.282
−0.397
1.00
51.28
N


ATOM
2652
N
ALA
A
1146
−6.471
6.138
−2.060
1.00
61.50
N


ATOM
2653
CA
ALA
A
1146
−7.312
6.707
−3.108
1.00
61.91
C


ATOM
2654
C
ALA
A
1146
−8.784
6.717
−2.708
1.00
64.09
C


ATOM
2655
O
ALA
A
1146
−9.503
7.674
−2.988
1.00
75.03
O


ATOM
2656
CB
ALA
A
1146
−7.120
5.951
−4.415
1.00
52.79
C


ATOM
2657
N
LYS
A
1147
−9.226
5.648
−2.055
1.00
59.77
N


ATOM
2658
CA
LYS
A
1147
−10.618
5.533
−1.634
1.00
61.60
C


ATOM
2659
C
LYS
A
1147
−10.986
6.634
−0.644
1.00
61.82
C


ATOM
2660
O
LYS
A
1147
−12.112
7.134
−0.650
1.00
66.82
O


ATOM
2661
CB
LYS
A
1147
−10.886
4.154
−1.026
1.00
74.76
C


ATOM
2662
CG
LYS
A
1147
−12.350
3.879
−0.732
1.00
89.83
C


ATOM
2663
CD
LYS
A
1147
−12.571
2.431
−0.327
1.00
103.23
C


ATOM
2664
CE
LYS
A
1147
−14.042
2.153
−0.057
1.00
111.04
C


ATOM
2665
NZ
LYS
A
1147
−14.293
0.716
0.244
1.00
110.51
N


ATOM
2666
N
ARG
A
1148
−10.031
7.009
0.203
1.00
49.88
N


ATOM
2667
CA
ARG
A
1148
−10.244
8.088
1.160
1.00
60.19
C


ATOM
2668
C
ARG
A
1148
−10.282
9.443
0.462
1.00
59.00
C


ATOM
2669
O
ARG
A
1148
−11.135
10.281
0.758
1.00
56.07
O


ATOM
2670
CB
ARG
A
1148
−9.156
8.087
2.236
1.00
63.82
C


ATOM
2671
CG
ARG
A
1148
−9.321
7.010
3.295
1.00
53.31
C


ATOM
2672
CD
ARG
A
1148
−8.343
7.215
4.442
1.00
55.62
C


ATOM
2673
NE
ARG
A
1148
−6.955
7.072
4.011
1.00
60.50
N


ATOM
2674
CZ
ARG
A
1148
−6.285
5.925
4.027
1.00
67.27
C


ATOM
2675
NH1
ARG
A
1148
−6.876
4.818
4.454
1.00
66.92
N


ATOM
2676
NH2
ARG
A
1148
−5.024
5.884
3.617
1.00
61.65
N


ATOM
2677
N
VAL
A
1149
−9.349
9.652
−0.462
1.00
53.90
N


ATOM
2678
CA
VAL
A
1149
−9.290
10.892
−1.227
1.00
46.34
C


ATOM
2679
C
VAL
A
1149
−10.569
11.103
−2.029
1.00
56.23
C


ATOM
2680
O
VAL
A
1149
−11.103
12.210
−2.087
1.00
59.39
O


ATOM
2681
CB
VAL
A
1149
−8.093
10.901
−2.191
1.00
50.28
C


ATOM
2682
CG1
VAL
A
1149
−8.109
12.160
−3.046
1.00
52.16
C


ATOM
2683
CG2
VAL
A
1149
−6.787
10.788
−1.417
1.00
54.62
C


ATOM
2684
N
ILE
A
1150
−11.056
10.031
−2.645
1.00
64.09
N


ATOM
2685
CA
ILE
A
1150
−12.266
10.092
−3.458
1.00
67.54
C


ATOM
2686
C
ILE
A
1150
−13.495
10.411
−2.609
1.00
66.26
C


ATOM
2687
O
ILE
A
1150
−14.348
11.205
−3.008
1.00
59.60
O


ATOM
2688
CB
ILE
A
1150
−12.489
8.776
−4.231
1.00
68.99
C


ATOM
2689
CG1
ILE
A
1150
−11.375
8.574
−5.262
1.00
63.66
C


ATOM
2690
CG2
ILE
A
1150
−13.847
8.777
−4.912
1.00
67.65
C


ATOM
2691
CD1
ILE
A
1150
−11.494
7.285
−6.045
1.00
60.75
C


ATOM
2692
N
THR
A
1151
−13.577
9.792
−1.435
1.00
65.25
N


ATOM
2693
CA
THR
A
1151
−14.662
10.067
−0.499
1.00
60.60
C


ATOM
2694
C
THR
A
1151
−14.667
11.543
−0.113
1.00
57.87
C


ATOM
2695
O
THR
A
1151
−15.721
12.133
0.121
1.00
70.20
O


ATOM
2696
CB
THR
A
1151
−14.544
9.205
0.774
1.00
65.32
C


ATOM
2697
OG1
THR
A
1151
−14.723
7.823
0.438
1.00
61.51
O


ATOM
2698
CG2
THR
A
1151
−15.592
9.610
1.804
1.00
66.20
C


ATOM
2699
N
THR
A
1152
−13.479
12.135
−0.053
1.00
57.71
N


ATOM
2700
CA
THR
A
1152
−13.337
13.548
0.276
1.00
60.97
C


ATOM
2701
C
THR
A
1152
−13.888
14.427
−0.846
1.00
57.37
C


ATOM
2702
O
THR
A
1152
−14.475
15.478
−0.588
1.00
52.14
O


ATOM
2703
CB
THR
A
1152
−11.863
13.913
0.547
1.00
63.82
C


ATOM
2704
OG1
THR
A
1152
−11.327
13.034
1.544
1.00
70.01
O


ATOM
2705
CG2
THR
A
1152
−11.742
15.352
1.026
1.00
51.81
C


ATOM
2706
N
PHE
A
1153
−13.694
13.991
−2.089
1.00
61.62
N


ATOM
2707
CA
PHE
A
1153
−14.252
14.688
−3.246
1.00
65.28
C


ATOM
2708
C
PHE
A
1153
−15.774
14.561
−3.274
1.00
63.37
C


ATOM
2709
O
PHE
A
1153
−16.485
15.520
−3.570
1.00
54.96
O


ATOM
2710
CB
PHE
A
1153
−13.668
14.135
−4.549
1.00
62.83
C


ATOM
2711
CG
PHE
A
1153
−12.306
14.678
−4.891
1.00
60.26
C


ATOM
2712
CD1
PHE
A
1153
−12.067
16.042
−4.887
1.00
55.39
C


ATOM
2713
CD2
PHE
A
1153
−11.273
13.823
−5.245
1.00
59.43
C


ATOM
2714
CE1
PHE
A
1153
−10.817
16.543
−5.210
1.00
58.69
C


ATOM
2715
CE2
PHE
A
1153
−10.023
14.318
−5.572
1.00
57.71
C


ATOM
2716
CZ
PHE
A
1153
−9.795
15.679
−5.555
1.00
58.36
C


ATOM
2717
N
ARG
A
1154
−16.262
13.364
−2.967
1.00
59.14
N


ATOM
2718
CA
ARG
A
1154
−17.692
13.081
−2.941
1.00
64.04
C


ATOM
2719
C
ARG
A
1154
−18.437
13.954
−1.937
1.00
70.56
C


ATOM
2720
O
ARG
A
1154
−19.396
14.643
−2.286
1.00
62.30
O


ATOM
2721
CB
ARG
A
1154
−17.923
11.608
−2.595
1.00
68.25
C


ATOM
2722
CG
ARG
A
1154
−17.793
10.657
−3.770
1.00
78.87
C


ATOM
2723
CD
ARG
A
1154
−19.144
10.097
−4.178
1.00
84.33
C


ATOM
2724
NE
ARG
A
1154
−19.489
8.909
−3.401
1.00
88.22
N


ATOM
2725
CZ
ARG
A
1154
−20.657
8.278
−3.470
1.00
93.03
C


ATOM
2726
NH1
ARG
A
1154
−21.611
8.725
−4.276
1.00
94.35
N


ATOM
2727
NH2
ARG
A
1154
−20.876
7.202
−2.726
1.00
93.11
N


ATOM
2728
N
THR
A
1155
−17.981
13.918
−0.689
1.00
74.01
N


ATOM
2729
CA
THR
A
1155
−18.716
14.509
0.423
1.00
62.69
C


ATOM
2730
C
THR
A
1155
−18.280
15.931
0.756
1.00
64.45
C


ATOM
2731
O
THR
A
1155
−19.099
16.761
1.152
1.00
68.53
O


ATOM
2732
CB
THR
A
1155
−18.559
13.651
1.688
1.00
64.46
C


ATOM
2733
OG1
THR
A
1155
−17.194
13.690
2.122
1.00
66.24
O


ATOM
2734
CG2
THR
A
1155
−18.952
12.209
1.401
1.00
63.74
C


ATOM
2735
N
GLY
A
1156
−16.990
16.209
0.604
1.00
63.43
N


ATOM
2736
CA
GLY
A
1156
−16.451
17.504
0.976
1.00
52.38
C


ATOM
2737
C
GLY
A
1156
−16.272
17.619
2.478
1.00
59.38
C


ATOM
2738
O
GLY
A
1156
−16.257
18.720
3.029
1.00
65.43
O


ATOM
2739
N
THR
A
1157
−16.144
16.473
3.140
1.00
60.48
N


ATOM
2740
CA
THR
A
1157
−15.913
16.428
4.581
1.00
59.84
C


ATOM
2741
C
THR
A
1157
−14.654
15.619
4.889
1.00
62.03
C


ATOM
2742
O
THR
A
1157
−13.999
15.108
3.980
1.00
54.89
O


ATOM
2743
CB
THR
A
1157
−17.102
15.796
5.328
1.00
60.37
C


ATOM
2744
OG1
THR
A
1157
−17.213
14.412
4.973
1.00
61.50
O


ATOM
2745
CG2
THR
A
1157
−18.399
16.511
4.979
1.00
57.26
C


ATOM
2746
N
TRP
A
1158
−14.322
15.504
6.172
1.00
62.65
N


ATOM
2747
CA
TRP
A
1158
−13.158
14.731
6.597
1.00
50.99
C


ATOM
2748
C
TRP
A
1158
−13.567
13.332
7.050
1.00
55.09
C


ATOM
2749
O
TRP
A
1158
−12.792
12.634
7.703
1.00
53.77
O


ATOM
2750
CB
TRP
A
1158
−12.424
15.438
7.739
1.00
49.70
C


ATOM
2751
CG
TRP
A
1158
−11.927
16.819
7.410
1.00
53.10
C


ATOM
2752
CD1
TRP
A
1158
−12.463
18.003
7.828
1.00
48.59
C


ATOM
2753
CD2
TRP
A
1158
−10.788
17.156
6.606
1.00
52.69
C


ATOM
2754
NE1
TRP
A
1158
−11.733
19.056
7.331
1.00
47.52
N


ATOM
2755
CE2
TRP
A
1158
−10.699
18.564
6.578
1.00
51.49
C


ATOM
2756
CE3
TRP
A
1158
−9.836
16.406
5.906
1.00
54.55
C


ATOM
2757
CZ2
TRP
A
1158
−9.697
19.236
5.878
1.00
54.10
C


ATOM
2758
CZ3
TRP
A
1158
−8.842
17.076
5.209
1.00
56.12
C


ATOM
2759
CH2
TRP
A
1158
−8.781
18.477
5.201
1.00
54.28
C


ATOM
2760
N
ASP
A
1159
−14.785
12.931
6.698
1.00
65.51
N


ATOM
2761
CA
ASP
A
1159
−15.348
11.656
7.142
1.00
64.81
C


ATOM
2762
C
ASP
A
1159
−14.380
10.482
7.040
1.00
63.07
C


ATOM
2763
O
ASP
A
1159
−14.143
9.777
8.021
1.00
65.38
O


ATOM
2764
CB
ASP
A
1159
−16.624
11.333
6.361
1.00
72.61
C


ATOM
2765
CG
ASP
A
1159
−17.812
12.150
6.822
1.00
82.71
C


ATOM
2766
OD1
ASP
A
1159
−17.631
13.026
7.695
1.00
86.35
O


ATOM
2767
OD2
ASP
A
1159
−18.927
11.911
6.313
1.00
86.00
O


ATOM
2768
N
ALA
A
1160
−13.831
10.273
5.847
1.00
61.75
N


ATOM
2769
CA
ALA
A
1160
−12.965
9.126
5.588
1.00
62.25
C


ATOM
2770
C
ALA
A
1160
−11.776
9.063
6.543
1.00
59.90
C


ATOM
2771
O
ALA
A
1160
−11.276
7.982
6.855
1.00
64.16
O


ATOM
2772
CB
ALA
A
1160
−12.487
9.138
4.141
1.00
57.82
C


ATOM
2773
N
TYR
A
1161
−11.326
10.223
7.007
1.00
46.32
N


ATOM
2774
CA
TYR
A
1161
−10.160
10.285
7.878
1.00
56.11
C


ATOM
2775
C
TYR
A
1161
−10.552
10.249
9.353
1.00
64.26
C


ATOM
2776
O
TYR
A
1161
−9.767
9.828
10.203
1.00
63.26
O


ATOM
2777
CB
TYR
A
1161
−9.314
11.518
7.551
1.00
51.64
C


ATOM
2778
CG
TYR
A
1161
−8.725
11.472
6.159
1.00
48.58
C


ATOM
2779
CD1
TYR
A
1161
−7.438
10.995
5.944
1.00
52.84
C


ATOM
2780
CD2
TYR
A
1161
−9.463
11.884
5.057
1.00
51.32
C


ATOM
2781
CE1
TYR
A
1161
−6.899
10.941
4.673
1.00
56.31
C


ATOM
2782
CE2
TYR
A
1161
−8.932
11.833
3.782
1.00
50.11
C


ATOM
2783
CZ
TYR
A
1161
−7.650
11.361
3.596
1.00
53.47
C


ATOM
2784
OH
TYR
A
1161
−7.118
11.308
2.328
1.00
61.20
O


ATOM
2785
N
ARG
A
222
−11.775
10.677
9.647
1.00
63.22
N


ATOM
2786
CA
ARG
A
222
−12.290
10.630
11.008
1.00
54.85
C


ATOM
2787
C
ARG
A
222
−12.676
9.199
11.369
1.00
55.79
C


ATOM
2788
O
ARG
A
222
−12.618
8.803
12.533
1.00
59.44
O


ATOM
2789
CB
ARG
A
222
−13.496
11.559
11.158
1.00
47.89
C


ATOM
2790
CG
ARG
A
222
−13.821
11.937
12.594
1.00
44.51
C


ATOM
2791
CD
ARG
A
222
−14.998
12.896
12.650
1.00
57.47
C


ATOM
2792
NE
ARG
A
222
−14.928
13.901
11.592
1.00
64.41
N


ATOM
2793
CZ
ARG
A
222
−14.362
15.094
11.731
1.00
67.61
C


ATOM
2794
NH1
ARG
A
222
−14.343
15.944
10.714
1.00
70.49
N


ATOM
2795
NH2
ARG
A
222
−13.814
15.439
12.887
1.00
76.31
N


ATOM
2796
N
SER
A
223
−13.067
8.427
10.359
1.00
64.48
N


ATOM
2797
CA
SER
A
223
−13.426
7.025
10.553
1.00
61.21
C


ATOM
2798
C
SER
A
223
−12.208
6.202
10.949
1.00
55.59
C


ATOM
2799
O
SER
A
223
−12.293
5.325
11.807
1.00
66.27
O


ATOM
2800
CB
SER
A
223
−14.053
6.445
9.283
1.00
63.78
C


ATOM
2801
OG
SER
A
223
−15.348
6.975
9.063
1.00
73.65
O


ATOM
2802
N
THR
A
224
−11.078
6.488
10.312
1.00
59.77
N


ATOM
2803
CA
THR
A
224
−9.833
5.790
10.605
1.00
61.54
C


ATOM
2804
C
THR
A
224
−9.468
5.912
12.080
1.00
64.45
C


ATOM
2805
O
THR
A
224
−9.091
4.932
12.720
1.00
71.97
O


ATOM
2806
CB
THR
A
224
−8.672
6.335
9.756
1.00
65.38
C


ATOM
2807
OG1
THR
A
224
−8.951
6.118
8.367
1.00
66.37
O


ATOM
2808
CG2
THR
A
224
−7.371
5.638
10.122
1.00
72.97
C


ATOM
2809
N
LEU
A
225
−9.588
7.122
12.615
1.00
68.66
N


ATOM
2810
CA
LEU
A
225
−9.235
7.385
14.005
1.00
73.76
C


ATOM
2811
C
LEU
A
225
−10.215
6.742
14.985
1.00
70.02
C


ATOM
2812
O
LEU
A
225
−9.818
6.275
16.052
1.00
69.10
O


ATOM
2813
CB
LEU
A
225
−9.154
8.893
14.258
1.00
74.09
C


ATOM
2814
CG
LEU
A
225
−8.155
9.679
13.406
1.00
67.08
C


ATOM
2815
CD1
LEU
A
225
−8.248
11.168
13.704
1.00
63.25
C


ATOM
2816
CD2
LEU
A
225
−6.738
9.171
13.630
1.00
63.08
C


ATOM
2817
N
GLN
A
226
−11.494
6.719
14.619
1.00
68.18
N


ATOM
2818
CA
GLN
A
226
−12.534
6.208
15.510
1.00
74.09
C


ATOM
2819
C
GLN
A
226
−12.592
4.682
15.562
1.00
87.21
C


ATOM
2820
O
GLN
A
226
−13.175
4.109
16.483
1.00
93.97
O


ATOM
2821
CB
GLN
A
226
−13.902
6.788
15.137
1.00
79.24
C


ATOM
2822
CG
GLN
A
226
−14.149
8.182
15.698
1.00
92.86
C


ATOM
2823
CD
GLN
A
226
−15.426
8.812
15.175
1.00
103.30
C


ATOM
2824
OE1
GLN
A
226
−16.013
8.338
14.201
1.00
101.78
O


ATOM
2825
NE2
GLN
A
226
−15.861
9.889
15.818
1.00
106.94
N


ATOM
2826
N
LYS
A
227
−11.990
4.029
14.575
1.00
93.48
N


ATOM
2827
CA
LYS
A
227
−11.891
2.574
14.580
1.00
99.60
C


ATOM
2828
C
LYS
A
227
−10.575
2.157
15.222
1.00
97.48
C


ATOM
2829
O
LYS
A
227
−10.461
1.078
15.803
1.00
93.64
O


ATOM
2830
CB
LYS
A
227
−11.977
2.021
13.156
1.00
105.62
C


ATOM
2831
CG
LYS
A
227
−13.293
2.310
12.452
1.00
113.43
C


ATOM
2832
CD
LYS
A
227
−13.339
1.654
11.081
1.00
121.57
C


ATOM
2833
CE
LYS
A
227
−14.691
1.854
10.415
1.00
126.74
C


ATOM
2834
NZ
LYS
A
227
−14.764
1.183
9.087
1.00
125.91
N


ATOM
2835
N
GLU
A
228
−9.586
3.037
15.115
1.00
99.97
N


ATOM
2836
CA
GLU
A
228
−8.250
2.792
15.640
1.00
102.09
C


ATOM
2837
C
GLU
A
228
−8.217
3.003
17.153
1.00
95.46
C


ATOM
2838
O
GLU
A
228
−7.149
3.043
17.761
1.00
97.03
O


ATOM
2839
CB
GLU
A
228
−7.256
3.732
14.951
1.00
110.17
C


ATOM
2840
CG
GLU
A
228
−5.793
3.347
15.081
1.00
116.21
C


ATOM
2841
CD
GLU
A
228
−4.899
4.177
14.175
1.00
121.31
C


ATOM
2842
OE1
GLU
A
228
−5.392
4.661
13.133
1.00
122.62
O


ATOM
2843
OE2
GLU
A
228
−3.704
4.342
14.501
1.00
121.41
O


ATOM
2844
N
VAL
A
229
−9.397
3.131
17.754
1.00
89.29
N


ATOM
2845
CA
VAL
A
229
−9.511
3.446
19.176
1.00
87.67
C


ATOM
2846
C
VAL
A
229
−10.665
2.692
19.841
1.00
94.90
C


ATOM
2847
O
VAL
A
229
−10.672
2.495
21.057
1.00
100.49
O


ATOM
2848
CB
VAL
A
229
−9.673
4.973
19.393
1.00
74.61
C


ATOM
2849
CG1
VAL
A
229
−10.374
5.271
20.710
1.00
79.78
C


ATOM
2850
CG2
VAL
A
229
−8.320
5.666
19.329
1.00
71.97
C


ATOM
2851
N
HIS
A
230
−11.631
2.262
19.035
1.00
94.88
N


ATOM
2852
CA
HIS
A
230
−12.804
1.554
19.544
1.00
93.82
C


ATOM
2853
C
HIS
A
230
−12.439
0.366
20.434
1.00
88.38
C


ATOM
2854
O
HIS
A
230
−13.137
0.068
21.403
1.00
85.57
O


ATOM
2855
CB
HIS
A
230
−13.693
1.089
18.388
1.00
101.70
C


ATOM
2856
CG
HIS
A
230
−14.795
0.167
18.806
1.00
110.55
C


ATOM
2857
ND1
HIS
A
230
−15.886
0.591
19.534
1.00
113.44
N


ATOM
2858
CD2
HIS
A
230
−14.977
−1.159
18.594
1.00
113.59
C


ATOM
2859
CE1
HIS
A
230
−16.691
−0.433
19.755
1.00
114.04
C


ATOM
2860
NE2
HIS
A
230
−16.162
−1.506
19.195
1.00
115.00
N


ATOM
2861
N
ALA
A
231
−11.346
−0.311
20.099
1.00
83.31
N


ATOM
2862
CA
ALA
A
231
−10.897
−1.466
20.869
1.00
73.51
C


ATOM
2863
C
ALA
A
231
−10.318
−1.045
22.217
1.00
67.57
C


ATOM
2864
O
ALA
A
231
−10.462
−1.754
23.214
1.00
63.31
O


ATOM
2865
CB
ALA
A
231
−9.874
−2.268
20.075
1.00
70.46
C


ATOM
2866
N
ALA
A
232
−9.666
0.112
22.242
1.00
62.86
N


ATOM
2867
CA
ALA
A
232
−9.054
0.617
23.465
1.00
58.92
C


ATOM
2868
C
ALA
A
232
−10.106
1.015
24.499
1.00
63.13
C


ATOM
2869
O
ALA
A
232
−9.813
1.103
25.692
1.00
62.57
O


ATOM
2870
CB
ALA
A
232
−8.133
1.788
23.156
1.00
56.61
C


ATOM
2871
N
LYS
A
233
−11.330
1.258
24.041
1.00
69.07
N


ATOM
2872
CA
LYS
A
233
−12.415
1.559
24.964
1.00
76.63
C


ATOM
2873
C
LYS
A
233
−12.798
0.302
25.738
1.00
72.76
C


ATOM
2874
O
LYS
A
233
−13.029
0.352
26.947
1.00
67.54
O


ATOM
2875
CB
LYS
A
233
−13.633
2.121
24.230
1.00
85.44
C


ATOM
2876
CG
LYS
A
233
−14.674
2.714
25.169
1.00
96.75
C


ATOM
2877
CD
LYS
A
233
−16.029
2.875
24.501
1.00
98.56
C


ATOM
2878
CE
LYS
A
233
−17.081
3.308
25.512
1.00
93.74
C


ATOM
2879
NZ
LYS
A
233
−18.444
3.366
24.917
1.00
92.86
N


ATOM
2880
N
SER
A
234
−12.859
−0.824
25.032
1.00
66.51
N


ATOM
2881
CA
SER
A
234
−13.153
−2.111
25.652
1.00
58.02
C


ATOM
2882
C
SER
A
234
−12.181
−2.393
26.791
1.00
55.39
C


ATOM
2883
O
SER
A
234
−12.586
−2.758
27.895
1.00
55.03
O


ATOM
2884
CB
SER
A
234
−13.064
−3.236
24.619
1.00
64.77
C


ATOM
2885
OG
SER
A
234
−13.873
−2.969
23.488
1.00
67.08
O


ATOM
2886
N
LEU
A
235
−10.893
−2.218
26.513
1.00
49.24
N


ATOM
2887
CA
LEU
A
235
−9.844
−2.486
27.491
1.00
56.30
C


ATOM
2888
C
LEU
A
235
−9.870
−1.488
28.646
1.00
60.55
C


ATOM
2889
O
LEU
A
235
−9.561
−1.838
29.784
1.00
62.35
O


ATOM
2890
CB
LEU
A
235
−8.473
−2.475
26.813
1.00
58.60
C


ATOM
2891
CG
LEU
A
235
−8.301
−3.468
25.659
1.00
64.45
C


ATOM
2892
CD1
LEU
A
235
−7.050
−3.159
24.851
1.00
67.68
C


ATOM
2893
CD2
LEU
A
235
−8.274
−4.899
26.177
1.00
62.86
C


ATOM
2894
N
ALA
A
236
−10.237
−0.245
28.350
1.00
65.50
N


ATOM
2895
CA
ALA
A
236
−10.314
0.791
29.375
1.00
65.44
C


ATOM
2896
C
ALA
A
236
−11.406
0.471
30.392
1.00
66.83
C


ATOM
2897
O
ALA
A
236
−11.276
0.775
31.580
1.00
63.16
O


ATOM
2898
CB
ALA
A
236
−10.554
2.152
28.741
1.00
58.67
C


ATOM
2899
N
ILE
A
237
−12.484
−0.144
29.916
1.00
61.25
N


ATOM
2900
CA
ILE
A
237
−13.571
−0.575
30.784
1.00
58.85
C


ATOM
2901
C
ILE
A
237
−13.067
−1.595
31.799
1.00
61.27
C


ATOM
2902
O
ILE
A
237
−13.527
−1.632
32.940
1.00
62.54
O


ATOM
2903
CB
ILE
A
237
−14.729
−1.177
29.965
1.00
63.78
C


ATOM
2904
CG1
ILE
A
237
−15.422
−0.080
29.154
1.00
67.34
C


ATOM
2905
CG2
ILE
A
237
−15.725
−1.885
30.874
1.00
59.36
C


ATOM
2906
CD1
ILE
A
237
−16.417
−0.598
28.141
1.00
65.54
C


ATOM
2907
N
ILE
A
238
−12.110
−2.417
31.377
1.00
54.13
N


ATOM
2908
CA
ILE
A
238
−11.506
−3.413
32.254
1.00
50.65
C


ATOM
2909
C
ILE
A
238
−10.858
−2.764
33.474
1.00
54.49
C


ATOM
2910
O
ILE
A
238
−10.987
−3.261
34.592
1.00
52.88
O


ATOM
2911
CB
ILE
A
238
−10.443
−4.243
31.512
1.00
63.67
C


ATOM
2912
CG1
ILE
A
238
−11.053
−4.929
30.288
1.00
65.11
C


ATOM
2913
CG2
ILE
A
238
−9.819
−5.269
32.447
1.00
67.31
C


ATOM
2914
CD1
ILE
A
238
−12.018
−6.042
30.624
1.00
57.47
C


ATOM
2915
N
VAL
A
239
−10.158
−1.655
33.255
1.00
58.50
N


ATOM
2916
CA
VAL
A
239
−9.477
−0.957
34.340
1.00
57.59
C


ATOM
2917
C
VAL
A
239
−10.471
−0.282
35.280
1.00
60.82
C


ATOM
2918
O
VAL
A
239
−10.279
−0.269
36.495
1.00
69.52
O


ATOM
2919
CB
VAL
A
239
−8.495
0.109
33.813
1.00
56.53
C


ATOM
2920
CG1
VAL
A
239
−7.679
0.688
34.962
1.00
52.49
C


ATOM
2921
CG2
VAL
A
239
−7.581
−0.482
32.751
1.00
47.11
C


ATOM
2922
N
GLY
A
240
−11.530
0.283
34.708
1.00
56.92
N


ATOM
2923
CA
GLY
A
240
−12.555
0.949
35.491
1.00
53.42
C


ATOM
2924
C
GLY
A
240
−13.228
0.010
36.473
1.00
55.72
C


ATOM
2925
O
GLY
A
240
−13.550
0.396
37.597
1.00
58.38
O


ATOM
2926
N
LEU
A
241
−13.437
−1.231
36.046
1.00
56.22
N


ATOM
2927
CA
LEU
A
241
−14.073
−2.234
36.893
1.00
53.25
C


ATOM
2928
C
LEU
A
241
−13.127
−2.721
37.986
1.00
52.70
C


ATOM
2929
O
LEU
A
241
−13.542
−2.934
39.126
1.00
53.95
O


ATOM
2930
CB
LEU
A
241
−14.577
−3.406
36.050
1.00
50.95
C


ATOM
2931
CG
LEU
A
241
−15.793
−3.087
35.176
1.00
56.54
C


ATOM
2932
CD1
LEU
A
241
−16.031
−4.179
34.148
1.00
61.81
C


ATOM
2933
CD2
LEU
A
241
−17.033
−2.873
36.033
1.00
53.32
C


ATOM
2934
N
PHE
A
242
−11.857
−2.893
37.637
1.00
52.97
N


ATOM
2935
CA
PHE
A
242
−10.845
−3.248
38.626
1.00
57.03
C


ATOM
2936
C
PHE
A
242
−10.835
−2.225
39.757
1.00
50.20
C


ATOM
2937
O
PHE
A
242
−10.903
−2.582
40.933
1.00
52.63
O


ATOM
2938
CB
PHE
A
242
−9.461
−3.326
37.979
1.00
61.25
C


ATOM
2939
CG
PHE
A
242
−8.366
−3.710
38.935
1.00
61.49
C


ATOM
2940
CD1
PHE
A
242
−7.961
−5.030
39.050
1.00
57.01
C


ATOM
2941
CD2
PHE
A
242
−7.745
−2.752
39.721
1.00
60.29
C


ATOM
2942
CE1
PHE
A
242
−6.956
−5.388
39.929
1.00
59.54
C


ATOM
2943
CE2
PHE
A
242
−6.740
−3.104
40.604
1.00
56.46
C


ATOM
2944
CZ
PHE
A
242
−6.344
−4.424
40.707
1.00
60.63
C


ATOM
2945
N
ALA
A
243
−10.750
−0.949
39.388
1.00
53.71
N


ATOM
2946
CA
ALA
A
243
−10.740
0.140
40.360
1.00
51.85
C


ATOM
2947
C
ALA
A
243
−11.982
0.108
41.240
1.00
57.86
C


ATOM
2948
O
ALA
A
243
−11.899
0.271
42.456
1.00
62.06
O


ATOM
2949
CB
ALA
A
243
−10.634
1.478
39.648
1.00
47.00
C


ATOM
2950
N
LEU
A
244
−13.134
−0.104
40.614
1.00
56.95
N


ATOM
2951
CA
LEU
A
244
−14.403
−0.139
41.328
1.00
59.28
C


ATOM
2952
C
LEU
A
244
−14.451
−1.279
42.344
1.00
58.13
C


ATOM
2953
O
LEU
A
244
−14.981
−1.119
43.443
1.00
56.58
O


ATOM
2954
CB
LEU
A
244
−15.560
−0.274
40.336
1.00
63.16
C


ATOM
2955
CG
LEU
A
244
−16.968
−0.045
40.883
1.00
71.96
C


ATOM
2956
CD1
LEU
A
244
−17.124
1.389
41.368
1.00
73.10
C


ATOM
2957
CD2
LEU
A
244
−18.009
−0.377
39.825
1.00
77.80
C


ATOM
2958
N
CYS
A
245
−13.890
−2.425
41.973
1.00
56.88
N


ATOM
2959
CA
CYS
A
245
−13.943
−3.617
42.816
1.00
53.36
C


ATOM
2960
C
CYS
A
245
−12.944
−3.597
43.974
1.00
56.84
C


ATOM
2961
O
CYS
A
245
−13.134
−4.295
44.971
1.00
56.12
O


ATOM
2962
CB
CYS
A
245
−13.727
−4.879
41.974
1.00
51.05
C


ATOM
2963
SG
CYS
A
245
−15.093
−5.300
40.862
1.00
71.51
S


ATOM
2964
N
TRP
A
246
−11.886
−2.802
43.845
1.00
62.05
N


ATOM
2965
CA
TRP
A
246
−10.810
−2.816
44.836
1.00
58.73
C


ATOM
2966
C
TRP
A
246
−10.731
−1.573
45.717
1.00
53.00
C


ATOM
2967
O
TRP
A
246
−10.282
−1.649
46.860
1.00
66.02
O


ATOM
2968
CB
TRP
A
246
−9.459
−3.066
44.161
1.00
49.83
C


ATOM
2969
CG
TRP
A
246
−9.238
−4.503
43.819
1.00
55.02
C


ATOM
2970
CD1
TRP
A
246
−9.386
−5.088
42.595
1.00
52.27
C


ATOM
2971
CD2
TRP
A
246
−8.842
−5.547
44.718
1.00
55.69
C


ATOM
2972
NE1
TRP
A
246
−9.100
−6.430
42.675
1.00
56.58
N


ATOM
2973
CE2
TRP
A
246
−8.763
−6.736
43.967
1.00
60.63
C


ATOM
2974
CE3
TRP
A
246
−8.542
−5.589
46.083
1.00
47.83
C


ATOM
2975
CZ2
TRP
A
246
−8.398
−7.956
44.536
1.00
57.03
C


ATOM
2976
CZ3
TRP
A
246
−8.178
−6.799
46.645
1.00
54.20
C


ATOM
2977
CH2
TRP
A
246
−8.110
−7.966
45.874
1.00
49.71
C


ATOM
2978
N
LEU
A
247
−11.160
−0.431
45.191
1.00
47.85
N


ATOM
2979
CA
LEU
A
247
−11.084
0.818
45.946
1.00
56.76
C


ATOM
2980
C
LEU
A
247
−11.787
0.768
47.308
1.00
53.51
C


ATOM
2981
O
LEU
A
247
−11.209
1.180
48.312
1.00
51.99
O


ATOM
2982
CB
LEU
A
247
−11.585
2.002
45.112
1.00
56.86
C


ATOM
2983
CG
LEU
A
247
−10.563
2.572
44.125
1.00
62.68
C


ATOM
2984
CD1
LEU
A
247
−11.165
3.706
43.310
1.00
65.61
C


ATOM
2985
CD2
LEU
A
247
−9.313
3.037
44.860
1.00
64.98
C


ATOM
2986
N
PRO
A
248
−13.033
0.263
47.348
1.00
50.58
N


ATOM
2987
CA
PRO
A
248
−13.748
0.185
48.629
1.00
54.33
C


ATOM
2988
C
PRO
A
248
−12.893
−0.404
49.751
1.00
58.13
C


ATOM
2989
O
PRO
A
248
−12.811
0.180
50.831
1.00
61.00
O


ATOM
2990
CB
PRO
A
248
−14.921
−0.741
48.311
1.00
53.67
C


ATOM
2991
CG
PRO
A
248
−15.196
−0.493
46.870
1.00
54.83
C


ATOM
2992
CD
PRO
A
248
−13.859
−0.221
46.227
1.00
50.82
C


ATOM
2993
N
LEU
A
249
−12.261
−1.544
49.495
1.00
60.08
N


ATOM
2994
CA
LEU
A
249
−11.425
−2.190
50.499
1.00
57.57
C


ATOM
2995
C
LEU
A
249
−10.244
−1.305
50.898
1.00
58.63
C


ATOM
2996
O
LEU
A
249
−9.921
−1.184
52.081
1.00
56.45
O


ATOM
2997
CB
LEU
A
249
−10.934
−3.548
49.990
1.00
61.18
C


ATOM
2998
CG
LEU
A
249
−10.316
−4.500
51.017
1.00
53.65
C


ATOM
2999
CD1
LEU
A
249
−11.125
−4.505
52.305
1.00
48.86
C


ATOM
3000
CD2
LEU
A
249
−10.203
−5.908
50.444
1.00
42.89
C


ATOM
3001
N
HIS
A
250
−9.606
−0.685
49.909
1.00
56.86
N


ATOM
3002
CA
HIS
A
250
−8.469
0.196
50.163
1.00
55.17
C


ATOM
3003
C
HIS
A
250
−8.866
1.403
51.006
1.00
63.80
C


ATOM
3004
O
HIS
A
250
−8.135
1.810
51.909
1.00
64.24
O


ATOM
3005
CB
HIS
A
250
−7.849
0.675
48.850
1.00
48.72
C


ATOM
3006
CG
HIS
A
250
−7.085
−0.383
48.119
1.00
50.95
C


ATOM
3007
ND1
HIS
A
250
−5.943
−0.961
48.627
1.00
59.40
N


ATOM
3008
CD2
HIS
A
250
−7.293
−0.958
46.911
1.00
55.60
C


ATOM
3009
CE1
HIS
A
250
−5.483
−1.854
47.767
1.00
57.33
C


ATOM
3010
NE2
HIS
A
250
−6.284
−1.870
46.718
1.00
60.80
N


ATOM
3011
N
ILE
A
251
−10.024
1.977
50.699
1.00
66.61
N


ATOM
3012
CA
ILE
A
251
−10.500
3.163
51.400
1.00
69.77
C


ATOM
3013
C
ILE
A
251
−10.815
2.855
52.860
1.00
68.61
C


ATOM
3014
O
ILE
A
251
−10.497
3.643
53.751
1.00
63.38
O


ATOM
3015
CB
ILE
A
251
−11.743
3.762
50.714
1.00
73.55
C


ATOM
3016
CG1
ILE
A
251
−11.443
4.065
49.245
1.00
76.67
C


ATOM
3017
CG2
ILE
A
251
−12.195
5.023
51.437
1.00
70.80
C


ATOM
3018
CD1
ILE
A
251
−12.633
4.593
48.472
1.00
83.10
C


ATOM
3019
N
ILE
A
252
−11.437
1.704
53.098
1.00
66.56
N


ATOM
3020
CA
ILE
A
252
−11.742
1.268
54.457
1.00
58.35
C


ATOM
3021
C
ILE
A
252
−10.462
1.104
55.274
1.00
63.00
C


ATOM
3022
O
ILE
A
252
−10.417
1.455
56.453
1.00
66.64
O


ATOM
3023
CB
ILE
A
252
−12.530
−0.052
54.464
1.00
49.93
C


ATOM
3024
CG1
ILE
A
252
−13.925
0.161
53.877
1.00
48.84
C


ATOM
3025
CG2
ILE
A
252
−12.633
−0.604
55.875
1.00
46.06
C


ATOM
3026
CD1
ILE
A
252
−14.764
−1.098
53.831
1.00
44.16
C


ATOM
3027
N
ASN
A
253
−9.423
0.569
54.641
1.00
58.47
N


ATOM
3028
CA
ASN
A
253
−8.125
0.442
55.292
1.00
51.43
C


ATOM
3029
C
ASN
A
253
−7.597
1.802
55.737
1.00
57.18
C


ATOM
3030
O
ASN
A
253
−7.055
1.940
56.834
1.00
55.26
O


ATOM
3031
CB
ASN
A
253
−7.119
−0.239
54.362
1.00
54.71
C


ATOM
3032
CG
ASN
A
253
−7.341
−1.736
54.258
1.00
61.98
C


ATOM
3033
OD1
ASN
A
253
−8.046
−2.329
55.073
1.00
66.43
O


ATOM
3034
ND2
ASN
A
253
−6.734
−2.355
53.254
1.00
61.89
N


ATOM
3035
N
CYS
A
254
−7.766
2.803
54.879
1.00
55.71
N


ATOM
3036
CA
CYS
A
254
−7.315
4.158
55.176
1.00
58.66
C


ATOM
3037
C
CYS
A
254
−8.019
4.726
56.405
1.00
64.06
C


ATOM
3038
O
CYS
A
254
−7.388
5.357
57.252
1.00
58.54
O


ATOM
3039
CB
CYS
A
254
−7.531
5.073
53.968
1.00
53.92
C


ATOM
3040
SG
CYS
A
254
−6.517
4.654
52.531
1.00
64.49
S


ATOM
3041
N
PHE
A
255
−9.327
4.503
56.495
1.00
63.30
N


ATOM
3042
CA
PHE
A
255
−10.099
4.925
57.661
1.00
66.97
C


ATOM
3043
C
PHE
A
255
−9.546
4.321
58.942
1.00
66.28
C


ATOM
3044
O
PHE
A
255
−9.179
5.035
59.878
1.00
67.75
O


ATOM
3045
CB
PHE
A
255
−11.572
4.538
57.501
1.00
76.04
C


ATOM
3046
CG
PHE
A
255
−12.398
5.571
56.783
1.00
87.32
C


ATOM
3047
CD1
PHE
A
255
−12.154
5.875
55.453
1.00
88.11
C


ATOM
3048
CD2
PHE
A
255
−13.432
6.227
57.434
1.00
87.19
C


ATOM
3049
CE1
PHE
A
255
−12.917
6.822
54.790
1.00
86.46
C


ATOM
3050
CE2
PHE
A
255
−14.199
7.174
56.776
1.00
90.16
C


ATOM
3051
CZ
PHE
A
255
−13.940
7.471
55.451
1.00
87.09
C


ATOM
3052
N
THR
A
256
−9.510
2.993
58.979
1.00
63.39
N


ATOM
3053
CA
THR
A
256
−8.965
2.266
60.111
1.00
62.41
C


ATOM
3054
C
THR
A
256
−7.596
2.810
60.418
1.00
61.04
C


ATOM
3055
O
THR
A
256
−7.298
3.123
61.556
1.00
61.76
O


ATOM
3056
CB
THR
A
256
−8.810
0.762
59.806
1.00
65.65
C


ATOM
3057
OG1
THR
A
256
−10.077
0.227
59.397
1.00
75.23
O


ATOM
3058
CG2
THR
A
256
−8.272
0.017
61.030
1.00
57.49
C


ATOM
3059
N
PHE
A
257
−6.746
2.919
59.411
1.00
57.43
N


ATOM
3060
CA
PHE
A
257
−5.420
3.428
59.649
1.00
60.42
C


ATOM
3061
C
PHE
A
257
−5.300
4.856
60.222
1.00
68.32
C


ATOM
3062
O
PHE
A
257
−4.646
5.052
61.263
1.00
67.03
O


ATOM
3063
CB
PHE
A
257
−4.624
3.425
58.356
1.00
61.65
C


ATOM
3064
CG
PHE
A
257
−3.129
3.605
58.553
1.00
60.88
C


ATOM
3065
CD1
PHE
A
257
−2.457
4.625
57.895
1.00
62.58
C


ATOM
3066
CD2
PHE
A
257
−2.396
2.738
59.351
1.00
65.29
C


ATOM
3067
CE1
PHE
A
257
−1.084
4.801
58.055
1.00
64.53
C


ATOM
3068
CE2
PHE
A
257
−1.026
2.907
59.516
1.00
63.61
C


ATOM
3069
CZ
PHE
A
257
−0.365
3.937
58.870
1.00
62.25
C


ATOM
3070
N
PHE
A
258
−5.989
5.811
59.600
1.00
70.62
N


ATOM
3071
CA
PHE
A
258
−5.833
7.229
59.892
1.00
70.28
C


ATOM
3072
C
PHE
A
258
−6.705
7.669
61.074
1.00
71.13
C


ATOM
3073
O
PHE
A
258
−6.415
8.683
61.684
1.00
77.95
O


ATOM
3074
CB
PHE
A
258
−6.105
8.120
58.661
1.00
68.91
C


ATOM
3075
CG
PHE
A
258
−5.030
8.047
57.627
1.00
64.33
C


ATOM
3076
CD1
PHE
A
258
−5.313
7.633
56.338
1.00
56.40
C


ATOM
3077
CD2
PHE
A
258
−3.714
8.336
57.961
1.00
55.61
C


ATOM
3078
CE1
PHE
A
258
−4.319
7.544
55.393
1.00
55.10
C


ATOM
3079
CE2
PHE
A
258
−2.711
8.245
57.013
1.00
55.98
C


ATOM
3080
CZ
PHE
A
258
−3.019
7.849
55.731
1.00
56.46
C


ATOM
3081
N
CYS
A
259
−7.757
6.922
61.389
1.00
64.15
N


ATOM
3082
CA
CYS
A
259
−8.599
7.266
62.537
1.00
69.23
C


ATOM
3083
C
CYS
A
259
−8.664
6.097
63.508
1.00
73.08
C


ATOM
3084
O
CYS
A
259
−9.649
5.353
63.526
1.00
60.95
O


ATOM
3085
CB
CYS
A
259
−10.016
7.641
62.090
1.00
76.04
C


ATOM
3086
SG
CYS
A
259
−11.014
8.532
63.314
1.00
116.36
S


ATOM
3087
N
PRO
A
260
−7.610
5.929
64.318
1.00
82.55
N


ATOM
3088
CA
PRO
A
260
−7.395
4.767
65.187
1.00
85.53
C


ATOM
3089
C
PRO
A
260
−8.511
4.559
66.206
1.00
88.89
C


ATOM
3090
O
PRO
A
260
−8.921
3.421
66.432
1.00
86.25
O


ATOM
3091
CB
PRO
A
260
−6.087
5.109
65.911
1.00
90.07
C


ATOM
3092
CG
PRO
A
260
−5.415
6.114
65.041
1.00
92.31
C


ATOM
3093
CD
PRO
A
260
−6.520
6.910
64.429
1.00
88.02
C


ATOM
3094
N
ASP
A
261
−8.991
5.641
66.810
1.00
96.10
N


ATOM
3095
CA
ASP
A
261
−9.975
5.531
67.883
1.00
105.20
C


ATOM
3096
C
ASP
A
261
−11.417
5.743
67.423
1.00
108.40
C


ATOM
3097
O
ASP
A
261
−12.277
6.134
68.212
1.00
110.57
O


ATOM
3098
CB
ASP
A
261
−9.634
6.484
69.034
1.00
112.67
C


ATOM
3099
CG
ASP
A
261
−9.600
7.935
68.600
1.00
119.70
C


ATOM
3100
OD1
ASP
A
261
−10.062
8.237
67.479
1.00
122.59
O


ATOM
3101
OD2
ASP
A
261
−9.112
8.776
69.384
1.00
120.66
O


ATOM
3102
N
CYS
A
262
−11.676
5.488
66.145
1.00
106.67
N


ATOM
3103
CA
CYS
A
262
−13.041
5.484
65.634
1.00
98.77
C


ATOM
3104
C
CYS
A
262
−13.572
4.058
65.659
1.00
98.45
C


ATOM
3105
O
CYS
A
262
−12.797
3.103
65.648
1.00
96.66
O


ATOM
3106
CB
CYS
A
262
−13.092
6.036
64.211
1.00
93.04
C


ATOM
3107
SG
CYS
A
262
−12.743
7.799
64.087
1.00
150.04
S


ATOM
3108
N
SER
A
263
−14.892
3.914
65.699
1.00
100.70
N


ATOM
3109
CA
SER
A
263
−15.500
2.589
65.689
1.00
99.62
C


ATOM
3110
C
SER
A
263
−15.206
1.894
64.364
1.00
88.02
C


ATOM
3111
O
SER
A
263
−15.559
2.398
63.298
1.00
83.87
O


ATOM
3112
CB
SER
A
263
−17.010
2.676
65.929
1.00
98.59
C


ATOM
3113
OG
SER
A
263
−17.646
3.451
64.928
1.00
101.70
O


ATOM
3114
N
HIS
A
264
−14.550
0.741
64.439
1.00
80.43
N


ATOM
3115
CA
HIS
A
264
−14.152
0.005
63.245
1.00
73.18
C


ATOM
3116
C
HIS
A
264
−15.355
−0.349
62.375
1.00
71.92
C


ATOM
3117
O
HIS
A
264
−16.475
−0.476
62.868
1.00
74.56
O


ATOM
3118
CB
HIS
A
264
−13.393
−1.268
63.630
1.00
69.10
C


ATOM
3119
CG
HIS
A
264
−12.692
−1.924
62.481
1.00
66.84
C


ATOM
3120
ND1
HIS
A
264
−13.353
−2.688
61.543
1.00
57.95
N


ATOM
3121
CD2
HIS
A
264
−11.387
−1.931
62.120
1.00
63.05
C


ATOM
3122
CE1
HIS
A
264
−12.486
−3.134
60.651
1.00
54.47
C


ATOM
3123
NE2
HIS
A
264
−11.286
−2.690
60.979
1.00
62.11
N


ATOM
3124
N
ALA
A
265
−15.114
−0.502
61.077
1.00
72.64
N


ATOM
3125
CA
ALA
A
265
−16.159
−0.912
60.149
1.00
66.14
C


ATOM
3126
C
ALA
A
265
−16.736
−2.260
60.568
1.00
63.94
C


ATOM
3127
O
ALA
A
265
−15.990
−3.186
60.889
1.00
59.55
O


ATOM
3128
CB
ALA
A
265
−15.610
−0.984
58.735
1.00
57.93
C


ATOM
3129
N
PRO
A
266
−18.071
−2.373
60.568
1.00
60.88
N


ATOM
3130
CA
PRO
A
266
−18.739
−3.617
60.964
1.00
61.26
C


ATOM
3131
C
PRO
A
266
−18.298
−4.791
60.095
1.00
68.46
C


ATOM
3132
O
PRO
A
266
−17.888
−4.588
58.951
1.00
66.26
O


ATOM
3133
CB
PRO
A
266
−20.226
−3.314
60.740
1.00
63.31
C


ATOM
3134
CG
PRO
A
266
−20.270
−2.098
59.875
1.00
63.38
C


ATOM
3135
CD
PRO
A
266
−19.020
−1.331
60.141
1.00
62.42
C


ATOM
3136
N
LEU
A
267
−18.386
−6.002
60.637
1.00
73.04
N


ATOM
3137
CA
LEU
A
267
−17.934
−7.196
59.931
1.00
68.76
C


ATOM
3138
C
LEU
A
267
−18.657
−7.409
58.606
1.00
73.92
C


ATOM
3139
O
LEU
A
267
−18.049
−7.843
57.628
1.00
76.91
O


ATOM
3140
CB
LEU
A
267
−18.089
−8.438
60.811
1.00
74.70
C


ATOM
3141
CG
LEU
A
267
−17.278
−8.465
62.105
1.00
87.75
C


ATOM
3142
CD1
LEU
A
267
−17.136
−9.895
62.602
1.00
93.88
C


ATOM
3143
CD2
LEU
A
267
−15.914
−7.840
61.890
1.00
88.32
C


ATOM
3144
N
TRP
A
268
−19.953
−7.112
58.574
1.00
75.29
N


ATOM
3145
CA
TRP
A
268
−20.738
−7.305
57.358
1.00
72.96
C


ATOM
3146
C
TRP
A
268
−20.199
−6.449
56.216
1.00
68.67
C


ATOM
3147
O
TRP
A
268
−20.115
−6.904
55.076
1.00
70.33
O


ATOM
3148
CB
TRP
A
268
−22.226
−7.020
57.600
1.00
71.74
C


ATOM
3149
CG
TRP
A
268
−22.551
−5.571
57.818
1.00
72.86
C


ATOM
3150
CD1
TRP
A
268
−22.734
−4.943
59.016
1.00
72.03
C


ATOM
3151
CD2
TRP
A
268
−22.738
−4.571
56.809
1.00
69.70
C


ATOM
3152
NE1
TRP
A
268
−23.018
−3.614
58.816
1.00
72.90
N


ATOM
3153
CE2
TRP
A
268
−23.026
−3.360
57.470
1.00
68.79
C


ATOM
3154
CE3
TRP
A
268
−22.686
−4.581
55.410
1.00
68.51
C


ATOM
3155
CZ2
TRP
A
268
−23.262
−2.171
56.781
1.00
63.90
C


ATOM
3156
CZ3
TRP
A
268
−22.919
−3.399
54.728
1.00
67.40
C


ATOM
3157
CH2
TRP
A
268
−23.205
−2.211
55.414
1.00
68.89
C


ATOM
3158
N
LEU
A
269
−19.827
−5.211
56.528
1.00
61.76
N


ATOM
3159
CA
LEU
A
269
−19.253
−4.318
55.529
1.00
66.77
C


ATOM
3160
C
LEU
A
269
−17.882
−4.817
55.097
1.00
70.22
C


ATOM
3161
O
LEU
A
269
−17.525
−4.755
53.920
1.00
68.84
O


ATOM
3162
CB
LEU
A
269
−19.139
−2.893
56.075
1.00
60.72
C


ATOM
3163
CG
LEU
A
269
−18.371
−1.905
55.191
1.00
60.57
C


ATOM
3164
CD1
LEU
A
269
−18.995
−1.813
53.805
1.00
59.88
C


ATOM
3165
CD2
LEU
A
269
−18.301
−0.533
55.842
1.00
57.44
C


ATOM
3166
N
MET
A
270
−17.118
−5.319
56.060
1.00
69.40
N


ATOM
3167
CA
MET
A
270
−15.766
−5.786
55.795
1.00
66.60
C


ATOM
3168
C
MET
A
270
−15.766
−6.934
54.790
1.00
64.78
C


ATOM
3169
O
MET
A
270
−15.067
−6.886
53.778
1.00
70.55
O


ATOM
3170
CB
MET
A
270
−15.090
−6.221
57.096
1.00
68.62
C


ATOM
3171
CG
MET
A
270
−13.621
−5.860
57.165
1.00
75.47
C


ATOM
3172
SD
MET
A
270
−13.379
−4.076
57.266
1.00
69.50
S


ATOM
3173
CE
MET
A
270
−11.601
−3.970
57.080
1.00
77.08
C


ATOM
3174
N
TYR
A
271
−16.559
−7.964
55.069
1.00
58.09
N


ATOM
3175
CA
TYR
A
271
−16.615
−9.132
54.197
1.00
63.50
C


ATOM
3176
C
TYR
A
271
−17.362
−8.845
52.899
1.00
61.99
C


ATOM
3177
O
TYR
A
271
−17.279
−9.615
51.943
1.00
66.32
O


ATOM
3178
CB
TYR
A
271
−17.221
−10.332
54.931
1.00
65.57
C


ATOM
3179
CG
TYR
A
271
−16.272
−10.942
55.937
1.00
72.21
C


ATOM
3180
CD1
TYR
A
271
−15.270
−11.813
55.531
1.00
76.07
C


ATOM
3181
CD2
TYR
A
271
−16.364
−10.632
57.287
1.00
74.68
C


ATOM
3182
CE1
TYR
A
271
−14.392
−12.366
56.441
1.00
79.02
C


ATOM
3183
CE2
TYR
A
271
−15.489
−11.181
58.206
1.00
80.17
C


ATOM
3184
CZ
TYR
A
271
−14.505
−12.048
57.777
1.00
82.39
C


ATOM
3185
OH
TYR
A
271
−13.631
−12.599
58.686
1.00
86.30
O


ATOM
3186
N
LEU
A
272
−18.080
−7.729
52.866
1.00
58.87
N


ATOM
3187
CA
LEU
A
272
−18.768
−7.311
51.652
1.00
61.48
C


ATOM
3188
C
LEU
A
272
−17.763
−6.709
50.676
1.00
63.21
C


ATOM
3189
O
LEU
A
272
−17.865
−6.901
49.465
1.00
63.88
O


ATOM
3190
CB
LEU
A
272
−19.875
−6.308
51.980
1.00
63.94
C


ATOM
3191
CG
LEU
A
272
−20.917
−6.032
50.893
1.00
71.79
C


ATOM
3192
CD1
LEU
A
272
−22.254
−5.654
51.514
1.00
78.35
C


ATOM
3193
CD2
LEU
A
272
−20.438
−4.952
49.933
1.00
78.54
C


ATOM
3194
N
ALA
A
273
−16.787
−5.985
51.214
1.00
65.29
N


ATOM
3195
CA
ALA
A
273
−15.734
−5.393
50.399
1.00
65.95
C


ATOM
3196
C
ALA
A
273
−14.786
−6.473
49.892
1.00
62.33
C


ATOM
3197
O
ALA
A
273
−14.212
−6.356
48.809
1.00
58.46
O


ATOM
3198
CB
ALA
A
273
−14.974
−4.345
51.194
1.00
69.13
C


ATOM
3199
N
ILE
A
274
−14.629
−7.527
50.687
1.00
70.67
N


ATOM
3200
CA
ILE
A
274
−13.780
−8.654
50.319
1.00
66.36
C


ATOM
3201
C
ILE
A
274
−14.413
−9.482
49.202
1.00
60.04
C


ATOM
3202
O
ILE
A
274
−13.742
−9.855
48.241
1.00
57.42
O


ATOM
3203
CB
ILE
A
274
−13.480
−9.550
51.535
1.00
63.35
C


ATOM
3204
CG1
ILE
A
274
−12.554
−8.819
52.511
1.00
54.86
C


ATOM
3205
CG2
ILE
A
274
−12.860
−10.864
51.091
1.00
61.51
C


ATOM
3206
CD1
ILE
A
274
−12.396
−9.515
53.846
1.00
52.45
C


ATOM
3207
N
VAL
A
275
−15.707
−9.761
49.329
1.00
51.59
N


ATOM
3208
CA
VAL
A
275
−16.438
−10.478
48.289
1.00
55.45
C


ATOM
3209
C
VAL
A
275
−16.405
−9.700
46.977
1.00
60.96
C


ATOM
3210
O
VAL
A
275
−16.211
−10.274
45.903
1.00
63.73
O


ATOM
3211
CB
VAL
A
275
−17.906
−10.723
48.693
1.00
58.12
C


ATOM
3212
CG1
VAL
A
275
−18.697
−11.279
47.517
1.00
56.24
C


ATOM
3213
CG2
VAL
A
275
−17.979
−11.666
49.883
1.00
52.83
C


ATOM
3214
N
LEU
A
276
−16.591
−8.389
47.076
1.00
62.28
N


ATOM
3215
CA
LEU
A
276
−16.586
−7.512
45.909
1.00
55.72
C


ATOM
3216
C
LEU
A
276
−15.272
−7.592
45.134
1.00
56.54
C


ATOM
3217
O
LEU
A
276
−15.271
−7.709
43.907
1.00
53.88
O


ATOM
3218
CB
LEU
A
276
−16.862
−6.068
46.338
1.00
60.34
C


ATOM
3219
CG
LEU
A
276
−16.746
−4.977
45.273
1.00
58.30
C


ATOM
3220
CD1
LEU
A
276
−17.644
−5.280
44.082
1.00
51.32
C


ATOM
3221
CD2
LEU
A
276
−17.084
−3.622
45.874
1.00
51.37
C


ATOM
3222
N
SER
A
277
−14.154
−7.530
45.852
1.00
54.17
N


ATOM
3223
CA
SER
A
277
−12.841
−7.559
45.218
1.00
55.56
C


ATOM
3224
C
SER
A
277
−12.603
−8.874
44.481
1.00
59.78
C


ATOM
3225
O
SER
A
277
−11.899
−8.910
43.471
1.00
64.00
O


ATOM
3226
CB
SER
A
277
−11.735
−7.324
46.250
1.00
52.24
C


ATOM
3227
OG
SER
A
277
−11.650
−8.403
47.164
1.00
53.55
O


ATOM
3228
N
HIS
A
278
−13.194
−9.952
44.989
1.00
59.02
N


ATOM
3229
CA
HIS
A
278
−13.048
−11.266
44.370
1.00
61.28
C


ATOM
3230
C
HIS
A
278
−13.870
−11.380
43.093
1.00
58.63
C


ATOM
3231
O
HIS
A
278
−13.520
−12.134
42.185
1.00
51.04
O


ATOM
3232
CB
HIS
A
278
−13.449
−12.376
45.344
1.00
65.43
C


ATOM
3233
CG
HIS
A
278
−12.540
−12.501
46.525
1.00
67.86
C


ATOM
3234
ND1
HIS
A
278
−12.995
−12.832
47.782
1.00
67.54
N


ATOM
3235
CD2
HIS
A
278
−11.202
−12.329
46.641
1.00
74.86
C


ATOM
3236
CE1
HIS
A
278
−11.974
−12.867
48.621
1.00
75.63
C


ATOM
3237
NE2
HIS
A
278
−10.876
−12.564
47.954
1.00
77.19
N


ATOM
3238
N
THR
A
279
−14.968
−10.633
43.031
1.00
59.28
N


ATOM
3239
CA
THR
A
279
−15.844
−10.652
41.867
1.00
63.73
C


ATOM
3240
C
THR
A
279
−15.120
−10.105
40.640
1.00
61.31
C


ATOM
3241
O
THR
A
279
−15.466
−10.429
39.502
1.00
57.13
O


ATOM
3242
CB
THR
A
279
−17.134
−9.843
42.122
1.00
72.10
C


ATOM
3243
OG1
THR
A
279
−17.865
−10.435
43.204
1.00
63.41
O


ATOM
3244
CG2
THR
A
279
−18.012
−9.825
40.881
1.00
80.19
C


ATOM
3245
N
ASN
A
280
−14.103
−9.284
40.882
1.00
56.25
N


ATOM
3246
CA
ASN
A
280
−13.321
−8.689
39.805
1.00
58.40
C


ATOM
3247
C
ASN
A
280
−12.632
−9.731
38.929
1.00
63.48
C


ATOM
3248
O
ASN
A
280
−12.240
−9.443
37.798
1.00
70.65
O


ATOM
3249
CB
ASN
A
280
−12.281
−7.722
40.374
1.00
55.54
C


ATOM
3250
CG
ASN
A
280
−11.432
−7.081
39.294
1.00
61.10
C


ATOM
3251
OD1
ASN
A
280
−10.209
−7.212
39.291
1.00
68.02
O


ATOM
3252
ND2
ASN
A
280
−12.081
−6.389
38.364
1.00
56.63
N


ATOM
3253
N
SER
A
281
−12.484
−10.942
39.456
1.00
60.18
N


ATOM
3254
CA
SER
A
281
−11.821
−12.015
38.725
1.00
59.56
C


ATOM
3255
C
SER
A
281
−12.802
−12.799
37.858
1.00
61.03
C


ATOM
3256
O
SER
A
281
−12.443
−13.813
37.259
1.00
64.30
O


ATOM
3257
CB
SER
A
281
−11.101
−12.956
39.691
1.00
59.85
C


ATOM
3258
OG
SER
A
281
−10.035
−12.289
40.346
1.00
59.65
O


ATOM
3259
N
VAL
A
282
−14.038
−12.318
37.788
1.00
58.12
N


ATOM
3260
CA
VAL
A
282
−15.079
−12.993
37.025
1.00
64.59
C


ATOM
3261
C
VAL
A
282
−15.547
−12.167
35.827
1.00
60.34
C


ATOM
3262
O
VAL
A
282
−15.970
−12.719
34.812
1.00
60.47
O


ATOM
3263
CB
VAL
A
282
−16.301
−13.303
37.915
1.00
68.02
C


ATOM
3264
CG1
VAL
A
282
−17.359
−14.060
37.126
1.00
74.18
C


ATOM
3265
CG2
VAL
A
282
−15.875
−14.093
39.142
1.00
65.29
C


ATOM
3266
N
VAL
A
283
−15.455
−10.846
35.949
1.00
56.58
N


ATOM
3267
CA
VAL
A
283
−16.075
−9.930
34.990
1.00
55.89
C


ATOM
3268
C
VAL
A
283
−15.399
−9.853
33.619
1.00
59.63
C


ATOM
3269
O
VAL
A
283
−16.071
−9.657
32.606
1.00
58.80
O


ATOM
3270
CB
VAL
A
283
−16.187
−8.504
35.574
1.00
51.46
C


ATOM
3271
CG1
VAL
A
283
−17.233
−8.466
36.678
1.00
46.59
C


ATOM
3272
CG2
VAL
A
283
−14.839
−8.034
36.097
1.00
46.82
C


ATOM
3273
N
ASN
A
284
−14.078
−10.003
33.587
1.00
59.43
N


ATOM
3274
CA
ASN
A
284
−13.316
−9.827
32.350
1.00
58.91
C


ATOM
3275
C
ASN
A
284
−13.806
−10.646
31.149
1.00
59.42
C


ATOM
3276
O
ASN
A
284
−14.026
−10.091
30.072
1.00
56.86
O


ATOM
3277
CB
ASN
A
284
−11.820
−10.062
32.587
1.00
64.06
C


ATOM
3278
CG
ASN
A
284
−11.172
−8.939
33.371
1.00
59.03
C


ATOM
3279
OD1
ASN
A
284
−11.850
−8.030
33.851
1.00
60.87
O


ATOM
3280
ND2
ASN
A
284
−9.851
−8.994
33.504
1.00
52.55
N


ATOM
3281
N
PRO
A
285
−13.970
−11.968
31.324
1.00
58.83
N


ATOM
3282
CA
PRO
A
285
−14.420
−12.801
30.202
1.00
59.51
C


ATOM
3283
C
PRO
A
285
−15.742
−12.309
29.612
1.00
64.98
C


ATOM
3284
O
PRO
A
285
−15.917
−12.343
28.393
1.00
69.54
O


ATOM
3285
CB
PRO
A
285
−14.605
−14.180
30.843
1.00
57.41
C


ATOM
3286
CG
PRO
A
285
−13.697
−14.173
32.023
1.00
56.69
C


ATOM
3287
CD
PRO
A
285
−13.722
−12.764
32.539
1.00
55.55
C


ATOM
3288
N
PHE
A
286
−16.654
−11.860
30.470
1.00
62.03
N


ATOM
3289
CA
PHE
A
286
−17.950
−11.357
30.023
1.00
66.17
C


ATOM
3290
C
PHE
A
286
−17.789
−10.122
29.145
1.00
62.53
C


ATOM
3291
O
PHE
A
286
−18.522
−9.937
28.174
1.00
64.75
O


ATOM
3292
CB
PHE
A
286
−18.847
−11.034
31.221
1.00
65.80
C


ATOM
3293
CG
PHE
A
286
−19.409
−12.249
31.906
1.00
66.00
C


ATOM
3294
CD1
PHE
A
286
−18.751
−12.822
32.982
1.00
63.52
C


ATOM
3295
CD2
PHE
A
286
−20.595
−12.817
31.473
1.00
67.24
C


ATOM
3296
CE1
PHE
A
286
−19.267
−13.939
33.613
1.00
68.78
C


ATOM
3297
CE2
PHE
A
286
−21.115
−13.935
32.101
1.00
65.33
C


ATOM
3298
CZ
PHE
A
286
−20.451
−14.496
33.171
1.00
69.42
C


ATOM
3299
N
ILE
A
287
−16.823
−9.280
29.495
1.00
59.29
N


ATOM
3300
CA
ILE
A
287
−16.561
−8.055
28.750
1.00
60.52
C


ATOM
3301
C
ILE
A
287
−16.008
−8.349
27.358
1.00
66.84
C


ATOM
3302
O
ILE
A
287
−16.424
−7.735
26.375
1.00
74.69
O


ATOM
3303
CB
ILE
A
287
−15.589
−7.145
29.515
1.00
64.57
C


ATOM
3304
CG1
ILE
A
287
−16.139
−6.861
30.913
1.00
63.24
C


ATOM
3305
CG2
ILE
A
287
−15.358
−5.850
28.750
1.00
64.66
C


ATOM
3306
CD1
ILE
A
287
−15.083
−6.504
31.922
1.00
70.55
C


ATOM
3307
N
TYR
A
288
−15.072
−9.289
27.275
1.00
69.29
N


ATOM
3308
CA
TYR
A
288
−14.516
−9.687
25.988
1.00
65.51
C


ATOM
3309
C
TYR
A
288
−15.621
−10.195
25.067
1.00
68.22
C


ATOM
3310
O
TYR
A
288
−15.616
−9.926
23.866
1.00
64.34
O


ATOM
3311
CB
TYR
A
288
−13.449
−10.771
26.159
1.00
54.27
C


ATOM
3312
CG
TYR
A
288
−12.305
−10.390
27.072
1.00
57.57
C


ATOM
3313
CD1
TYR
A
288
−11.762
−9.115
27.042
1.00
65.41
C


ATOM
3314
CD2
TYR
A
288
−11.756
−11.315
27.950
1.00
61.99
C


ATOM
3315
CE1
TYR
A
288
−10.713
−8.765
27.872
1.00
70.11
C


ATOM
3316
CE2
TYR
A
288
−10.706
−10.976
28.782
1.00
61.62
C


ATOM
3317
CZ
TYR
A
288
−10.188
−9.700
28.739
1.00
68.27
C


ATOM
3318
OH
TYR
A
288
−9.142
−9.354
29.565
1.00
65.39
O


ATOM
3319
N
ALA
A
289
−16.567
−10.931
25.641
1.00
71.89
N


ATOM
3320
CA
ALA
A
289
−17.669
−11.501
24.875
1.00
65.85
C


ATOM
3321
C
ALA
A
289
−18.582
−10.419
24.304
1.00
69.72
C


ATOM
3322
O
ALA
A
289
−18.965
−10.472
23.134
1.00
66.15
O


ATOM
3323
CB
ALA
A
289
−18.465
−12.472
25.735
1.00
49.46
C


ATOM
3324
N
TYR
A
290
−18.924
−9.436
25.132
1.00
65.07
N


ATOM
3325
CA
TYR
A
290
−19.839
−8.374
24.725
1.00
76.34
C


ATOM
3326
C
TYR
A
290
−19.234
−7.391
23.725
1.00
75.32
C


ATOM
3327
O
TYR
A
290
−19.890
−7.001
22.759
1.00
74.69
O


ATOM
3328
CB
TYR
A
290
−20.354
−7.604
25.944
1.00
85.34
C


ATOM
3329
CG
TYR
A
290
−21.489
−8.283
26.676
1.00
100.57
C


ATOM
3330
CD1
TYR
A
290
−22.657
−8.634
26.012
1.00
105.71
C


ATOM
3331
CD2
TYR
A
290
−21.401
−8.556
28.034
1.00
110.70
C


ATOM
3332
CE1
TYR
A
290
−23.700
−9.250
26.678
1.00
109.30
C


ATOM
3333
CE2
TYR
A
290
−22.439
−9.172
28.709
1.00
113.10
C


ATOM
3334
CZ
TYR
A
290
−23.586
−9.516
28.025
1.00
110.15
C


ATOM
3335
OH
TYR
A
290
−24.622
−10.128
28.692
1.00
108.86
O


ATOM
3336
N
ARG
A
291
−17.987
−6.990
23.957
1.00
70.17
N


ATOM
3337
CA
ARG
A
291
−17.407
−5.882
23.201
1.00
70.63
C


ATOM
3338
C
ARG
A
291
−16.383
−6.289
22.145
1.00
67.32
C


ATOM
3339
O
ARG
A
291
−16.150
−5.549
21.190
1.00
71.30
O


ATOM
3340
CB
ARG
A
291
−16.798
−4.847
24.151
1.00
75.59
C


ATOM
3341
CG
ARG
A
291
−17.736
−4.406
25.261
1.00
76.34
C


ATOM
3342
CD
ARG
A
291
−17.363
−3.033
25.793
1.00
82.64
C


ATOM
3343
NE
ARG
A
291
−17.908
−1.957
24.969
1.00
89.34
N


ATOM
3344
CZ
ARG
A
291
−17.265
−1.390
23.954
1.00
94.49
C


ATOM
3345
NH1
ARG
A
291
−16.046
−1.792
23.629
1.00
90.92
N


ATOM
3346
NH2
ARG
A
291
−17.842
−0.417
23.262
1.00
100.91
N


ATOM
3347
N
ILE
A
292
−15.769
−7.455
22.311
1.00
67.04
N


ATOM
3348
CA
ILE
A
292
−14.772
−7.912
21.345
1.00
63.61
C


ATOM
3349
C
ILE
A
292
−15.295
−9.067
20.496
1.00
71.59
C


ATOM
3350
O
ILE
A
292
−15.572
−10.154
20.999
1.00
75.25
O


ATOM
3351
CB
ILE
A
292
−13.446
−8.301
22.020
1.00
58.94
C


ATOM
3352
CG1
ILE
A
292
−12.979
−7.180
22.950
1.00
59.71
C


ATOM
3353
CG2
ILE
A
292
−12.387
−8.599
20.969
1.00
47.29
C


ATOM
3354
CD1
ILE
A
292
−11.564
−7.352
23.455
1.00
63.50
C


ATOM
3355
N
ARG
A
293
−15.416
−8.811
19.198
1.00
80.32
N


ATOM
3356
CA
ARG
A
293
−16.036
−9.744
18.263
1.00
81.56
C


ATOM
3357
C
ARG
A
293
−15.274
−11.063
18.111
1.00
73.75
C


ATOM
3358
O
ARG
A
293
−15.871
−12.140
18.167
1.00
64.51
O


ATOM
3359
CB
ARG
A
293
−16.206
−9.066
16.901
1.00
86.33
C


ATOM
3360
CG
ARG
A
293
−16.739
−9.965
15.804
1.00
93.96
C


ATOM
3361
CD
ARG
A
293
−16.782
−9.220
14.480
1.00
104.85
C


ATOM
3362
NE
ARG
A
293
−16.744
−10.130
13.339
1.00
115.28
N


ATOM
3363
CZ
ARG
A
293
−15.636
−10.707
12.885
1.00
117.34
C


ATOM
3364
NH1
ARG
A
293
−14.474
−10.474
13.480
1.00
115.03
N


ATOM
3365
NH2
ARG
A
293
−15.688
−11.521
11.839
1.00
117.81
N


ATOM
3366
N
GLU
A
294
−13.961
−10.979
17.920
1.00
71.43
N


ATOM
3367
CA
GLU
A
294
−13.154
−12.171
17.670
1.00
70.71
C


ATOM
3368
C
GLU
A
294
−13.092
−13.104
18.885
1.00
69.04
C


ATOM
3369
O
GLU
A
294
−12.837
−14.300
18.741
1.00
70.01
O


ATOM
3370
CB
GLU
A
294
−11.743
−11.790
17.206
1.00
77.58
C


ATOM
3371
CG
GLU
A
294
−10.964
−12.934
16.557
1.00
87.68
C


ATOM
3372
CD
GLU
A
294
−11.184
−13.028
15.055
1.00
94.15
C


ATOM
3373
OE1
GLU
A
294
−11.220
−11.972
14.390
1.00
102.95
O


ATOM
3374
OE2
GLU
A
294
−11.306
−14.159
14.536
1.00
88.18
O


ATOM
3375
N
PHE
A
295
−13.317
−12.556
20.077
1.00
65.53
N


ATOM
3376
CA
PHE
A
295
−13.416
−13.376
21.282
1.00
58.28
C


ATOM
3377
C
PHE
A
295
−14.772
−14.065
21.330
1.00
66.01
C


ATOM
3378
O
PHE
A
295
−14.863
−15.276
21.531
1.00
67.76
O


ATOM
3379
CB
PHE
A
295
−13.225
−12.532
22.546
1.00
54.43
C


ATOM
3380
CG
PHE
A
295
−11.796
−12.427
23.000
1.00
61.07
C


ATOM
3381
CD1
PHE
A
295
−11.181
−13.488
23.646
1.00
65.14
C


ATOM
3382
CD2
PHE
A
295
−11.071
−11.266
22.791
1.00
58.98
C


ATOM
3383
CE1
PHE
A
295
−9.866
−13.395
24.067
1.00
61.07
C


ATOM
3384
CE2
PHE
A
295
−9.756
−11.166
23.210
1.00
60.30
C


ATOM
3385
CZ
PHE
A
295
−9.153
−12.231
23.849
1.00
58.30
C


ATOM
3386
N
ARG
A
296
−15.825
−13.276
21.140
1.00
61.80
N


ATOM
3387
CA
ARG
A
296
−17.193
−13.776
21.163
1.00
62.20
C


ATOM
3388
C
ARG
A
296
−17.389
−14.945
20.198
1.00
65.25
C


ATOM
3389
O
ARG
A
296
−17.998
−15.956
20.548
1.00
66.81
O


ATOM
3390
CB
ARG
A
296
−18.168
−12.643
20.831
1.00
64.51
C


ATOM
3391
CG
ARG
A
296
−19.635
−13.035
20.882
1.00
69.78
C


ATOM
3392
CD
ARG
A
296
−20.543
−11.810
20.794
1.00
70.98
C


ATOM
3393
NE
ARG
A
296
−20.388
−11.085
19.534
1.00
72.95
N


ATOM
3394
CZ
ARG
A
296
−19.688
−9.962
19.395
1.00
72.01
C


ATOM
3395
NH1
ARG
A
296
−19.604
−9.375
18.208
1.00
64.97
N


ATOM
3396
NH2
ARG
A
296
−19.073
−9.425
20.440
1.00
72.68
N


ATOM
3397
N
GLN
A
297
−16.866
−14.804
18.985
1.00
62.87
N


ATOM
3398
CA
GLN
A
297
−17.005
−15.846
17.973
1.00
63.27
C


ATOM
3399
C
GLN
A
297
−16.233
−17.111
18.339
1.00
62.10
C


ATOM
3400
O
GLN
A
297
−16.684
−18.222
18.061
1.00
56.97
O


ATOM
3401
CB
GLN
A
297
−16.562
−15.329
16.602
1.00
71.42
C


ATOM
3402
CG
GLN
A
297
−17.526
−14.334
15.978
1.00
83.47
C


ATOM
3403
CD
GLN
A
297
−17.069
−13.852
14.615
1.00
91.02
C


ATOM
3404
OE1
GLN
A
297
−15.887
−13.929
14.279
1.00
94.57
O


ATOM
3405
NE2
GLN
A
297
−18.008
−13.349
13.821
1.00
90.28
N


ATOM
3406
N
THR
A
298
−15.071
−16.940
18.960
1.00
66.11
N


ATOM
3407
CA
THR
A
298
−14.259
−18.079
19.370
1.00
60.32
C


ATOM
3408
C
THR
A
298
−14.892
−18.796
20.559
1.00
61.09
C


ATOM
3409
O
THR
A
298
−14.816
−20.020
20.668
1.00
60.48
O


ATOM
3410
CB
THR
A
298
−12.821
−17.659
19.724
1.00
59.44
C


ATOM
3411
OG1
THR
A
298
−12.229
−16.988
18.605
1.00
61.44
O


ATOM
3412
CG2
THR
A
298
−11.983
−18.879
20.075
1.00
54.14
C


ATOM
3413
N
PHE
A
299
−15.520
−18.030
21.446
1.00
61.13
N


ATOM
3414
CA
PHE
A
299
−16.214
−18.612
22.588
1.00
61.43
C


ATOM
3415
C
PHE
A
299
−17.369
−19.496
22.127
1.00
69.99
C


ATOM
3416
O
PHE
A
299
−17.487
−20.647
22.552
1.00
69.95
O


ATOM
3417
CB
PHE
A
299
−16.725
−17.526
23.537
1.00
55.14
C


ATOM
3418
CG
PHE
A
299
−15.636
−16.784
24.258
1.00
58.19
C


ATOM
3419
CD1
PHE
A
299
−14.375
−17.338
24.398
1.00
58.68
C


ATOM
3420
CD2
PHE
A
299
−15.883
−15.541
24.817
1.00
60.11
C


ATOM
3421
CE1
PHE
A
299
−13.374
−16.657
25.066
1.00
58.66
C


ATOM
3422
CE2
PHE
A
299
−14.887
−14.857
25.490
1.00
65.03
C


ATOM
3423
CZ
PHE
A
299
−13.631
−15.416
25.614
1.00
61.60
C


ATOM
3424
N
ARG
A
300
−18.221
−18.954
21.260
1.00
64.87
N


ATOM
3425
CA
ARG
A
300
−19.321
−19.728
20.691
1.00
69.72
C


ATOM
3426
C
ARG
A
300
−18.828
−21.043
20.103
1.00
70.15
C


ATOM
3427
O
ARG
A
300
−19.433
−22.094
20.313
1.00
67.05
O


ATOM
3428
CB
ARG
A
300
−20.048
−18.931
19.607
1.00
76.69
C


ATOM
3429
CG
ARG
A
300
−21.392
−18.376
20.035
1.00
86.88
C


ATOM
3430
CD
ARG
A
300
−22.287
−18.144
18.829
1.00
91.46
C


ATOM
3431
NE
ARG
A
300
−21.705
−17.181
17.901
1.00
87.22
N


ATOM
3432
CZ
ARG
A
300
−21.814
−15.864
18.033
1.00
86.03
C


ATOM
3433
NH1
ARG
A
300
−22.483
−15.354
19.059
1.00
92.89
N


ATOM
3434
NH2
ARG
A
300
−21.254
−15.056
17.144
1.00
75.92
N


ATOM
3435
N
LYS
A
301
−17.728
−20.972
19.361
1.00
69.60
N


ATOM
3436
CA
LYS
A
301
−17.153
−22.144
18.715
1.00
71.56
C


ATOM
3437
C
LYS
A
301
−16.710
−23.177
19.744
1.00
68.82
C


ATOM
3438
O
LYS
A
301
−16.936
−24.374
19.572
1.00
68.48
O


ATOM
3439
CB
LYS
A
301
−15.962
−21.735
17.848
1.00
79.63
C


ATOM
3440
CG
LYS
A
301
−15.271
−22.892
17.148
1.00
85.03
C


ATOM
3441
CD
LYS
A
301
−13.883
−22.491
16.677
1.00
95.12
C


ATOM
3442
CE
LYS
A
301
−13.921
−21.198
15.875
1.00
102.40
C


ATOM
3443
NZ
LYS
A
301
−12.554
−20.679
15.589
1.00
100.76
N


ATOM
3444
N
ILE
A
302
−16.077
−22.705
20.813
1.00
63.47
N


ATOM
3445
CA
ILE
A
302
−15.558
−23.588
21.851
1.00
67.91
C


ATOM
3446
C
ILE
A
302
−16.682
−24.247
22.642
1.00
68.98
C


ATOM
3447
O
ILE
A
302
−16.663
−25.455
22.881
1.00
71.20
O


ATOM
3448
CB
ILE
A
302
−14.629
−22.831
22.822
1.00
68.50
C


ATOM
3449
CG1
ILE
A
302
−13.359
−22.378
22.098
1.00
59.47
C


ATOM
3450
CG2
ILE
A
302
−14.283
−23.702
24.020
1.00
55.95
C


ATOM
3451
CD1
ILE
A
302
−12.365
−21.674
22.992
1.00
56.73
C


ATOM
3452
N
ILE
A
303
−17.660
−23.446
23.047
1.00
67.06
N


ATOM
3453
CA
ILE
A
303
−18.774
−23.945
23.842
1.00
66.18
C


ATOM
3454
C
ILE
A
303
−19.618
−24.951
23.064
1.00
71.40
C


ATOM
3455
O
ILE
A
303
−20.005
−25.992
23.595
1.00
76.63
O


ATOM
3456
CB
ILE
A
303
−19.660
−22.791
24.351
1.00
66.28
C


ATOM
3457
CG1
ILE
A
303
−18.863
−21.901
25.307
1.00
68.36
C


ATOM
3458
CG2
ILE
A
303
−20.904
−23.332
25.038
1.00
65.78
C


ATOM
3459
CD1
ILE
A
303
−19.660
−20.756
25.890
1.00
67.48
C


ATOM
3460
N
ARG
A
304
−19.891
−24.647
21.800
1.00
74.11
N


ATOM
3461
CA
ARG
A
304
−20.729
−25.516
20.981
1.00
75.45
C


ATOM
3462
C
ARG
A
304
−20.014
−26.773
20.489
1.00
74.61
C


ATOM
3463
O
ARG
A
304
−20.600
−27.854
20.461
1.00
73.65
O


ATOM
3464
CB
ARG
A
304
−21.341
−24.736
19.812
1.00
76.96
C


ATOM
3465
CG
ARG
A
304
−22.727
−24.203
20.133
1.00
87.23
C


ATOM
3466
CD
ARG
A
304
−23.068
−22.925
19.386
1.00
92.33
C


ATOM
3467
NE
ARG
A
304
−24.231
−22.277
19.989
1.00
101.86
N


ATOM
3468
CZ
ARG
A
304
−24.817
−21.181
19.516
1.00
103.97
C


ATOM
3469
NH1
ARG
A
304
−25.869
−20.670
20.141
1.00
98.37
N


ATOM
3470
NH2
ARG
A
304
−24.354
−20.598
18.419
1.00
105.11
N


ATOM
3471
N
SER
A
305
−18.747
−26.635
20.117
1.00
77.95
N


ATOM
3472
CA
SER
A
305
−18.000
−27.764
19.572
1.00
82.94
C


ATOM
3473
C
SER
A
305
−17.352
−28.649
20.637
1.00
80.18
C


ATOM
3474
O
SER
A
305
−17.592
−29.855
20.673
1.00
81.74
O


ATOM
3475
CB
SER
A
305
−16.951
−27.284
18.565
1.00
89.74
C


ATOM
3476
OG
SER
A
305
−17.557
−26.887
17.348
1.00
91.81
O


ATOM
3477
N
HIS
A
306
−16.537
−28.051
21.501
1.00
77.09
N


ATOM
3478
CA
HIS
A
306
−15.743
−28.826
22.454
1.00
77.23
C


ATOM
3479
C
HIS
A
306
−16.439
−29.072
23.793
1.00
75.01
C


ATOM
3480
O
HIS
A
306
−16.175
−30.071
24.457
1.00
74.86
O


ATOM
3481
CB
HIS
A
306
−14.384
−28.162
22.690
1.00
77.17
C


ATOM
3482
CG
HIS
A
306
−13.657
−27.813
21.431
1.00
88.23
C


ATOM
3483
ND1
HIS
A
306
−13.664
−26.542
20.896
1.00
99.08
N


ATOM
3484
CD2
HIS
A
306
−12.906
−28.568
20.595
1.00
93.77
C


ATOM
3485
CE1
HIS
A
306
−12.946
−26.529
19.788
1.00
99.06
C


ATOM
3486
NE2
HIS
A
306
−12.476
−27.747
19.582
1.00
96.06
N


ATOM
3487
N
VAL
A
307
−17.320
−28.163
24.191
1.00
68.66
N


ATOM
3488
CA
VAL
A
307
−17.978
−28.270
25.491
1.00
62.67
C


ATOM
3489
C
VAL
A
307
−19.256
−29.103
25.432
1.00
69.88
C


ATOM
3490
O
VAL
A
307
−19.410
−30.068
26.178
1.00
73.85
O


ATOM
3491
CB
VAL
A
307
−18.260
−26.879
26.099
1.00
56.26
C


ATOM
3492
CG1
VAL
A
307
−19.165
−26.999
27.314
1.00
48.63
C


ATOM
3493
CG2
VAL
A
307
−16.956
−26.186
26.469
1.00
52.95
C


ATOM
3494
N
LEU
A
308
−20.175
−28.725
24.553
1.00
80.85
N


ATOM
3495
CA
LEU
A
308
−21.364
−29.522
24.324
1.00
92.67
C


ATOM
3496
C
LEU
A
308
−20.998
−30.704
23.454
1.00
107.73
C


ATOM
3497
O
LEU
A
308
−21.699
−31.715
23.435
1.00
111.66
O


ATOM
3498
CB
LEU
A
308
−22.461
−28.668
23.673
1.00
86.67
C


ATOM
3499
CG
LEU
A
308
−23.432
−27.973
24.646
1.00
84.53
C


ATOM
3500
CD1
LEU
A
308
−22.791
−27.762
25.997
1.00
78.57
C


ATOM
3501
CD2
LEU
A
308
−23.883
−26.652
24.058
1.00
83.22
C


ATOM
2227
N
ARG
A
309
−19.878
−30.584
22.758
1.00
115.37
N


ATOM
2228
CA
ARG
A
309
−19.477
−31.616
21.824
1.00
114.52
C


ATOM
2229
C
ARG
A
309
−20.459
−31.736
20.690
1.00
110.36
C


ATOM
2237
O
ARG
A
309
−20.645
−32.827
20.154
1.00
107.74
O


ATOM
2230
CB
ARG
A
309
−19.368
−32.969
22.507
1.00
112.30
C


ATOM
2231
CG
ARG
A
309
−18.201
−33.061
23.453
1.00
103.01
C


ATOM
2232
CD
ARG
A
309
−16.877
−32.644
22.807
1.00
104.12
C


ATOM
2233
NE
ARG
A
309
−16.070
−33.794
22.388
1.00
113.70
N


ATOM
2234
CZ
ARG
A
309
−14.862
−33.698
21.840
1.00
125.17
C


ATOM
2235
NH1
ARG
A
309
−14.333
−32.500
21.621
1.00
130.11
N


ATOM
2236
NH2
ARG
A
309
−14.194
−34.792
21.497
1.00
126.66
N


ATOM
3513
N
GLN
A
310
−21.100
−30.616
20.366
1.00
111.32
N


ATOM
3514
CA
GLN
A
310
−22.030
−30.506
19.246
1.00
113.48
C


ATOM
3515
C
GLN
A
310
−23.336
−29.820
19.651
1.00
112.38
C


ATOM
3516
O
GLN
A
310
−23.606
−28.679
19.263
1.00
107.05
O


ATOM
3517
CB
GLN
A
310
−22.314
−31.870
18.620
1.00
118.22
C


ATOM
3518
CG
GLN
A
310
−22.486
−31.839
17.115
1.00
120.97
C


ATOM
3519
CD
GLN
A
310
−21.312
−31.188
16.403
1.00
120.49
C


ATOM
3520
OE1
GLN
A
310
−20.703
−30.245
16.912
1.00
119.20
O


ATOM
3521
NE2
GLN
A
310
−20.989
−31.690
15.215
1.00
118.40
N


TER
3522

GLN
A
310








HETATM
3523
C1
ZMA
A
401
−10.992
−8.796
60.617
1.00
104.51
C


HETATM
3524
C2
ZMA
A
401
−11.241
−8.297
61.889
1.00
106.65
C


HETATM
3525
C3
ZMA
A
401
−11.984
−7.133
62.045
1.00
104.03
C


HETATM
3526
C4
ZMA
A
401
−12.231
−6.638
63.286
1.00
109.18
O


HETATM
3527
C5
ZMA
A
401
−12.476
−6.469
60.928
1.00
95.90
C


HETATM
3528
C6
ZMA
A
401
−12.230
−6.969
59.657
1.00
93.55
C


HETATM
3529
C7
ZMA
A
401
−11.492
−8.135
59.501
1.00
91.84
C


HETATM
3530
C8
ZMA
A
401
−11.208
−8.677
58.101
1.00
72.50
C


HETATM
3531
C9
ZMA
A
401
−9.746
−9.104
58.006
1.00
56.96
C


HETATM
3532
N10
ZMA
A
401
−9.420
−9.544
56.644
1.00
49.16
N


HETATM
3533
C11
ZMA
A
401
−8.953
−8.593
55.842
1.00
53.12
C


HETATM
3534
N12
ZMA
A
401
−8.585
−8.857
54.578
1.00
51.75
N


HETATM
3535
N13
ZMA
A
401
−8.833
−7.359
56.358
1.00
54.15
N


HETATM
3536
C14
ZMA
A
401
−8.365
−6.342
55.626
1.00
57.39
C


HETATM
3537
N15
ZMA
A
401
−8.266
−5.125
56.156
1.00
58.08
N


HETATM
3538
N16
ZMA
A
401
−7.981
−6.582
54.309
1.00
52.32
N


HETATM
3539
N17
ZMA
A
401
−7.525
−5.852
53.428
1.00
49.90
N


HETATM
3540
C18
ZMA
A
401
−8.104
−7.874
53.800
1.00
47.64
C


HETATM
3541
N19
ZMA
A
401
−7.676
−7.829
52.544
1.00
53.04
N


HETATM
3542
C20
ZMA
A
401
−7.313
−6.565
52.320
1.00
51.81
C


HETATM
3543
C21
ZMA
A
401
−6.809
−6.054
51.131
1.00
49.80
C


HETATM
3544
C22
ZMA
A
401
−6.554
−6.688
49.991
1.00
47.99
C


HETATM
3545
C23
ZMA
A
401
−6.081
−5.796
49.121
1.00
53.65
C


HETATM
3546
C24
ZMA
A
401
−6.034
−4.598
49.703
1.00
50.25
C


HETATM
3547
O25
ZMA
A
401
−6.492
−4.739
50.984
1.00
51.60
O


HETATM
3548
C1
STE
A
402
−1.046
−19.906
26.269
1.00
101.96
C


HETATM
3549
O1
STE
A
402
−2.118
−20.474
26.029
1.00
102.79
O


HETATM
3550
O2
STE
A
402
−0.204
−19.579
25.428
1.00
104.67
O


HETATM
3551
C2
STE
A
402
−0.729
−19.550
27.709
1.00
95.33
C


HETATM
3552
C3
STE
A
402
−1.574
−20.321
28.715
1.00
89.62
C


HETATM
3553
C4
STE
A
402
−1.071
−20.087
30.137
1.00
79.90
C


HETATM
3554
C5
STE
A
402
−2.210
−20.089
31.126
1.00
76.48
C


HETATM
3555
C6
STE
A
402
−1.759
−20.748
32.401
1.00
80.09
C


HETATM
3556
C7
STE
A
402
−2.794
−20.596
33.492
1.00
80.87
C


HETATM
3557
C8
STE
A
402
−2.128
−20.715
34.853
1.00
85.07
C


HETATM
3558
C9
STE
A
402
−3.140
−21.015
35.946
1.00
84.90
C


HETATM
3559
C10
STE
A
402
−2.471
−21.555
37.199
1.00
84.71
C


HETATM
3560
C11
STE
A
402
−3.435
−21.496
38.371
1.00
78.33
C


HETATM
3561
C12
STE
A
402
−3.300
−22.696
39.292
1.00
77.12
C


HETATM
3562
C13
STE
A
402
−2.601
−22.325
40.583
1.00
78.65
C


HETATM
3563
C14
STE
A
402
−2.992
−23.264
41.711
1.00
89.02
C


HETATM
3564
C15
STE
A
402
−2.591
−24.716
41.436
1.00
96.19
C


HETATM
3565
C16
STE
A
402
−2.905
−25.630
42.614
1.00
93.19
C


HETATM
3566
C17
STE
A
402
−1.785
−26.625
42.842
1.00
91.32
C


HETATM
3567
C18
STE
A
402
−0.942
−26.260
44.054
1.00
92.30
C


HETATM
3568
C1
STE
A
403
2.094
−15.536
27.760
1.00
95.00
C


HETATM
3569
O1
STE
A
403
1.634
−15.661
26.622
1.00
93.81
O


HETATM
3570
O2
STE
A
403
3.214
−15.136
28.033
1.00
94.58
O


HETATM
3571
C2
STE
A
403
1.234
−15.919
28.942
1.00
92.42
C


HETATM
3572
C3
STE
A
403
2.079
−15.994
30.201
1.00
81.66
C


HETATM
3573
C4
STE
A
403
1.459
−16.895
31.248
1.00
70.47
C


HETATM
3574
C5
STE
A
403
1.973
−16.537
32.624
1.00
64.66
C


HETATM
3575
C6
STE
A
403
1.270
−17.363
33.677
1.00
69.35
C


HETATM
3576
C7
STE
A
403
2.021
−17.249
34.975
1.00
77.72
C


HETATM
3577
C8
STE
A
403
1.190
−17.752
36.135
1.00
91.26
C


HETATM
3578
C9
STE
A
403
2.067
−17.815
37.367
1.00
96.45
C


HETATM
3579
C10
STE
A
403
3.484
−17.447
36.957
1.00
96.09
C


HETATM
3580
C11
STE
A
403
4.480
−17.662
38.082
1.00
92.60
C


HETATM
3581
C12
STE
A
403
5.858
−17.424
37.530
1.00
90.95
C


HETATM
3582
C13
STE
A
403
5.691
−16.968
36.100
1.00
96.43
C


HETATM
3583
C14
STE
A
403
7.001
−16.997
35.326
1.00
98.01
C


HETATM
3584
C15
STE
A
403
6.760
−17.508
33.912
1.00
93.82
C


HETATM
3585
C16
STE
A
403
6.664
−16.379
32.898
1.00
88.04
C


HETATM
3586
C17
STE
A
403
6.587
−16.970
31.505
1.00
84.21
C


HETATM
3587
C18
STE
A
403
6.655
−15.899
30.432
1.00
81.40
C


HETATM
3588
C1
STE
A
404
−3.153
−27.554
60.261
1.00
103.30
C


HETATM
3589
O1
STE
A
404
−3.529
−28.476
59.547
1.00
109.79
O


HETATM
3590
O2
STE
A
404
−2.690
−27.688
61.393
1.00
104.10
O


HETATM
3591
C2
STE
A
404
−3.247
−26.158
59.677
1.00
102.90
C


HETATM
3592
C3
STE
A
404
−3.762
−26.201
58.238
1.00
101.88
C


HETATM
3593
C4
STE
A
404
−3.659
−24.839
57.554
1.00
98.59
C


HETATM
3594
C5
STE
A
404
−4.563
−24.744
56.330
1.00
91.91
C


HETATM
3595
C6
STE
A
404
−3.844
−24.106
55.159
1.00
87.51
C


HETATM
3596
C7
STE
A
404
−4.829
−23.479
54.190
1.00
88.98
C


HETATM
3597
C8
STE
A
404
−5.435
−24.525
53.268
1.00
93.83
C


HETATM
3598
C9
STE
A
404
−5.568
−24.029
51.829
1.00
94.43
C


HETATM
3599
C10
STE
A
404
−6.379
−24.985
50.965
1.00
88.89
C


HETATM
3600
C11
STE
A
404
−5.803
−25.169
49.565
1.00
87.37
C


HETATM
3601
C12
STE
A
404
−6.926
−25.384
48.569
1.00
88.79
C


HETATM
3602
C13
STE
A
404
−6.499
−26.077
47.286
1.00
92.60
C


HETATM
3603
C14
STE
A
404
−7.391
−25.619
46.131
1.00
92.44
C


HETATM
3604
C15
STE
A
404
−8.219
−26.742
45.516
1.00
89.47
C


HETATM
3605
C16
STE
A
404
−9.211
−26.219
44.473
1.00
87.54
C


HETATM
3606
C17
STE
A
404
−10.544
−25.833
45.105
1.00
87.34
C


HETATM
3607
C18
STE
A
404
−11.596
−25.386
44.090
1.00
89.75
C


HETATM
3608
C1
STE
A
405
0.152
−23.528
58.196
1.00
111.30
C


HETATM
3609
O1
STE
A
405
−0.397
−24.603
58.468
1.00
110.51
O


HETATM
3610
O2
STE
A
405
1.288
−23.176
58.523
1.00
109.34
O


HETATM
3611
C2
STE
A
405
−0.636
−22.544
57.379
1.00
110.04
C


HETATM
3612
C3
STE
A
405
0.092
−22.221
56.093
1.00
104.17
C


HETATM
3613
C4
STE
A
405
0.265
−23.452
55.238
1.00
99.26
C


HETATM
3614
C5
STE
A
405
1.325
−23.189
54.196
1.00
95.55
C


HETATM
3615
C6
STE
A
405
0.675
−22.754
52.908
1.00
95.95
C


HETATM
3616
C7
STE
A
405
−0.185
−23.862
52.352
1.00
94.84
C


HETATM
3617
C8
STE
A
405
−0.125
−23.885
50.837
1.00
96.47
C


HETATM
3618
C9
STE
A
405
−1.337
−24.617
50.305
1.00
100.46
C


HETATM
3619
C10
STE
A
405
−1.074
−25.145
48.916
1.00
103.76
C


HETATM
3620
C11
STE
A
405
0.168
−24.495
48.340
1.00
109.11
C


HETATM
3621
C12
STE
A
405
0.141
−24.617
46.825
1.00
115.54
C


HETATM
3622
C13
STE
A
405
1.293
−23.853
46.197
1.00
118.55
C


HETATM
3623
C14
STE
A
405
0.982
−22.369
46.115
1.00
117.71
C


HETATM
3624
C15
STE
A
405
2.032
−21.637
45.292
1.00
115.56
C


HETATM
3625
C16
STE
A
405
1.465
−21.223
43.950
1.00
115.41
C


HETATM
3626
C17
STE
A
405
1.803
−22.236
42.876
1.00
119.40
C


HETATM
3627
C18
STE
A
405
1.285
−21.764
41.521
1.00
121.54
C


HETATM
3628
C1
STE
A
406
−20.891
−16.658
25.051
1.00
114.47
C


HETATM
3629
O1
STE
A
406
−21.979
−17.227
24.883
1.00
113.81
O


HETATM
3630
O2
STE
A
406
−20.005
−16.531
24.201
1.00
120.50
O


HETATM
3631
C2
STE
A
406
−20.650
−16.009
26.398
1.00
105.97
C


HETATM
3632
C3
STE
A
406
−19.392
−16.484
27.101
1.00
94.17
C


HETATM
3633
C4
STE
A
406
−19.595
−16.363
28.606
1.00
88.47
C


HETATM
3634
C5
STE
A
406
−18.551
−15.501
29.283
1.00
84.32
C


HETATM
3635
C6
STE
A
406
−17.889
−16.272
30.404
1.00
84.58
C


HETATM
3636
C7
STE
A
406
−18.833
−17.282
31.044
1.00
83.94
C


HETATM
3637
C8
STE
A
406
−18.047
−18.291
31.866
1.00
84.78
C


HETATM
3638
C9
STE
A
406
−18.937
−19.293
32.581
1.00
94.09
C


HETATM
3639
C10
STE
A
406
−19.734
−20.139
31.598
1.00
101.66
C


HETATM
3640
C11
STE
A
406
−19.111
−21.519
31.398
1.00
102.56
C


HETATM
3641
C12
STE
A
406
−18.779
−21.810
29.936
1.00
98.89
C


HETATM
3642
C13
STE
A
406
−18.055
−23.146
29.786
1.00
94.04
C


HETATM
3643
C14
STE
A
406
−16.542
−22.999
29.854
1.00
84.78
C


HETATM
3644
C15
STE
A
406
−15.874
−24.343
29.625
1.00
82.44
C


HETATM
3645
C16
STE
A
406
−14.484
−24.391
30.239
1.00
82.54
C


HETATM
3646
C17
STE
A
406
−13.974
−25.820
30.413
1.00
86.31
C


HETATM
3647
C18
STE
A
406
−15.032
−26.777
30.967
1.00
89.29
C


HETATM
3648
S
SO4
A
407
−16.013
17.889
8.618
1.00
71.08
S


HETATM
3649
O1
SO4
A
407
−15.772
18.606
7.369
1.00
70.79
O


HETATM
3650
O2
SO4
A
407
−17.363
18.170
9.099
1.00
74.80
O


HETATM
3651
O3
SO4
A
407
−15.870
16.454
8.388
1.00
69.56
O


HETATM
3652
O4
SO4
A
407
−15.045
18.330
9.618
1.00
70.02
O


HETATM
3653
S
SO4
A
408
−21.572
−11.702
15.804
1.00
103.32
S


HETATM
3654
O1
SO4
A
408
−20.339
−12.039
15.098
1.00
95.44
O


HETATM
3655
O2
SO4
A
408
−22.722
−12.153
15.025
1.00
98.95
O


HETATM
3656
O3
SO4
A
408
−21.583
−12.357
17.108
1.00
106.55
O


HETATM
3657
O4
SO4
A
408
−21.648
−10.256
15.992
1.00
111.08
O


HETATM
3658
S
SO4
A
409
−1.181
13.819
19.630
1.00
161.08
S


HETATM
3659
O1
SO4
A
409
0.240
13.789
19.297
1.00
160.17
O


HETATM
3660
O2
SO4
A
409
−1.947
14.230
18.457
1.00
155.72
O


HETATM
3661
O3
SO4
A
409
−1.611
12.489
20.052
1.00
163.96
O


HETATM
3662
O4
SO4
A
409
−1.405
14.770
20.715
1.00
161.31
O


HETATM
3663
S
SO4
A
410
7.972
−18.865
62.180
1.00
120.92
S


HETATM
3664
O1
SO4
A
410
9.335
−19.359
62.016
1.00
120.10
O


HETATM
3665
O2
SO4
A
410
7.149
−19.327
61.066
1.00
121.73
O


HETATM
3666
O3
SO4
A
410
7.421
−19.370
63.435
1.00
126.13
O


HETATM
3667
O4
SO4
A
410
7.981
−17.405
62.209
1.00
117.47
O


HETATM
3668
S
SO4
A
411
−2.727
1.729
0.249
1.00
90.85
S


HETATM
3669
O1
SO4
A
411
−1.641
1.037
−0.437
1.00
93.45
O


HETATM
3670
O2
SO4
A
411
−3.903
1.753
−0.615
1.00
84.30
O


HETATM
3671
O3
SO4
A
411
−3.047
1.025
1.487
1.00
94.36
O


HETATM
3672
O4
SO4
A
411
−2.316
3.097
0.556
1.00
85.38
O


HETATM
3673
S
SO4
A
412
−9.473
10.595
−16.897
1.00
125.46
S


HETATM
3674
O1
SO4
A
412
−9.342
10.984
−15.496
1.00
123.21
O


HETATM
3675
O2
SO4
A
412
−8.433
9.627
−17.233
1.00
129.64
O


HETATM
3676
O3
SO4
A
412
−10.785
9.994
−17.117
1.00
125.41
O


HETATM
3677
O4
SO4
A
412
−9.327
11.772
−17.748
1.00
124.48
O


HETATM
3678
S
SO4
A
413
8.313
27.080
−6.220
1.00
135.28
S


HETATM
3679
O1
SO4
A
413
9.329
26.447
−7.057
1.00
136.47
O


HETATM
3680
O2
SO4
A
413
7.125
26.232
−6.170
1.00
135.42
O


HETATM
3681
O3
SO4
A
413
8.841
27.259
−4.871
1.00
134.96
O


HETATM
3682
O4
SO4
A
413
7.961
28.381
−6.781
1.00
133.33
O


HETATM
3683
O
HOH
A
501
−4.003
−15.002
49.894
1.00
39.38
O


HETATM
3684
O
HOH
A
502
−13.677
−3.697
47.669
1.00
56.51
O


HETATM
3685
O
HOH
A
503
4.543
14.639
0.918
1.00
61.93
O


HETATM
3686
O
HOH
A
504
−9.158
−12.000
33.321
1.00
49.62
O


HETATM
3687
O
HOH
A
505
−5.127
−1.172
51.443
1.00
46.10
O


HETATM
3688
O
HOH
A
506
−17.101
19.986
5.313
1.00
51.47
O


HETATM
3689
O
HOH
A
507
−5.526
−1.444
30.482
1.00
66.44
O


HETATM
3690
O
HOH
A
508
6.640
17.769
7.739
1.00
44.24
O


HETATM
3691
O
HOH
A
509
−7.997
−11.369
30.954
1.00
54.25
O


HETATM
3692
O
HOH
A
510
−3.644
10.800
−3.036
1.00
58.38
O


HETATM
3693
O
HOH
A
511
6.256
17.895
5.014
1.00
57.31
O


HETATM
3694
O
HOH
A
512
−11.483
−5.432
35.855
1.00
55.90
O


HETATM
3695
O
HOH
A
513
−7.564
−3.600
29.891
1.00
63.07
O


HETATM
3696
O
HOH
A
514
−6.981
−14.619
50.159
1.00
62.37
O


HETATM
3697
O
HOH
A
515
−20.577
15.269
−20.283
1.00
70.43
O


HETATM
3698
O
HOH
A
516
22.234
6.137
7.747
1.00
71.40
O


HETATM
3699
O
HOH
A
517
1.310
10.014
14.672
1.00
75.11
O


HETATM
3700
O
HOH
A
518
−14.139
−2.114
0.075
1.00
90.93
O


HETATM
3701
O
HOH
A
519
−12.282
−4.739
64.998
1.00
81.01
O


HETATM
3702
O
HOH
A
520
−12.042
14.729
14.732
1.00
57.68
O


HETATM
3703
O
HOH
A
521
11.352
11.509
0.390
1.00
75.94
O


HETATM
3704
O
HOH
A
522
−5.987
−12.917
52.690
1.00
58.26
O


HETATM
3705
O
HOH
A
523
−3.607
−14.642
12.010
1.00
71.00
O


HETATM
3706
O
HOH
A
524
6.119
16.982
0.205
1.00
67.99
O


HETATM
3707
O
HOH
A
525
−15.752
22.470
−8.387
1.00
84.60
O


HETATM
3708
O
HOH
A
526
−16.644
9.344
19.939
1.00
85.78
O


HETATM
3709
O
HOH
A
527
−6.739
16.284
20.625
1.00
58.78
O


HETATM
3710
O
HOH
A
528
−11.834
−13.848
54.529
1.00
65.53
O


HETATM
3711
O
HOH
A
529
23.206
13.737
16.558
1.00
88.35
O


HETATM
3712
O
HOH
A
530
−4.087
15.393
21.026
1.00
66.04
O


HETATM
3713
O
HOH
A
531
−9.101
−27.460
21.785
1.00
68.34
O


HETATM
3714
O
HOH
A
532
−4.878
−5.438
20.147
1.00
70.43
O


HETATM
3715
O
HOH
A
533
−1.895
5.381
2.984
1.00
67.30
O


HETATM
3716
O
HOH
A
534
11.438
26.901
12.887
1.00
69.64
O


HETATM
3717
O
HOH
A
535
−25.023
−20.750
22.895
1.00
86.87
O


HETATM
3718
O
HOH
A
536
20.060
24.828
0.145
1.00
77.10
O


HETATM
3719
O
HOH
A
537
−19.015
13.447
−21.620
1.00
86.21
O


HETATM
3720
O
HOH
A
538
−11.732
5.370
6.172
1.00
52.59
O


HETATM
3721
O
HOH
A
539
−26.040
11.567
−5.365
1.00
78.01
O


HETATM
3722
O
HOH
A
540
5.684
21.233
−2.210
1.00
78.48
O


HETATM
3723
O
HOH
A
541
−23.416
−15.905
21.628
1.00
95.02
O


HETATM
3724
O
HOH
A
542
−3.985
6.785
−13.345
1.00
76.20
O


HETATM
3725
O
HOH
A
543
−9.218
3.319
5.440
1.00
68.46
O


HETATM
3726
O
HOH
A
544
0.454
−4.371
14.142
1.00
84.88
O


HETATM
3727
O
HOH
A
545
25.820
8.802
7.267
1.00
71.66
O


HETATM
3728
O
HOH
A
546
−14.172
8.871
18.981
1.00
79.02
O


HETATM
3729
O
HOH
A
547
9.629
26.876
−9.684
1.00
85.70
O


HETATM
3730
O
HOH
A
548
−19.426
19.780
1.690
1.00
70.13
O


HETATM
3731
O
HOH
A
549
17.981
11.242
14.713
1.00
101.85
O


HETATM
3732
O
HOH
A
550
−8.855
−12.246
49.850
1.00
87.52
O


HETATM
3733
O
HOH
A
551
−3.487
12.915
12.787
1.00
81.37
O


HETATM
3734
O
HOH
A
552
−21.157
19.523
−1.468
1.00
65.04
O


HETATM
3735
O
HOH
A
553
−7.444
23.927
2.102
1.00
72.96
O


HETATM
3736
O
HOH
A
554
6.527
18.082
−13.999
1.00
72.46
O


HETATM
3737
O
HOH
A
555
2.725
27.302
9.910
1.00
83.25
O


HETATM
3738
O
HOH
A
556
2.815
8.178
12.101
1.00
65.16
O


HETATM
3739
O
HOH
A
557
−9.767
−27.548
18.960
1.00
83.73
O


HETATM
3740
O
HOH
A
558
−17.662
−33.104
19.064
1.00
74.19
O


HETATM
3741
O
HOH
A
559
−7.905
−10.299
51.015
1.00
78.06
O


HETATM
3742
O
HOH
A
560
−15.668
−5.885
18.003
1.00
64.11
O


HETATM
3743
O
HOH
A
561
4.221
13.041
23.505
1.00
87.64
O


HETATM
3744
O
HOH
A
562
−22.907
−19.674
24.204
1.00
100.51
O


HETATM
3745
O
HOH
A
563
−0.184
15.944
−18.355
1.00
71.91
O


HETATM
3746
O
HOH
A
564
0.221
−18.844
22.399
1.00
81.90
O


HETATM
3747
O
HOH
A
565
−3.535
−5.067
46.532
1.00
66.18
O


HETATM
3748
O
HOH
A
566
−13.528
12.732
3.850
1.00
60.28
O


HETATM
3749
O
HOH
A
567
−8.923
−11.777
53.200
1.00
80.35
O


HETATM
3750
O
HOH
A
568
−14.577
−0.624
66.710
1.00
70.25
O


HETATM
3751
O
HOH
A
569
0.504
−5.917
11.422
1.00
78.91
O


HETATM
3753
O
HOH
A
570
−0.067
−16.797
24.142
1.00
84.56
O


HETATM
3754
O
HOH
A
571
−17.836
−31.472
17.241
1.00
86.10
O


HETATM
3755
O
HOH
A
572
−5.995
−2.407
−6.585
1.00
77.37
O


HETATM
3756
O
HOH
A
573
−8.006
−8.469
64.051
1.00
62.98
O


HETATM
3757
O
HOH
A
574
−3.976
3.933
11.250
1.00
92.23
O


HETATM
3758
O
HOH
A
575
−2.323
−14.391
68.855
1.00
65.14
O


HETATM
3759
O
HOH
A
576
−7.912
−8.676
61.443
1.00
75.17
O


CONECT
507
1114











CONECT
523
1076











CONECT
543
1158











CONECT
1076
523











CONECT
1114
507











CONECT
1158
543











CONECT
3086
3107











CONECT
3107
3086











CONECT
3523
3524
3529










CONECT
3524
3523
3525










CONECT
3525
3524
3526
3527









CONECT
3526
3525











CONECT
3527
3525
3528










CONECT
3528
3527
3529










CONECT
3529
3523
3528
3530









CONECT
3530
3529
3531










CONECT
3531
3530
3532










CONECT
3532
3531
3533










CONECT
3533
3532
3534
3535









CONECT
3534
3533
3540










CONECT
3535
3533
3536










CONECT
3536
3535
3537
3538









CONECT
3537
3536











CONECT
3538
3536
3539
3540









CONECT
3539
3538
3542










CONECT
3540
3534
3538
3541









CONECT
3541
3540
3542










CONECT
3542
3539
3541
3543









CONECT
3543
3542
3544
3547









CONECT
3544
3543
3545










CONECT
3545
3544
3546










CONECT
3546
3545
3547










CONECT
3547
3543
3546










CONECT
3548
3549
3550
3551









CONECT
3549
3548











CONECT
3550
3548











CONECT
3551
3548
3552










CONECT
3552
3551
3553










CONECT
3553
3552
3554










CONECT
3554
3553
3555










CONECT
3555
3554
3556










CONECT
3556
3555
3557










CONECT
3557
3556
3558










CONECT
3558
3557
3559










CONECT
3559
3558
3560










CONECT
3560
3559
3561










CONECT
3561
3560
3562










CONECT
3562
3561
3563










CONECT
3563
3562
3564










CONECT
3564
3563
3565










CONECT
3565
3564
3566










CONECT
3566
3565
3567










CONECT
3567
3566











CONECT
3568
3569
3570
3571









CONECT
3569
3568











CONECT
3570
3568











CONECT
3571
3568
3572










CONECT
3572
3571
3573










CONECT
3573
3572
3574










CONECT
3574
3573
3575










CONECT
3575
3574
3576










CONECT
3576
3575
3577










CONECT
3577
3576
3578










CONECT
3578
3577
3579










CONECT
3579
3578
3580










CONECT
3580
3579
3581










CONECT
3581
3580
3582










CONECT
3582
3581
3583










CONECT
3583
3582
3584










CONECT
3584
3583
3585










CONECT
3585
3584
3586










CONECT
3586
3585
3587










CONECT
3587
3586











CONECT
3588
3589
3590
3591









CONECT
3589
3588











CONECT
3590
3588











CONECT
3591
3588
3592










CONECT
3592
3591
3593










CONECT
3593
3592
3594










CONECT
3594
3593
3595










CONECT
3595
3594
3596










CONECT
3596
3595
3597










CONECT
3597
3596
3598










CONECT
3598
3597
3599










CONECT
3599
3598
3600










CONECT
3600
3599
3601










CONECT
3601
3600
3602










CONECT
3602
3601
3603










CONECT
3603
3602
3604










CONECT
3604
3603
3605










CONECT
3605
3604
3606










CONECT
3606
3605
3607










CONECT
3607
3606











CONECT
3608
3609
3610
3611









CONECT
3609
3608











CONECT
3610
3608











CONECT
3611
3608
3612










CONECT
3612
3611
3613










CONECT
3613
3612
3614










CONECT
3614
3613
3615










CONECT
3615
3614
3616










CONECT
3616
3615
3617










CONECT
3617
3616
3618










CONECT
3618
3617
3619










CONECT
3619
3618
3620










CONECT
3620
3619
3621










CONECT
3621
3620
3622










CONECT
3622
3621
3623










CONECT
3623
3622
3624










CONECT
3624
3623
3625










CONECT
3625
3624
3626










CONECT
3626
3625
3627










CONECT
3627
3626











CONECT
3628
3629
3630
3631









CONECT
3629
3628











CONECT
3630
3628











CONECT
3631
3628
3632










CONECT
3632
3631
3633










CONECT
3633
3632
3634










CONECT
3634
3633
3635










CONECT
3635
3634
3636










CONECT
3636
3635
3637










CONECT
3637
3636
3638










CONECT
3638
3637
3639










CONECT
3639
3638
3640










CONECT
3640
3639
3641










CONECT
3641
3640
3642










CONECT
3642
3641
3643










CONECT
3643
3642
3644










CONECT
3644
3643
3645










CONECT
3645
3644
3646










CONECT
3646
3645
3647










CONECT
3647
3646











CONECT
3648
3649
3650
3651
3652








CONECT
3649
3648











CONECT
3650
3648











CONECT
3651
3648











CONECT
3652
3648











CONECT
3653
3654
3655
3656
3657








CONECT
3654
3653











CONECT
3655
3653











CONECT
3656
3653











CONECT
3657
3653











CONECT
3658
3659
3660
3661
3662








CONECT
3659
3658











CONECT
3660
3658











CONECT
3661
3658











CONECT
3662
3658











CONECT
3663
3664
3665
3666
3667








CONECT
3664
3663











CONECT
3665
3663











CONECT
3666
3663











CONECT
3667
3663











CONECT
3668
3669
3670
3671
3672








CONECT
3669
3668











CONECT
3670
3668











CONECT
3671
3668











CONECT
3672
3668











CONECT
3673
3674
3675
3676
3677








CONECT
3674
3673











CONECT
3675
3673











CONECT
3676
3673











CONECT
3677
3673











CONECT
3678
3679
3680
3681
3682








CONECT
3679
3678











CONECT
3680
3678











CONECT
3681
3678











CONECT
3682
3678


















MASTER
313
  0  13   25   5   0   18   6 3758   1  168   38


END



















INFORMAL SEQUENCE LISTING









SEQ




ID




NO:
DESCRIPTION
SEQUENCE





SEQ
A2A Adenosine
MKTIIALSYIFCLVFADYKDDDDAMGQPVGAPPIMGSSVYITVELAIAVLAILGWLVCW


ID
receptor with T4
AVWLNSNLQNVTNYFWSLAAADIAVGVLAIPFAITISTGFCMCHGCLFIACFVLVLTQ


NO: 1
lysozyme replacing
SSIFSLLAIAIDRYIAIRIPLRYNGLVTGTRAKGIIAICWVLSFAIGLTPMLGWNNCGQP



the 3rd cytoplasmic
KEGKNHSQGCGEGQVACLFEDWPMNYMVYFNFFACVLVPLLLMLGVYLRIFLMRRQLN



loop
IFEMLRIDEGLRLKIYKDTEGYYTIGIGHLLTKSPSLNMKSELDKAIGRNTNGVITKDE




AEKLFNQDVDMVRGILRNAKLKPVYDSLDAVR~LINMVFQMGETGVAGFTNSLRMLQ




QKRWDEMVNLAKSRWYNQTPNRAKRVITTFRTGTWDAYRSTLQKEVHMKSLAIIVGLF




ALCWLPLHIINCFTFFCPDCSHAPLWLMYLAIVLSHTNSVPFIYAYRIREFRQTFRKI




IRSHVLRQQEPFKAHHHHHHHHHH


 


SEQ
ADORA2A; A2A
MPIMGSSVYITVELAIAVLAILGNVLVCWAVWLNSNLQNVTNYFVVSLAAADIAVGVLAI


ID
adenosine receptor;
PFAITISTGFCAACHGCLFIACFVLVLTQSSIFSLLAIAIDRYIAIRIPLRYNGLVTGTR


NO: 2
P29274;
AKGIIAICWVLSFAIGLTPMLGWNNCGQPKEGKNHSQGCGEGQVACLFEDVVPMNYMVYF



protein sequence
NFFACVLVPLLLMLGVYLRIFLAARRQLKQMESQPLPGERARSTLQKEVHAAKSLAIIVG




LFALCWLPLHIINCFTFFCPDCSHAPLWLMYLAIVLSHTNSVVNPFIYAYRIREFRQTFR




KIIRSHVLRQQEPFKAAGTSARVLAAHGSDGEQVSLRLNGHPPGVWANGSAPHPERRPNG




YALGLVSGGSAQESQGNTGLPDVELLSHELKGVCPEPPGLDDPLAQDGAGVS


 


SEQ
Human β2
MGQPGNGSAFLLAPNRSHAPDHDVTQQRDEVWVVGMGIVMSLIV


ID
adrenergic receptor;
  LAIVFGNVLVITAIAKFERLQTVTNYFITSLACADLVMGLAVVPFGAAHILMKMWTFG


NO: 3
protein sequence
NFWCEFWTSIDVLCVTASIETLCVIAVDRYFAITSPFKYQSLLTKNKARVIILMVWIV




SGLTSFLPIQMHWYRATHQEAINCYANETCCDFFTNQAYAIASSIVSFYVPLVIMVFV




YSRVFQEAKRQLQKIDKSEGRFHVQNLSQVEQDGRTGHGLRRSSKFCLKEHKALKTLG




IIMGTFTLCWLPFFIVNIVHVIQDNLIRKEVYILLNWIGYVNSGFNPLIYCRSPDFRI




AFQELLCLRRSSLKAYGNGYSSNGNTGEQSGYHVEQEKENKLLCEDLPGTEDFVGHQG




TVPSDNIDSQGRNCSTNDSLL


 


SEQ
TACR1; tachykinin
MDNVLPVDSDLSPNISTNTSEPNQFVQPAWQIVLWAAAYTVIVV


ID
receptor 1;
TSVVGNVVVMWIILAHKRMRTVTNYFLVNLAFAEASMAAFNTVVNFTYAVHNEWYYGL


NO: 4
NM_001058;
FYCKFHNFFPIAAVFASIYSMTAVAFDRYMAIIHPLQPRLSATATKVVICVIWVLALL



protein sequence
LAFPQGYYSTTETMPSRVVCMIEWPEHPNKIYEKVYHICVTVLIYFLPLLVIGYAYTV




VGITLWASEIPGDSSDRYHEQVSAKRKVVKMMIVVVCTFAICWLPFHIFFLLPYINPD




LYLKKFIQQVYLAIMWLAMSSTMYNPIIYCCLNDRFRLGFKHAFRCCPFISAGDYEGL




EMKSTRYLQTQGSVYKVSRLETTISTVVGAHEEEPEDGPKATPSSLDLTSNCSSRSDS




                     KTMTESFSFSSNVLS


 


SEQ
ADRA1A;
MVFLSGNASDSSNCTQPPAPVNISKAILLGVILGGLILFGVLGN


ID
adrenergic, alpha-
ILVILSVACHRHLHSVTHYYIVNLAVADLLLTSTVLPFSAIFEVLGYWAFGRVFCNIW


NO: 5
1A-, receptor;
AAVDVLCCTASIMGLCIISIDRYIGVSYPLRYPTIVTQRRGLMALLCVWALSLVISIG



NM_000680;
PLFGWRQPAPEDETICQINEEPGYVLFSALGSFYLPLAIILVMYCRVYVVAKRESRGL



protein sequence
KSGLKTDKSDSEQVTLRIHRKNAPAGGSGMASAKTKTHFSVRLLKFSREKKAAKTLGI




VVGCFVLCWLPFFLVMPIGSFFPDFKPSETVFKIVFWLGYLNSCINPIIYPCSSQEFK




KAFQNVLRIQCLCRKQSSKHALGYTLHPPSQAVEGQHKDMVRIPVGSRETFYRISKTD




GVCEWKFFSSMPRGSARITVSKDQSSCTTARVRSKSFLQVCCCVGPSTPSLDKNHQVP




                     TIKVHTISLSENGEEV


 


SEQ
CHRM1;
MNTSAPPAVSPNITVLAPGKGPWQVAFIGITTGLLSLATVTGNL


ID
cholinergic
LVLISFKVNTELKTVNNYFLLSLACADLIIGTFSMNLYTTYLLMGHWALGTLACDLWL


NO: 6
receptor,
ALDYVASNASVMNLLLISFDRYFSVTRPLSYRAKRTPRRAALMIGLAWLVSFVLWAPA



muscarinic 1;
ILFWQYLVGERTVLAGQCYIQFLSQPIITFGTAMAAFYLPVTVMCTLYWRIYRETENR



NM_000738;
ARELAALQGSETPGKGGGSSSSSERSQPGAEGSPETPPGRCCRCCRAPRLLQAYSWKE



protein sequence
EEEEDEGSMESLTSSEGEEPGSEVVIKMPMVDPEAQAPTKQPPRSSPNTVKRPTKKGR




DRAGKGQKPRGKEQLAKRKTFSLVKEKKAARTLSAILLAFILTWTPYNIMVLVSTFCK




DCVPETLWELGYWLCYVNSTINPMCYALCNKAFRDTFRLLLLCRWDKRRWRKIPKRPG




                     SVHRTPSRQC


 


SEQ
DRD2; dopamine
MDPLNLSWYDDDLERQNWSRPFNGSDGKADRPHYNYYATLLTLL


ID
receptor D2;
IAVIVEGNVLVCMAVSREKALQTTTNYLIVSLAVADLLVATLVMPWVVYLEVVGEWKE


NO: 7
NM_000795;
SRIHCDIFVTLDVMMCTASILNLCAISIDRYTAVAMPMLYNTRYSSKRRVTVMISIVW



protein sequence
VLSFTISCPLLFGLNNADQNECIIANPAFVVYSSIVSFYVPFIVTLLVYIKIYIVLRR




RRKRVNTKRSSRAFRAHLRAPLKGNCTHPEDMKLCTVIMKSNGSFPVNRRRVEAARRA




QELEMEMLSSTSPPERTRYSPIPPSHHQLTLPDPSHHGLHSTPDSPAKPEKNGHAKDH




PKIAKIFEIQTMPNGKTRTSLKTMSRRKLSQQKEKKATQMLAIVLGVFIICWLPFFIT




HILNIHCDCNIPPVLYSAFTWLGYVNSAVNPIIYTTFNIEFRKAFLKILHC


 


SEQ
EDG1; endothelial
MGPTSVPLVKAHRSSVSDYVNYDIIVRHYNYTGKLNISADKENS


ID
differentiation,
IKLTSVVFILICCFIILENIFVLLTIWKTKKFHRPMYYFIGNLALSDLLAGVAYTANL


NO: 8
sphingolipidG-
LLSGATTYKLTPAQWFLREGSMFVALSASVFSLLAIAIERYITMLKMKLHNGSNNFRL



protein-coupled
FLLISACWVISLILGGLPIMGWNCISALSSCSTVLPLYHKHYILFCTTVPILLLLSIV



receptor, 1;
ILYCRIYSLVRTRSRRLTFRKNISKASRSSEKSLALLKTVIIVLSVFIACWAPLFILL



NM_001400;
LLDVGCKVKTCDILFRAEYFLVLAVLNSGTNPIIYTLTNKEMRRAFIRIMSCCKCPSG



protein sequence
DSAGKFKRPIIAGMEFSRSKSDNSSHPQKDEGDNPETIMSSGNVNSSS


 


SEQ
HTR1A; 5-
MDVLSPGQGNNTTSPPAPFETGGNTTGISDVTVSYQVITSLLLG


ID
hydroxytryptamine
TLIFCAVLGNACVVAAIALERSLQNVANYLIGSLAVTDLMVSVLVLPMAALYQVLNKW


NO: 9
(serotonin) receptor
TLGQVTCDLFIALDVLCCTSSILHLCAIALDRYWAITDPIDYVNKRTPRRAAALISLT



1A; NM_000524;
WLIGFLISIPPMLGWRTPEDRSDPDACTISKDHGYTIYSTFGAFYIPLLLMLVLYGRI



protein sequence
FRAARFRIRKTVKKVEKTGADTRHGASPAPQPKKSVNGESGSRNWRLGVESKAGGALC




ANGAVRQGDDGAALEVIEVHRVGNSKEHLPLPSEAGPTPCAPASFERKNERNAEAKRK




MALARERKTVKTLGIIMGTFILCWLPFFIVALVLPFCESSCHMPTLLGAIINWLGYSN




SLLNPVIYAYFNKDFQNAFKKIIKCKFCRQ


 


SEQ
MC2R;
MKHIINSYENINNTARNNSDCPRVVLPEEIFFTISIVGVLENLI


ID
melanocortin 2
VLLAVFKNKNLQAPMYFFICSLAISDMLGSLYKILENILIILRNMGYLKPRGSFETTA


NO: 10
receptor
DDIIDSLFVLSLLGSIFSLSVIAADRYITIFHALRYHSIVTMRRTVVVLTVIWTFCTG



(adrenocorticotropi
TGITMVIFSHHVPTVITFTSLFPLMLVFILCLYVHMFLLARSHTRKISTLPRANMKGA



c hormone);
ITLTILLGVFIFCWAPFVLHVLLMTFCPSNPYCACYMSLFQVNGMLIMCNAVIDPFIY



NM_000529;
AFRSPELRDAFKKMIFCSRYW



protein sequence



 


SEQ
NTSR1;
MRLNSSAPGTPGTPAADPFQRAQAGLEEALLAPGFGNASGNASE


ID
neurotensin
RVLAAPSSELDVNTDIYSKVLVTAVYLALFVVGTVGNTVTAFTLARKKSLQSLQSTVH


NO: 11
receptor 1;
YHLGSLALSDLLTLLLAMPVELYNFIWVHHPWAFGDAGCRGYYFLRDACTYATALNVA



NM_002531;
SLSVERYLAICHPFKAKTLMSRSRTKKFISAIWLASALLAVPMLFTMGEQNRSADGQH



protein sequence
AGGLVCTPTIHTATVKVVIQVNTFMSFIFPMVVISVLNTIIANKLTVMVRQAAEQGQV




CTVGGEHSTFSMAIEPGRVQALRHGVRVLRAVVIAFVVCWLPYHVRRLMFCYISDEQW




TPFLYDFYHYFYMVTNALFYVSSTINPILYNLVSANFRHIFLATLACLCPVWRRRRKR




PAFSRKADSVSSNHTLSSNATRETLY


 


SEQ
OXTR; oxytocin
MEGALAANWSAEAANASAAPPGAEGNRTAGPPRRNEALARVEVA


ID
receptor;
VLCLILLLALSGNACVLLALRTTRQKHSRLFFFMKHLSIADLVVAVFQVLPQLLWDIT


NO: 12
NM_000916;
FRFYGPDLLCRLVKYLQVVGMFASTYLLLLMSLDRCLAICQPLRSLRRRTDRLAVLAT



protein sequence
WLGCLVASAPQVHIFSLREVADGVFDCWAVFIQPWGPKAYITWITLAVYIVPVIVLAA




CYGLISFKIWQNLRLKTAAAAAAEAPEGAAAGDGGRVALARVSSVKLISKAKIRTVKM




TFIIVLAFIVCWTPFFFVQMWSVWDANAPKEASAFIIVMLLASLNSCCNPWIYMLFTG




HLFHELVQRFLCCSASYLKGRRLGETSASKKSNSSSFVLSHRSSSQRSCSQPSTA

## Claims

1. A crystalline form of a human A2A adenosine receptor protein in complex with (4-(2-[7-amino-2-(2-furyl)-[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl)-phenol (ZM241385), wherein the human A2A adenosine receptor protein comprises the amino acid sequence of SEQ ID NO: 1 and the crystalline form is of space group P21 and has unit cell dimensions of a=47.7±0.5 Angstroms, b=76.9±0.5 Angstroms, and c=86.8±0.5 Angstroms, and β=101.3°.

2. The crystalline form of claim 1, wherein said human A2A adenosine receptor protein comprises a binding pocket I site, and wherein said binding pocket I comprises a plurality of amino acid residues selected from the group consisting of Phe1685.29, Ile2747.39, Glu1695.30, Leu2496.51, and Asn2536.55.

3. The crystalline form of claim 1, wherein said human A2A adenosine receptor protein comprises a binding pocket II site, and wherein said binding pocket II comprises amino acid residues Phe622.60, Ile662.64, Ile803.28, Val843.32, Phe1685.29, Leu2496.51, Ile2747.39 and His2787.43.

4. The crystalline form of claim 1, wherein said human A2A adenosine receptor protein comprises a binding pocket III site, and wherein said binding pocket III site comprises a plurality of amino acid residues selected from the group consisting of Leu482.46, Ala512.49, Asp522.50, Val552.53, Val843.32, Leu873.35, Thr883.36, Ser913.39, Leu953.43, Ile2386.40, Phe2426.44, Trp2466.48, Ser2777.42, His2787.43, Asn2807.45, Ser2817.46 and Asn2847.49.