Crystal Structure of a Receptor-Ligand Complex and Methods of Use

Abstract

The invention relates to the three-dimensional structure of a crystal of an EphB4 receptor complexed with a ligand. The three-dimensional structure of a Receptor-Ligand Complex is disclosed. The receptor-ligand crystal structure, wherein the ligand is an inhibitor molecule, is useful for providing structural information that may be integrated into drug screening and drug design processes. Thus, the invention also relates to methods for utilizing the crystal structure of the Receptor-Ligand Complex for identifying, designing, selecting, or testing inhibitors of the EphB4 receptor protein, such inhibitors being useful as therapeutics for the treatment or modulation of i) diseases; ii) disease symptoms; or iii) the effect of other physiological events mediated by the receptor.

Description

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable.

INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC

The Sequence Listing, which is a part of the present disclosure, includes a computer file “10000-0027_ST25.txt” generated by U.S. Patent & Trademark Office Patent In Version 3.4 software comprising nucleotide and/or amino acid sequences of the present invention. The subject matter of the Sequence Listing is incorporated herein by reference in its entirety.

FIELD

The present invention relates to a three-dimensional structure of a receptor tyrosine kinase from the erythropoietin-producing hepatocellular carcinoma family of receptor tyrosine kinases (“Eph”), particularly EphB4 or similar polypeptide complexed with an ephrinB2 or ephrinB2 analog (“Receptor-Ligand Complex”), three-dimensional coordinates of a Receptor-Ligand Complex, models thereof, and uses of such structures and models.

INTRODUCTION

The Eph receptor tyrosine kinases and their ligands, the ephrins, regulate numerous biological processes in developing and adult tissues and have been implicated in cancer progression and in pathological forms of angiogenesis. For example, the Eph receptors and their ligands, the ephrins, play critical roles in angiogenesis during embryonic development as well as in adult tissues (Brantley-Sieders and Chen, 2004; Cheng et al., 2002; Gale and Yancopoulos, 1999; Kullander and Klein, 2002). The Eph family of receptor tyrosine kinases also regulates many other biological processes, including tissue patterning, axonal guidance, and as more recently discovered, tumorigenesis (Carmeliet and Collen, 1999; Ferrara, 1999; Pasquale, 2005; Wilkinson, 2000). Both the Eph receptor and the ephrin ligand are membrane bound, and therefore require cell-cell contact to signal a cellular response. The interaction between Eph receptors and ephrins on adjacent cell surfaces results in multimerization and clustering of the Eph-ephrin complexes, leading to forward signaling in the Eph-expressing cell and reverse signaling in the ephrin-expressing cell. EphB4 belongs to the Eph (erythropoietin-producing hepatocellular carcinoma) family of receptor tyrosine kinases, which is divided into two subclasses, A and B. based on binding preferences and sequence conservation (Gale et al., 1996). In general, EphA receptors (EphA1-EphA10) bind to glycosyl phosphatidyl inositol-(GPI) anchored ephrin-A ligands (ephrin-A1-ephrin-A6), while EphB receptors (EphB1-EphB6) interact with transmembrane ephrin-B ligands (ephrin-B1-ephrin-B3) (Eph Nomenclature Committee, 1997). While interactions between the Eph receptors and ephrin ligands of the same subclass are quite promiscuous, interactions between subclasses are rare. A few cross-subclass exceptions include the EphA4-ephrin-B2/B3 interactions (Takemoto et al., 2002), and the EphB2-ephrinA5 interaction, which has been characterized structurally (Himanen et al., 2004). EphB4 is unique within the Eph family in that it selectively binds ephrin-B2, while demonstrating only weak binding for both ephrin-B1 and ephrin-B3.

Eph receptors have a modular structure, consisting of an N-terminal ephrin binding domain adjacent to a cysteine-rich domain and two fibronectin type III repeats in the extracellular region. The intracellular region consists of a juxtamembrane domain, a conserved tyrosine kinase domain, a C-terminal sterile α-domain (SAM), and a PDZ binding motif. The N-terminal 180 amino acid globular domain is sufficient for high-affinity ligand binding (Himanen et al., 2001).

The EphB4-ephrinB2 interaction is important in angiogenesis and given that EphB4 is overexpressed in several tumor types (Dodelet, V. C., and Pasquale, E. B. (2000) Oncogene 19, 5614-5619; Nakamoto, M., and Bergemann, A. D. (2002) Microsc Res Tech 59, 58-67; Liu, W., Ahmad, S. A., Jung, Y. D., Reinmuth, N., Fan, F., Bucana, C. D., and Ellis, L. M. (2002) Cancer 94, 934-939; Berclaz, G., Karamitopoulou, E., Mazzucchelli, L., Rohrbach, V., Dreher, E., Ziemiecki, A., and Andres, A. C. (2003) Ann Oncol 14, 220-226), modulating this protein-protein interaction is a potential approach to slowing tumor angiogenesis and tumor growth. In mouse models of breast cancer, high EphB4 expression correlates with increased malignancy and tumor aggressiveness (Andres, A. C., Reid, H. H., Zurcher, G., Blaschke, R. J., Albrecht, D., and Ziemiecki, A. (1994) Oncogene 9, 1461-1467; Nikolova, Z., Djonov, V., Zuercher, G., Andres, A. C., and Ziemiecki, A. (1998) J Cell Sci 111 (Pt 18), 2741-2751; Munarini, N., Jager, R., Abderhalden, S., Zuercher, G., Rohrbach, V., Loercher, S., Pfanner-Meyer, B., Andres, A. C., and Ziemiecki, A. (2002) J Cell Sci 115, 25-37). EphB4 expression is also increased in human primary infiltrating ductal breast carcinoma and is correlated to increased malignancy (Berclaz, G., Andres, A. C., Albrecht, D., Dreher, E., Ziemiecki, A., Gusterson, B. A., and Crompton, M. R. (1996) Biochem Biophys Res Commun 226, 869-875). There is evidence that the EphB4 ectodomain stimulates endothelial cell migration and proliferation, suggesting that ephrinB2-expressing endothelial cells interact with the EphB4 ectodomain to promote angiogenesis and tumor progression. Furthermore, a kinase-deficient EphB4 mutant has been shown to increase breast cancer cell growth indicating that downstream forward kinase signaling is not an absolute requirement for tumorigenesis, at least in breast cancer cells (Noren, N. K., Lu, M., Freeman, A. L., Koolpe, M., and Pasquale, E. B. (2004) Proc Natl Acad Sci USA 101, 5583-5588). Several groups have more recently demonstrated that the full extracellular domain of EphB4 is indeed a viable therapeutic target First, the soluble extracellular domain of EphB4 was described to block both forward and reverse signaling, resulting in an inhibition of tumor growth in vivo (Kertesz, N., Krasnoperov, V., Reddy, R., Leshanski, L., Kumar, S. R., Zozulya, S., and Gill, P. S. (2006) Blood 107, 2330-2338; Martiny-Baron, G., Korff, T., Schaffner, F., Esser, N., Eggstein, S., Marme, D., and Augustin, H. G. (2004) Neoplasia 6, 248-257).

Second, phage display studies have identified a peptide (TNYL-RAW) which antagonizes the EphB4-ephrinB2 interaction in the high nanomolar range (Koolpe, M., Burgess, R., Dail, M., and Pasquale, E. B. (2005) J Biol Chem 280, 17301-17311). The crystal structure of the EphB4 receptor in complex with the phage-derived TNYL-RAW peptide (SEQ ID NO: 1) revealed that the peptide binds to the ephrin binding cavity of the receptor, effectively inhibiting interaction with the ligand (Chrencik, J. E., Brooun, A., Recht, M. I., Kraus, M. L., Koolpe, M., Kolatkar, A. R., Bruce, R. H., Martiny-Baron, G., Widmer, H., Pasquale, E. B., and Kuhn, P. (2006) Structure 14, 321-330). However, a more complete understanding of the biological role of EphB4-ephrinB2 signaling in tumorigenesis and in forms of pathological angiogenesis is now required.

Despite attempts to model the structural changes of EphB4 upon ligand binding, a detailed view of conformational arrangements of an EphB4 receptor in complex with ephrinB2 has remained elusive. Thus, the development of useful reagents for treatment or diagnosis of disease was hindered by lack of structural information of such a Receptor-Ligand Complex. Therefore, there is a need in the art to elucidate the three-dimensional structure and models of Receptor-Ligand Complexes, and to use such structures and models in therapeutic strategies, such as drug design.

DRAWINGS

Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

FIG. 1. The ephrin binding domain of the EphB4 receptor in complex with the ephrinB2 extracellular domain. The EphB4 receptor (right) consists of a jellyroll folding topology with 13 anti-parallel B-sheets connected by loops of varying lengths, whereas the ephrin ligand (left) is similar to the Greek key folding topology. The interface is formed by insertion of the ligand G-H loop into the hydrophobic binding cleft of EphB4.

FIG. 2. Stereoview of the superposition of the Eph receptor ligand binding domains from the EphB4.ephrinB2 (thick grey line), EphB2.ephrinB2 (thin grey line), and EphB4.TNYL-RAW complex structures (thick line with spheres). Clear deviation is seen at the J-K loop, whereas more minor changes are seen in the receptor D-E and G-H loops (Protein Data Bank code 1 KGY). The overall root mean square deviation between the EphB4.ephrinB2 and the EphB2.ephrinB2 and EphB4-TNYL-RAW structures is 5.0 and 2.5 Å, respectively. FIG. 3. Stereoview of σA weighted 2 F_obs-F_calc electron density at 2.0 Å resolution, contoured at 1σ for the EphB4.ephrinB2 interface. The ephrinB2 is the leftmost molecule (labeled) and the EphB4 is at the right (labeled). Clear density of the interface shows Phe-120 in a novel position with respect to previously described structures in order to interact with Leu-95.

FIG. 4. Detailed ligplot diagram of critical EphB4.ephrinB2 interactions. All interactions are less than 4 Å and are indicated by dashed lines. The ligand is depicted with all bonds shown, whereas receptor residues are drawn schematically.

FIG. 5. EphrinB2 specificity region in the EphB2/EphB4.ephrinB2 complexes. Left, the region near the EphB4 Leu-95R of the EphB4.ephrinB2 complex structure is shown in schematic representation. The van der Waals interaction between the ephrinB2 Phe-120L and the EphB4 Leu-95R is depicted as a dotted line. Right, the region near the EphB2 Arg-103R of the EphB2.ephrinB2 complex structure is shown in the same orientation as that on the left. The EphB2 Arg-103R, Ser-156R, and Ser-107R side chains are shown as grey sticks. Hydrogen bonds between Arg-103R and the two serines are shown as dotted lines. The J-K loops of EphB2 and EphB4 are labeled highlighting the change in loop position between the two complexes.

FIG. 6. This figure illustrates binding of fluorescent peptide to wild type EphB4, EphB4 K149Q (A) and EphB4 L95R mutants. Increasing amount of EphB4 protein was added to wells containing 75 nM of fluorescent TNYL-RAW peptide. Fluorescent polarization was measured at room temperature after 30 min of incubation. Based on the structure of EphB4-ephrin-B2 complex, the substitution of L95 was predicted to impair EphB4 binding to ephrin-B2.

FIG. 7. This figure illustrates determination of K_i for TNYL-RAW. K_i were determined for both wild-type EphB4 (filled triangles) and EphB4 (K149Q) mutant (filled squares).

FIG. 8. This figure illustrates binding of fluorescent TNYL-RAW peptide in the presence of increasing concentration of DMSO. Increasing amounts of EphB4 protein were added to wells containing 75 nM of TNYL-RAW-Alexa-532 peptide. Fluorescent polarization was measured at room temperature.

FIG. 9. This figure illustrates Z-factor determination for EphB4-Alexa-532-TNYL-RAW fluorescent polarization assay.

DETAILED DESCRIPTION

The present invention relates to the discovery of the three-dimensional structure of a Receptor-Ligand Complex, models of such three-dimensional structures, a method of structure-based drug design using such structures, the compounds identified by such methods and the use of such compounds in therapeutic compositions. In particular, the present invention involves the crystal structure of the EphB4 receptor in complex with ephrinB2 at a resolution of 2.0 Å. EphrinB2 is situated in a hydrophobic cleft of EphB4 corresponding to the cleft in EphB2 occupied by the ephrinB2 G-H loop. The crystal reveals critical structural features of EphB4 that, when in complex ephrinB2, provides a basis for antagonist design and modeling.

In particular, the structural and thermodynamic characterization of the EphB4 receptor in complex with ephrinB2 is described. The structure reveals that the flexible J-K loop of EphB4 shifts significantly as compared to previous crystal structures, providing a new network of contacts to secure the interaction. In addition, using biophysical analysis, one amino acid, Leu-95, is identified which lines the ligand binding cavity of the EphB4 receptor and provides the molecular determinants for the unique specificity exhibited by the EphB4 receptor for the ephrinB2 ligand.

A multiple sequence alignment with members of the EphB subclass reveals that the EphB4 receptor lacks a conserved arginine and instead contains a leucine at position 95. A Leu-95-Arg mutation was previously predicted to result in steric interference with the antagonistic TNYL-RAW peptide ligand (Chrencik et al., Structure, 2006, incorporated herein by reference in its entirety; SEQ ID NO: 1). This mutation also results in steric interference with Phe-120 in the G-H loop of ephrinB2 due to the different positioning of the J-K loop of EphB4. A leucine instead of an arginine at position 95 of the EphB4 receptor is sufficient to cause substantial structural rearrangement of the receptor J-K loop. Also provided is a novel position of the conserved Phe-120 in the high affinity FSPN sequence of the ephrinB2 G-H loop, suggesting that although ephrinB2 is conserved in structure in both receptor-bound and apo structures, there is variability within the rigid G-H loop to conform to a specific receptor.

EphB4 binds only weakly to both ephrinB1 and ephrinB3, while exhibiting high affinity for ephrinB2. Considering the B-subclass ephrin G-H loop (ephrinB1-B3), it is interesting to speculate on why EphB4 preferentially binds ephrinB2 over other B-subclass ligands. EphrinB1 shares significant sequence identity with the high affinity ephrinB2 G-H loop, except at position 124, which is a Tyr in ephrinB1 and a Leu in ephrinB2. While Leu-124 forms no integral interactions with EphB4, the small size of the leucine allows tight packing within the receptor binding cavity. A leucine also maintains the hydrophobic nature of the binding cleft. Superposition of a tyrosine on the ephrinB2 structure would require the rearrangement of the EphB4 J-K loop in order to accommodate the bulky tyrosine, and, without being bound by a particular theory, this likely accounts for the reduced affinity of EphB4 for ephrinB1. The ephrinB3 G-H loop is also very similar to the ephrinB2 G-H loop but deviates in the FSPN sequence, which contains a tyrosine instead of the phenylalanine (YSPN). Phe-120 forms critical interactions with residues lining the EphB receptor-ephrinB2 binding cavity in the three complex crystal structures thus far described. In the previous crystal structures, Phe-120 extends to the surface of the binding cavity, adjacent to the receptor G-H loop. Superposition of a tyrosine on the EphB2-ephrinB2 structure would not affect the dynamics of the ligand binding cavity, and this residue is predicted to interact with several water molecules on the surface of the complex. However, in the present crystal structure, the Phe-120 of ephrinB2 is observed in a novel position, buried within the hydrophic binding cleft and forming interactions with Leu-95R and the Cys-61-Cys-184 disulfide bridge. Insertion of a tyrosine at this position would therefore result in both steric interference within the receptor binding cavity and a polar redistribution of the active site.

Thermodynamic discrepancies between Eph receptor and ephrin binding can be considered in the design of therapeutics to treat disease related to the Eph receptor family. Iterative rounds of structure based drug design provide an understanding of the enthalpic and entropic contributions of small molecule compounds. In the case of the ephrin ligand, the G-H loop is predicted to reduce conformational entropy losses due to its rigidity, maximizing the effects of solvation entropy due to the hydrophobic nature of the Eph ligand binding cavity. The ephrin, on the other hand, can experience large losses in conformational entropy upon receptor binding which are compensated by favorable enthalpic gains between receptor and ephrin residues. The ephrin ligand, with entropically-driven binding, can interact with multiple members of the EphB family. In contrast, the TNYL-RAW peptide, with enthalpically-driven binding, is a specific inhibitor of the EphB4-ephrinB2 interaction.

Accordingly, one aspect of the present invention includes a model of a Receptor-Ligand Complex in which the model represents a three-dimensional structure of a Receptor-Ligand Complex. Another aspect of the present invention includes the three-dimensional structure of a Receptor-Ligand Complex. A three-dimensional structure of a Receptor-Ligand Complex substantially conforms with the atomic coordinates represented in Table 1. According to the present invention, the use of the term “substantially conforms” refers to at least a portion of a three-dimensional structure of a Receptor-Ligand Complex which is sufficiently spatially similar to at least a portion of a specified three-dimensional configuration of a particular set of atomic coordinates (e.g., those represented by Table 1) to allow the three-dimensional structure of a Receptor-Ligand Complex to be modeled or calculated using the particular set of atomic coordinates as a basis for determining the atomic coordinates defining the three-dimensional configuration of a Receptor-Ligand Complex.

More particularly, a structure that substantially conforms to a given set of atomic coordinates is a structure wherein at least about 50% of such structure has an average root-mean-square deviation (RMSD) of less than about 2.0 Å for the backbone atoms in secondary structure elements in each domain, and in various aspects, less than about 1.25 Å for the backbone atoms in secondary structure elements in each domain, and, in various aspects less than about 1.0 Å, in other aspects less than about 0.75 Å, less than about 0.5 Å, and, less than about 0.25 Å for the backbone atoms in secondary structure elements in each domain. In one aspect of the present invention, a structure that substantially conforms to a given set of atomic coordinates is a structure wherein at least about 75% of such structure has the recited average RMSD value, and in some aspects, at least about 90% of such structure has the recited average RMSD value, and in some aspects, about 100% of such structure has the recited average RMSD value. In particular, the above definition of “substantially conforms” can be extended to include atoms of amino acid side chains. As used herein, the phrase “common amino acid side chains” refers to amino acid side chains that are common to both the structure which substantially conforms to a given set of atomic coordinates and the structure that is actually represented by such atomic coordinates.

In another aspect of the present invention, a three-dimensional structure that substantially conforms to a given set of atomic coordinates is a structure wherein at least about 50% of the common amino acid side chains have an average RMSD of less than about 2.0 Å, and in various aspects, less than about 1.25 Å, and, in other aspects, less than about 1.0 Å, less than about 0.75 Å, less than about 0.5 Å, and less than about 0.25 Å. In one aspect of the present invention, a structure that substantially conforms to a given set of atomic coordinates is a structure wherein at least about 75% of the common amino acid side chains have the recited average RMSD value, and in some aspects, at least about 90% of the common amino acid side chains have the recited average RMSD value, and in some aspects, about 100% of the common amino acid side chains have the recited average RMSD value.

A three-dimensional structure of a Receptor-Ligand Complex which substantially conforms to a specified set of atomic coordinates can be modeled by a suitable modeling computer program such as MODELER (A. Sali and T. L. Blundell, J. Mol. Biol., vol. 234:779-815, 1993 as implemented in the Insight II software package Insight II, available from Accelerys (San Diego, Calif.)) and those software packages listed in the Examples, using information, for example, derived from the following data: (1) the amino acid sequence of the Receptor-Ligand Complex; (2) the amino acid sequence of the related portion(s) of the protein represented by the specified set of atomic coordinates having a three-dimensional configuration; and, (3) the atomic coordinates of the specified three-dimensional configuration. A three-dimensional structure of a Receptor-Ligand Complex which substantially conforms to a specified set of atomic coordinates can also be calculated by a method such as molecular replacement, which is described in detail below.

A suitable three-dimensional structure of the Receptor-Ligand Complex for use in modeling or calculating the three-dimensional structure of another Receptor-Ligand Complex comprises the set of atomic coordinates represented in Table 1. The set of three-dimensional coordinates set forth in Table 1 is represented in standard Protein Data Bank format. The atomic coordinates have been deposited in the Protein Data Bank, having Accession No. 2HLE. According to the present invention, a Receptor-Ligand Complex has a three-dimensional structure which substantially conforms to the set of atomic coordinates represented by Table 1. As used herein, a three-dimensional structure can also be a most probable, or significant, fit with a set of atomic coordinates. According to the present invention, a most probable or significant fit refers to the fit that a particular Receptor-Ligand Complex has with a set of atomic coordinates derived from that particular Receptor-Ligand Complex. Such atomic coordinates can be derived, for example, from the crystal structure of the protein such as the coordinates determined for the Receptor-Ligand Complex structure provided herein, or from a model of the structure of the protein. For example, the three-dimensional structure of a dimeric protein, including a naturally occurring or recombinantly produced EphB4 receptor protein in complex with ephrinB2, substantially conforms to and is a most probable fit, or significant fit, with the atomic coordinates of Table 1. The three-dimensional crystal structure of the Receptor-Ligand Complex may comprise the atomic coordinates of Table 1. Also as an example, the three-dimensional structure of another Receptor-Ligand Complex would be understood by one of skill in the art to substantially conform to the atomic coordinates of Table 1. This definition can be applied to the other EphB4 receptor proteins in a similar manner.

For example, the structure of the EphB4 receptor establishes the general architecture of the EphB receptor family. Accordingly, in some configurations, EphB4 receptor protein sequence homology across eukaryotes can be used as a basis to predict the structure of such receptors, in particular the structure for such receptor-ligand binding sites and other conserved regions.

In various aspects of the present invention, a structure of a Receptor-Ligand Complex substantially conforms to the atomic coordinates represented in Table 1. Such values as listed in Table 1 can be interpreted by one of skill in the art. In other aspects, a three-dimensional structure of a Receptor-Ligand Complex substantially conforms to the three-dimensional coordinates represented in Table 1. In other aspects, a three-dimensional structure of a Receptor-Ligand Complex is a most probable fit with the three-dimensional coordinates represented in Table 1. Methods to determine a substantially conforming and probable fit are within the expertise of skill in the art and are described herein in the Examples section.

A Receptor-Ligand Complex that has a three-dimensional structure which substantially conforms to the atomic coordinates represented by Table 1 includes an EphB4 receptor protein having an amino acid sequence that is at least about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an amino acid sequence of a human EphB4 receptor protein, in particular an amino acid sequence having SEQ ID NO: 4, across the full-length of the EphB4 receptor sequence. A sequence alignment program such as BLAST (available from the National Institutes of Health Internet web site http://www.ncbi.nlm.nih.gov/BLAST) may be used by one of skill in the art to compare sequences of an EphB receptor to the EphB4 receptor.

A three-dimensional structure of any Receptor-Ligand Complex can be modeled using methods generally known in the art based on information obtained from analysis of a Receptor-Ligand Complex crystal, and from other Receptor-Ligand Complex structures which are derived from a Receptor-Ligand Complex crystal. The Examples section below discloses the production of a Receptor-Ligand Complex crystal, in particular a truncated EphB4 receptor having SEQ ID NO: 2 or 3 complexed with ephrinB2 (SEQ ID NO: 6), and a model of a Receptor-Ligand Complex, in particular a truncated EphB4 receptor having SEQ ID NO: 2 or 3 complexed with ephrinB2, using methods generally known in the art based on the information obtained from analysis of a Receptor-Ligand Complex crystal.

An aspect of the present invention comprises using the three-dimensional structure of a crystalline Receptor-Ligand Complex to derive the three-dimensional structure of another Receptor-Ligand Complex. Therefore, the crystalline EphB4 receptor complexed with ephrinB2 (SEQ ID NO: 6), and the three-dimensional structure of EphB4 complexed with ephrinB2 permits one of ordinary skill in the art to now derive the three-dimensional structure, and models thereof, of another Receptor-Ligand Complex having highly specific EphB4 binding characteristics. The derivation of the structure of such Receptor-Ligand Complexes can now be achieved even in the absence of having crystal structure data for such other Receptor-Ligand Complexes, and when the crystal structure of another Receptor-Ligand Complex is available, the modeling of the three-dimensional structure of the new Receptor-Ligand Complex can be refined using the knowledge already gained from the Receptor-Ligand Complex structure.

In some configurations of the present teachings, the absence of crystal structure data for other Receptor-Ligand Complexes, the three-dimensional structures of other Receptor-Ligand Complexes can be modeled, taking into account differences in the amino acid sequence of the other Receptor-Ligand Complex. Moreover, the present invention allows for structure-based drug design of compounds which affect the activity of virtually any EphB receptor, and particularly, of EphB4.

One aspect of the present invention includes a three-dimensional structure of a Receptor-Ligand Complex, in which the atomic coordinates of the Receptor-Ligand Complex are generated by the method comprising: (a) providing an EphB4 receptor complexed with ephrinB2 in crystalline form; (b) generating an electron-density map of the crystalline EphB4 receptor complexed with ephrinB2; and (c) analyzing the electron-density map to produce the atomic coordinates. For example, the structure of human EphB4 receptor in complex with ephrinB2 (SEQ ID NO: 6) is provided herein.

The present invention also provides a three-dimensional structure of the EphB4 receptor protein complexed with ephrinB2 (SEQ ID NO: 6), can be used to derive a model of the three-dimensional structure of another Receptor-Ligand Complex (i.e., a structure to be modeled). As used herein, a “structure” of a protein refers to the components and the manner of arrangement of the components to constitute the protein. As used herein, the term “model” refers to a representation in a tangible medium of the three-dimensional structure of a protein, polypeptide or peptide. For example, a model can be a representation of the three-dimensional structure in an electronic file, on a computer screen, on a piece of paper (i.e., on a two dimensional medium), and/or as a ball-and-stick figure. Physical three-dimensional models are tangible and include, but are not limited to, stick models and space-filling models. The phrase “imaging the model on a computer screen” refers to the ability to express (or represent) and manipulate the model on a computer screen using appropriate computer hardware and software technology known to those skilled in the art. Such technology is available from a variety of sources including, for example, Accelrys, Inc. (San Diego, Calif.). The phrase “providing a picture of the model” refers to the ability to generate a “hard copy” of the model. Hard copies include both motion and still pictures. Computer screen images and pictures of the model can be visualized in a number of formats including space-filling representations, α-carbon traces, ribbon diagrams and electron density maps.

Suitable target Receptor-Ligand Complex structures to model using a method of the present invention include any EphB receptor protein, polypeptide or peptide that is substantially structurally related to an EphB4 receptor protein complexed with ephrinB2. In various embodiments, a target Receptor-Ligand Complex structure that is substantially structurally related to an EphB4 receptor protein includes a target Receptor-Ligand Complex structure having an amino acid sequence that is at least about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an amino acid sequence of a human EphB4 receptor protein, in particular an amino acid sequence having SEQ ID NO: 4, across the full-length of the EphB4 receptor sequence when using, for example, a sequence alignment program such as BLAST (supra). In various aspects of the present invention, target Receptor-Ligand Complex structures to model include proteins comprising amino acid sequences that are at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acid sequence of a truncated EphB4 receptor, EphB4(17-196), having SEQ ID NO: 2 or EphB4 17-198, having SEQ ID NO: 3, when comparing suitable regions of the sequence, such as the amino acid sequence for an ephrin binding site of any one of the amino acid sequences, when using an alignment program such as BLAST (supra) to align the amino acid sequences.

According to the present invention, a structure can be modeled using techniques generally described by, for example, Sali, Current Opinions in Biotechnology, vol. 6, pp. 437-451, 1995, and algorithms can be implemented in program packages such as Insight II, available from Accelerys (San Diego, Calif.). Use of Insight II HOMOLOGY requires an alignment of an amino acid sequence of a known structure having a known three-dimensional structure with an amino acid sequence of a target structure to be modeled. The alignment can be a pairwise alignment or a multiple sequence alignment including other related sequences (for example, using the method generally described by Rost, Meth. Enzymol., vol. 266, pp. 525-539, 1996) to improve accuracy. Structurally conserved regions can be identified by comparing related structural features, or by examining the degree of sequence homology between the known structure and the target structure. Certain coordinates for the target structure are assigned using known structures from the known structure. Coordinates for other regions of the target structure can be generated from fragments obtained from known structures such as those found in the Protein Data Bank. Conformation of side chains of the target structure can be assigned with reference to what is sterically allowable and using a library of rotamers and their frequency of occurrence (as generally described in Ponder and Richards, J. Mol. Biol., vol. 193, pp. 775-791, 1987). The resulting model of the target structure, can be refined by molecular mechanics to ensure that the model is chemically and conformationally reasonable.

Accordingly, one embodiment of the present invention is a method to derive a model of the three-dimensional structure of a target Receptor-Ligand Complex structure, the method comprising the steps of: (a) providing an amino acid sequence of a Receptor-Ligand Complex and an amino acid sequence of a target ligand-complexed EphB receptor; (b) identifying structurally conserved regions shared between the Receptor-Ligand Complex amino acid sequence and the target ligand-complexed EphB4 receptor amino acid sequence; (c) determining atomic coordinates for the target ligand-complexed EphB4 receptor by assigning said structurally conserved regions of the target ligand-complexed EphB4 receptor to a three-dimensional structure using a three-dimensional structure of a Receptor-Ligand Complex based on atomic coordinates that substantially conform to the atomic coordinates represented in Table 1, to derive a model of the three-dimensional structure of the target ligand-complexed EphB4 receptor amino acid sequence. A model according to the present invention has been previously described herein. In one aspect, the model comprises a computer model. The method can further comprise the step of electronically simulating the structural assignments to derive a computer model of the three-dimensional structure of the target ligand-complexed EphB4 receptor amino acid sequence.

Another embodiment of the present invention is a method to derive a computer model of the three-dimensional structure of a target ephrinB2-complexed EphB4 receptor structure for which a crystal has been produced (referred to herein as a “crystallized target structure”). A suitable method to produce such a model includes the method comprising molecular replacement. Methods of molecular replacement are generally known by those of skill in the art and are performed in a software program including, for example, X-PLOR available from Accelerys (San Diego, Calif.). In various aspects, a crystallized target ligand-complexed EphB receptor structure useful in a method of molecular replacement according to the present invention has an amino acid sequence that is at least about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the search structure (e.g., human EphB4), when the two amino acid sequences are compared using an alignment program such as BLAST (supra). A suitable search structure of the present invention includes a Receptor-Ligand Complex having a three-dimensional structure that substantially conforms with the atomic coordinates listed in Table 1.

Another aspect of the present invention is a method to determine a three-dimensional structure of a target Receptor-Ligand Complex structure, in which the three-dimensional structure of the target Receptor-Ligand Complex structure is not known. Such a method is useful for identifying structures that are related to the three-dimensional structure of a Receptor-Ligand Complex based only on the three-dimensional structure of the target structure. For example, the present method enables identification of structures that do not have high amino acid identity with an EphB4 receptor protein but which share three-dimensional structure similarities of a ligand-complexed EphB4 receptor. In various aspects of the present invention, a method to determine a three-dimensional structure of a target Receptor-Ligand Complex structure comprises: (a) providing an amino acid sequence of a target structure, wherein the three-dimensional structure of the target structure is not known; (b) analyzing the pattern of folding of the amino acid sequence in a three-dimensional conformation by fold recognition; and (c) comparing the pattern of folding of the target structure amino acid sequence with the three-dimensional structure of a Receptor-Ligand Complex to determine the three-dimensional structure of the target structure, wherein the three-dimensional structure of the Receptor-Ligand Complex substantially conforms to the atomic coordinates represented in Table 1. For example, methods of fold recognition can include the methods generally described in Jones, Curr. Opinion Struc. Biol., vol. 7, pp. 377-387, 1997. Such folding can be analyzed based on hydrophobic and/or hydrophilic properties of a target structure.

One aspect of the present invention includes a three-dimensional computer image of the three-dimensional structure of a Receptor-Ligand Complex. In one aspect, a computer image is created to a structure which substantially conforms with the three-dimensional coordinates listed in Table 1. A computer image of the present invention can be produced using any suitable software program, including, but not limited to, Pymol available from DeLano Scientific, LLC (South San Francisco, Calif.). Suitable computer hardware useful for producing an image of the present invention are known to those of skill in the art.

Another aspect of the present invention relates to a computer-readable medium encoded with a set of three-dimensional coordinates represented in Table 1, wherein, using a graphical display software program, the three-dimensional coordinates create an electronic file that can be visualized on a computer capable of representing said electronic file as a three-dimensional image. Yet another aspect of the present invention relates to a computer-readable medium encoded with a set of three-dimensional coordinates of a three-dimensional structure which substantially conforms to the three-dimensional coordinates represented in Table 1, wherein, using a graphical display software program, the set of three-dimensional coordinates create an electronic file that can be visualized on a computer capable of representing said electronic file as a three-dimensional image.

The present invention also includes a three-dimensional model of the three-dimensional structure of a target structure, such a three-dimensional model being produced by the method comprising: (a) providing an amino acid sequences of an EphB4 receptor comprised by a Receptor-Ligand Complex and an amino acid sequence of a target Receptor-Ligand Complex structure; (b) identifying structurally conserved regions shared between the EphB4 receptor amino acid sequence and the amino acid sequence comprised by the target Receptor-Ligand Complex structure; (c) determining atomic coordinates for the target Receptor-Ligand Complex by assigning the structurally conserved regions of the target Receptor-Ligand Complex to a three-dimensional structure using a three-dimensional structure of the EphB4 receptor comprised by a Receptor-Ligand Complex based on atomic coordinates that substantially conform to the atomic coordinates represented in Table 1 to derive a model of the three-dimensional structure of the target Receptor-Ligand Complex. In one aspect, the model comprises a computer model.

Another isolated EphB receptor protein can be used with the methods of the present invention. An isolated EphB receptor protein can be isolated from its natural milieu or produced using recombinant DNA technology (e.g., polymerase chain reaction (PCR) amplification, cloning) or chemical synthesis. To produce recombinant EphB receptor protein, a nucleic acid molecule encoding EphB receptor protein (e.g., SEQ ID NO: 5) can be inserted into any vector capable of delivering the nucleic acid molecule into a host cell. A nucleic acid molecule of the present invention can encode any portion of an EphB receptor protein, in various aspects a full-length EphB receptor protein, and in various aspects a soluble or truncated form of EphB4 receptor protein (i.e., a form of EphB4 receptor protein capable of being secreted by a cell that produces such protein). A suitable nucleic acid molecule to include in a recombinant vector, and particularly in a recombinant molecule, includes a nucleic acid molecule encoding a protein having the amino acid sequence represented by SEQ ID NOs: 2 or 3 and SEQ ID NO: 4.

A recombinant vector can be either RNA or DNA, either prokaryotic or eukaryotic, and typically is a virus or a plasmid. In various aspects, a nucleic acid molecule encoding an EphB4 receptor protein is inserted into a vector comprising an expression vector to form a recombinant molecule. As used herein, an expression vector is a DNA or RNA vector that is capable of transforming a host cell and of affecting expression of a specified nucleic acid molecule. Expression vectors of the present invention include any vectors that function (i.e., direct gene expression) in recombinant cells of the present invention, including in bacterial, fungal, endoparasite, insect, other animal, and plant cells.

An expression vector can be transformed into any suitable host cell to form a recombinant cell. A suitable host cell includes any cell capable of expressing a nucleic acid molecule inserted into the expression vector. For example, a prokaryotic expression vector can be transformed into a bacterial host cell. One method to isolate EphB4 receptor protein useful for producing ligand-complexed EphB4 receptor crystals includes recovery of recombinant proteins from cell cultures of recombinant cells expressing such EphB4 receptor protein.

EphB4 receptor proteins of the present invention can be purified using a variety of standard protein purification techniques, such as, but not limited to, affinity chromatography, ion exchange chromatography, filtration, electrophoresis, hydrophobic interaction chromatography, gel filtration chromatography, reverse phase chromatography, chromatofocusing and differential solubilization. In various aspects of the present invention, an EphB4 receptor protein is purified in such a manner that the protein is purified sufficiently for formation of crystals useful for obtaining information related to the three-dimensional structure of a Receptor-Ligand Complex. In some aspects, a composition of EphB4 receptor protein is about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% pure.

Another embodiment of the present invention includes a composition comprising a Receptor-Ligand Complex in a crystalline form (i.e., Receptor-Ligand Complex crystals). As used herein, the terms “crystalline Receptor-Ligand Complex” and “Receptor-Ligand Complex crystal” both refer to crystallized a Receptor-Ligand Complex and are intended to be used interchangeably. In various aspects of the present invention, a crystalline Receptor-Ligand Complex is produced using the crystal formation method described in the Examples.

In particular, the present invention includes a composition comprising EphB4 receptor complexed with ephrinB2 in a crystalline form (i.e., ephrinB2-complexed EphB4 crystals). As used herein, the terms “crystalline ephrinB2-complexed EphB4” and “ephrinB2-complexed EphB4 crystal” both refer to crystallized EphB4 receptor complexed with ephrinB2 and are intended to be used interchangeably. In various aspects of the present invention, a crystal ephrinB2-complexed EphB4 is produced using the crystal formation method described in the Examples. In some aspects, a composition of the present invention includes ephrinB2-complexed EphB4 molecules arranged in a crystalline manner in a space group P4₁ so as to form a unit cell of dimensions a=81.09 Å, b=81.09 Å, and c=50.95 Å. A suitable crystal of the present invention provides X-ray diffraction data for determination of atomic coordinates of the ephrinB2-complexed EphB4 to a resolution of about 2.0 Å, and in some aspects about 1.8 Å, and in other aspects at about 1.6 Å.

According to an aspect of the present invention, crystalline Receptor-Ligand Complex can be used to determine the ability of a compound of the present invention to bind to an EphB4 receptor in a manner predicted by a structure based drug design method of the present invention. In various aspects of the present invention, a Receptor-Ligand Complex crystal is soaked in a solution containing a chemical compound of the present invention. Binding of the chemical compound to the crystal is then determined by methods standard in the art.

One aspect of the present invention is a therapeutic composition. A therapeutic composition of the present invention comprises one or more therapeutic compounds. In one aspect, a therapeutic composition is provided that is capable of antagonizing the EphB4 receptor. For example, a therapeutic composition of the present invention can inhibit (i.e., prevent, block) binding of an EphB4 receptor on a cell having an EphB4 receptor (e.g., human cells) to a, e.g., ephrinB2 or ephrinB2 analog by interfering with the ligand binding domain of an EphB4 receptor. As used herein, the term “ligand binding domain” refers to the region of a molecule to which another molecule specifically binds.

Suitable inhibitory compounds of the present invention are compounds that interact directly with an EphB4 receptor protein or truncated EphB4 receptor protein (e.g., SEQ ID NOs: 2 or 3), thereby inhibiting the binding of ephrin-B2 to an EphB4 receptor by blocking the ligand binding domain of an EphB4 receptor (referred to herein as substrate analogs). An EphB4 receptor substrate analog refers to a compound that interacts with (e.g., binds to, associates with, modifies) the ligand binding domain of an EphB4 receptor. An EphB4 receptor substrate analog can, for example, comprise a chemical compound that mimics a polypeptide having SEQ ID NO: 6, truncated polypeptides comprised by SEQ ID NO: 6, or that binds specifically to the ephrin binding globular domain of an EphB4 receptor. Particularly, a substrate analog can comprise the G-H loop of ephrinB2 (SEQ ID NO: 7). Additionally, amino acids 120 through 127 of SEQ ID NO: 6 are useful in various aspects. In various aspects, an EphB4 receptor substrate analog useful in the present invention has an amino acid sequence that is at least about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7 and amino acids 120 through 127 of SEQ ID NO: 6.

According to the present invention, suitable therapeutic compounds of the present invention include peptides or other organic molecules, and inorganic molecules. Suitable organic molecules include small organic molecules. In various aspects, a therapeutic compound of the present invention is not harmful (e.g., toxic) to an animal when such compound is administered to an animal. Peptides refer to a class of compounds that is small in molecular weight and yields two or more amino acids upon hydrolysis. A polypeptide is comprised of two or more peptides. As used herein, a protein is comprised of one or more polypeptides. Suitable therapeutic compounds to design include peptides composed of “L” and/or “D” amino acids that are configured as normal or retroinverso peptides, peptidomimetic compounds, small organic molecules, or homo- or hetero-polymers thereof, in linear or branched configurations.

Therapeutic compounds of the present invention can be designed using structure based drug design. Structure based drug design refers to the use of computer simulation to predict a conformation of a peptide, polypeptide, protein, or conformational interaction between a peptide or polypeptide, and a therapeutic compound. In the present teachings, knowledge of the three-dimensional structure of the EphB4 ligand binding domain of an EphB4 receptor when bound with ephrinB2 provide one of skill in the art the ability to design a therapeutic compound that binds to EphB4 receptors, is stable and results in inhibition of a biological response, such as tumorigenesis. For example, knowledge of the three-dimensional structure of the EphB4 ligand binding domain of an EphB4 receptor in complex with ephrinB2 provides to a skilled artisan the ability to design a ligand or an analog of a ligand which can function as a substrate or ligand of an EphB4 receptor.

Suitable structures and models useful for structure-based drug design are disclosed herein. Models of target structures to use in a method of structure-based drug design include models produced by any modeling method disclosed herein, such as, for example, molecular replacement and fold recognition related methods. In some aspects of the present invention, structure based drug design can be applied to a structure of EphB4 in complex with ephrinB2 (SEQ ID NO: 6), and to a model of a target EphB receptor structure.

One embodiment of the present invention is a method for designing a drug which interferes with an activity of an EphB4 receptor. In various configurations, the method comprises providing a three-dimensional structure of a Receptor-Ligand Complex comprising the EphB4 receptor and at least one ligand of the receptor; and designing a chemical compound which is predicted to bind to the EphB4 receptor. The designing can comprise using physical models, such as, for example, ball-and-stick representations of atoms and bonds, or on a digital computer equipped with molecular modeling software. In some configurations, these methods can further include synthesizing the chemical compound, and evaluating the chemical compound for ability to interfere with an activity of the EphB4 receptor.

Suitable three-dimensional structures of a Receptor-Ligand Complex and models to use with the present method are disclosed herein. According to the present invention, designing a compound can include creating a new chemical compound or searching databases of libraries of known compounds (e.g., a compound listed in a computational screening database containing three-dimensional structures of known compounds). Designing can also include simulating chemical compounds having substitute moieties at certain structural features. In some configurations, designing can include selecting a chemical compound based on a known function of the compound. In some configurations designing can comprise computational screening of one or more databases of compounds in which three-dimensional structures of the compounds are known. In these configurations, a candidate compound can be interacted virtually (e.g., docked, aligned, matched, interfaced) with the three-dimensional structure of a Receptor-Ligand Complex by computer equipped with software such as, for example, the AutoDock software package, (The Scripps Research Institute, La Jolla, Calif.) or described by Humblet and Dunbar, Animal Reports in Medicinal Chemistry, vol. 28, pp. 275-283, 1993, M Venuti, ed., Academic Press. Methods for synthesizing candidate chemical compounds are known to those of skill in the art.

Various other methods of structure-based drug design are disclosed in references such as Maulik et al., 1997, Molecular Biotechnology: Therapeutic Applications and Strategies, Wiley-Liss, Inc., which is incorporated herein by reference in its entirety. Maulik et al. disclose, for example, methods of directed design, in which the user directs the process of creating novel molecules from a fragment library of appropriately selected fragments; random design, in which the user uses a genetic or other algorithm to randomly mutate fragments and their combinations while simultaneously applying a selection criterion to evaluate the fitness of candidate ligands; and a grid-based approach in which the user calculates the interaction energy between three-dimensional structures and small fragment probes, followed by linking together of favorable probe sites.

In one aspect, a chemical compound of the present invention that binds to the ligand binding domain of a Receptor-Ligand Complex can be a chemical compound having chemical and/or stereochemical complementarity with an EphB4 receptor, e.g., an EphB4 receptor or ligand such as, for example, ephrinB2. In particular, the amino acid sequence of SEQ ID NO: 7, amino acids 120 through 127 of SEQ ID NO: 6, and analogs thereof can be complimentary. In some configurations, a chemical compound that binds to the ligand binding domain of an EphB4 receptor can associate with an affinity of at least about 10⁻⁶ M, at least about 10⁻⁷ M, or at least about 10⁻⁸ M.

Several sites of an EphB4 receptor can be targeted for structure based drug design. These sites include, in non-limiting example residues which contact ephrin-B2 or a polypeptide having SEQ ID NO: 1, e.g., EphB4 D-E and J-K loops; Leu-48, Cys-61, Leu-95, Ser-99 Leu-100, Pro-101, Thr-147, Lys-149, Ala-155, and Cys-184 of SEQ ID NO: 6. Conversely, the structure based drug design can be based upon the sites of the ligand which bind to the EphB4 receptor, e.g., Phe-120, Pro-122, Leu-124, Trp-125, and Leu-127 of ephrinB2.

Drug design strategies as specifically described above with regard to residues and regions of the ligand-complexed EphB4 receptor crystal can be similarly applied to the other EphB structures, including other EphB receptors disclosed herein. One of ordinary skill in the art, using the art recognized modeling programs and drug design methods, many of which are described herein, can modify the EphB4 design strategy according to differences in amino acid sequence. For example, this strategy can be used to design compounds which regulate a function of the EphB4 receptor in EphB receptors. In addition, one of skill in the art can use lead compound structures derived from one EphB receptor, such as the EphB4 receptor, and take into account differences in amino acid residues in other EphB4 receptors.

In the present method of structure-based drug design, it is not necessary to align a candidate chemical compound (i.e., a chemical compound being analyzed in, for example, a computational screening method of the present invention) to each residue in a target site. Suitable candidate chemical compounds can align to a subset of residues described for a target site. In some configurations of the present invention, a candidate chemical compound can comprise a conformation that promotes the formation of covalent or noncovalent crosslinking between the target site and the candidate chemical compound. In certain aspects, a candidate chemical compound can bind to a surface adjacent to a target site to provide an additional site of interaction in a complex. For example, when designing an antagonist (i.e., a chemical compound that inhibits the binding of ephrinB2 to an EphB4 receptor by blocking a ligand binding domain or interface), the antagonist can be designed to bind with sufficient affinity to the binding site or to substantially prohibit a ligand from binding to a target area. It will be appreciated by one of skill in the art that it is not necessary that the complementarity between a candidate chemical compound and a target site extend over all residues specified here.

In various aspects, the design of a chemical compound possessing stereochemical complementarity can be accomplished by means of techniques that optimize, chemically or geometrically, the “fit” between a chemical compound and a target site. Such techniques are disclosed by, for example, Sheridan and Venkataraghavan, Acc. Chem. Res., vol. 20, p. 322, 1987: Goodford, J. Med. Chem., vol. 27, p. 557, 1984; Beddell, Chem. Soc. Reviews, vol. 279, 1985; Hol, Angew. Chem., vol. 25, p. 767, 1986; and Verlinde and Hol, Structure, vol. 2, p. 577, 1994, each of which are incorporated by this reference herein in their entirety.

Some embodiments of the present invention for structure-based drug design comprise methods of identifying a chemical compound that complements the shape of an EphB4 receptor, particularly one that substantially conforms to the atomic coordinates of Table 1, or a structure that is related to an EphB4 receptor. Such method is referred to herein as a “geometric approach”. In a geometric approach of the present invention, the number of internal degrees of freedom (and the corresponding local minima in the molecular conformation space) can be reduced by considering only the geometric (hard-sphere) interactions of two rigid bodies, where one body (the active site) contains “pockets” or “grooves” that form binding sites for the second body (the complementing molecule, such as a ligand).

The geometric approach is described by Kuntz et al., J. Mol. Biol., vol. 161, p. 269, 1982, which is incorporated by this reference herein in its entirety. The algorithm for chemical compound design can be implemented using a software program such as AutoDock, available from the The Scripps Research Institute (La Jolla, Calif.). One or more extant databases of crystallographic data (e.g., the Cambridge Structural Database System maintained by University Chemical Laboratory, Cambridge University, Lensfield Road, Cambridge CB2 IEW, U.K. or the Protein Data Bank maintained by Rutgers University) can then be searched for chemical compounds that approximate the shape thus defined. Chemical compounds identified by the geometric approach can be modified to satisfy criteria associated with chemical complementarity, such as hydrogen bonding, ionic interactions or Van der Waals interactions.

In some embodiments, a therapeutic composition of the present invention can comprise one or more therapeutic compounds. A therapeutic composition can further comprise other compounds capable of inhibiting an EphB4 receptor. A therapeutic composition of the present invention can be used to treat disease in an animal such as, for example, a human in need of treatment by administering such composition to the human. Non-limiting examples of animals to treat include mammals, reptiles and birds, companion animals, food animals, zoo animals and other economically relevant animals (e.g., race horses and animals valued for their coats, such as minks). Additional animals to treat include dogs, cats, horses, cattle, sheep, swine, chickens, turkeys. Accordingly, in some aspects, animals to treat include humans.

A therapeutic composition of the present invention can also include an excipient, an adjuvant and/or carrier. Suitable excipients include compounds that the animal to be treated can tolerate. Examples of such excipients include water, saline, Ringer's solution, dextrose solution, Hank's solution, and other aqueous physiologically balanced salt solutions. Nonaqueous vehicles, such as fixed oils, sesame oil, ethyl oleate, or triglycerides may also be used. Other useful formulations include suspensions containing viscosity enhancing agents, such as sodium carboxymethylcellulose, sorbitol, or dextran. Excipients can also contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability. Examples of buffers include phosphate buffer, bicarbonate buffer and Tris buffer, while examples of preservatives include thimerosal, o-cresol, formalin and benzyl alcohol. Standard formulations can either be liquid injectables or solids which can be taken up in a suitable liquid as a suspension or solution for injection. Thus, in a non-liquid formulation, the excipient can comprise dextrose, human serum albumin, preservatives, etc., to which sterile water or saline can be added prior to administration.

In one embodiment of the present invention, a therapeutic composition can include a carrier. Carriers include compounds that increase the half-life of a therapeutic composition in the treated animal. Suitable carriers include, but are not limited to, polymeric controlled release vehicles, biodegradable implants, liposomes, bacteria, viruses, other cells, oils, esters, and glycols.

Acceptable protocols to administer therapeutic compositions of the present invention in an effective manner include individual dose size, number of doses, frequency of dose administration, and mode of administration. Determination of such protocols can be accomplished by those skilled in the art. Modes of administration can include, but are not limited to, subcutaneous, intradermal, intravenous, intranasal, oral, transdermal, intraocular and intramuscular routes.

In yet another embodiment, a method is provided for crystallizing an EphB4 receptor which includes providing an EphB4 receptor in contact with a polypeptide having SEQ ID NO: 1, followed by contacting the EphB4 receptor in contact with the polypeptide with a therapeutic compound as provided above, wherein the EphB4 receptor in contact with the polypeptide and the compound forms an EphB4 receptor crystal.

In another embodiment, a composition is provided comprising EphB4 receptor, a ligand, and a therapeutic compound as provided above. The EphB4 receptor can be a polypeptide having SEQ ID NO: 2 or 3. The EphB4 receptor can also consist essentially of EphB4 D-E and J-K loops or Leu-48, Cys-61, Leu-95, Ser-99 Leu-100, Pro-101, Thr-147, Lys-149, Ala-155, and Cys-184 of SEQ ID NO: 6. In certain embodiments, the EphB4 receptor can be a human EphB4 receptor.

In certain embodiments, the ligand can be a polypeptide having SEQ ID NO: 7 and amino acids 120 through 127 of SEQ ID NO: 6. In other embodiments, the ligand can be a polypeptide having at least 50%, 75% or 90% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 7 and amino acids 120 through 127 of SEQ ID NO: 6.

In some aspects, the present teachings include mutants of EphB4. In various configurations, these mutants can include at least one amino acid substitution, at least one amino acid addition, and/or at least one amino acid deletion. Such mutant EphB4 polypeptides and proteins can be constructed by methods well known to skilled artisans, such as site-directed mutagenesis. In some configurations, an EphB4 mutant can exhibit lower binding affinity (compared to wild type) for an EphB4 ligand such as EphrinB2, a TNYL-RAW peptide, or a labeled, e.g., fluorescently tagged, TNYL-RAW peptide. In some aspects, the binding affinity to an EphB4 ligand can be lower than that of wild type EphB4 (wtEphB4), without altering the binding specificity of the EphB4. Some non-limiting examples of EphB4 mutants of these aspects include T147F (i.e., threonine-147 to phenylalanine), K149Q (i.e., lysine-149 to glutamine), and A186S (i.e., alanine-186 to serine) as well as those found in FIG. 4. Accordingly, the dynamic range of binding of an EphB4 ligand to a mutant EphB4 can be greater than that of binding of an EphB4 ligand to wtEphB4. In some configurations, the dynamic range can be greater than about 2-fold (i.e., the dynamic range for a wtEphB4-ligand binding assay), such as, without limitation, a 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12-fold dynamic range.

In some aspects, a mutant EphB4 can be used in a screening assay for an EphB4 ligand, such as an EphB4 agonist or an EphB4 inhibitor. In a non-limiting example, an assay can comprise a fluorescence polarization (FP) assay using a fluorescent ligand such as a TNYL-RAW peptide labeled with a fluorophore such as Alexa-532 (Invitrogen). In various configurations, an assay can comprise contacting a complex comprising a mutant EphB4 and a fluorescent ligand with a candidate EphB4 ligand, and measuring a shift in the FP of the fluorescent ligand (Park, S. H., and Raines, R. T., Methods Mol. Biol. 261: 161-166, 2004). In some configurations, a mutant EphB4 can show a lower specificity to a ligand such as EphrinB2 or a fluorescent TNYL-RAW peptide. A shift in FP in such assays can indicate that a candidate EphB4 ligand binds to the EphB4. A compound identified by such a screening assay can be further tested, e.g., for pharmacological effectiveness and toxicity, using standard cell biological, biochemical and pharmacological tests well known to skilled artisans. Such assays can be used individually with candidate molecules, or at any scale of screening, such as, without limitation, high-throughput screening in which several thousand compounds can be rapidly tested for activity as ligands for EphB4.

TABLE 1
Protein Databank Coordinates
of EphB4 Receptor Complexed ephrinB2
REMARK 3 PROGRAM: REFMAC 5.2.0019
REMARK 3 AUTHORS: MURSHUDOV, VAGIN, DODSON
REMARK 3
REMARK 3 REFINEMENT TARGET: MAXIMUM LIKELIHOOD
REMARK 3
REMARK 3 DATA USED IN REFINEMENT.
REMARK 3 RESOLUTION RANGE HIGH (ANGSTROMS): 1.91
REMARK 3 RESOLUTION RANGE LOW (ANGSTROMS): 36.27
REMARK 3 DATA CUTOFF (SIGMA(F)): NONE
REMARK 3 COMPLETENESS FOR RANGE (%): 99.07
REMARK 3 NUMBER OF REFLECTIONS: 24232
REMARK 3
REMARK 3 FIT TO DATA USED IN REFINEMENT.
REMARK 3 CROSS-VALIDATION METHOD: THROUGHOUT
REMARK 3 FREE R VALUE TEST SET SELECTION: RANDOM
REMARK 3 R VALUE (WORKING + TEST SET): 0.26396
REMARK 3 R VALUE (WORKING SET): 0.26082
REMARK 3 FREE R VALUE: 0.32142
REMARK 3 FREE R VALUE TEST SET SIZE (%): 5.1
REMARK 3 FREE R VALUE TEST SET COUNT: 1304
REMARK 3
REMARK 3 FIT IN THE HIGHEST RESOLUTION BIN.
REMARK 3 TOTAL NUMBER OF BINS USED: 20
REMARK 3 BIN RESOLUTION RANGE HIGH: 1.912
REMARK 3 BIN RESOLUTION RANGE LOW: 1.962
REMARK 3 REFLECTION IN BIN (WORKING SET): 1659
REMARK 3 BIN COMPLETENESS (WORKING + TEST) (%): 92.46
REMARK 3 BIN R VALUE (WORKING SET): 0.331
REMARK 3 BIN FREE R VALUE SET COUNT: 94
REMARK 3 BIN FREE R VALUE: 0.413
REMARK 3
REMARK 3 NUMBER OF NON-HYDROGEN ATOMS USED IN
REFINEMENT.
REMARK 3 ALL ATOMS: 2510
REMARK 3
REMARK 3 B VALUES.
REMARK 3 FROM WILSON PLOT (A**2): NULL
REMARK 3 MEAN B VALUE (OVERALL, A**2): 46.363
REMARK 3 OVERALL ANISOTROPIC B VALUE.
REMARK 3 B11 (A**2): −0.18
REMARK 3 B22 (A**2): −0.18
REMARK 3 B33 (A**2): 0.36
REMARK 3 B12 (A**2): 0.00
REMARK 3 B13 (A**2): 0.00
REMARK 3 B23 (A**2): 0.00
REMARK 3
REMARK 3 ESTIMATED OVERALL COORDINATE ERROR.
REMARK 3 ESU BASED ON R VALUE (A): 0.214
REMARK 3 ESU BASED ON FREE R VALUE (A): 0.202
REMARK 3 ESU BASED ON MAXIMUM LIKELIHOOD (A): 0.220
REMARK 3 ESU FOR B VALUES BASED ON MAXIMUM
LIKELIHOOD (A**2): 16.948
REMARK 3
REMARK 3 CORRELATION COEFFICIENTS.
REMARK 3 CORRELATION COEFFICIENT FO-FC: 0.934
REMARK 3 CORRELATION COEFFICIENT FO-FC FREE: 0.893
REMARK 3
REMARK 3 RMS DEVIATIONS FROM IDEAL VALUES COUNT
RMS WEIGHT
REMARK 3 BOND LENGTHS REFINED ATOMS (A): 2577; 0.013;
0.022
REMARK 3 BOND ANGLES REFINED ATOMS (DEGREES): 3512;
1.579; 1.950
REMARK 3 TORSION ANGLES, PERIOD 1 (DEGREES): 323;
7.895; 5.000
REMARK 3 TORSION ANGLES, PERIOD 2 (DEGREES): 109;
37.322; 24.404
REMARK 3 TORSION ANGLES, PERIOD 3 (DEGREES): 406;
20.218; 15.000
REMARK 3 TORSION ANGLES, PERIOD 4 (DEGREES): 9;
14.327; 15.000
REMARK 3 CHIRAL-CENTER RESTRAINTS (A**3): 392; 0.103;
0.200
REMARK 3 GENERAL PLANES REFINED ATOMS (A): 1955;
0.006; 0.020
REMARK 3 NON-BONDED CONTACTS REFINED ATOMS (A):
976; 0.233; 0.200
REMARK 3 NON-BONDED TORSION REFINED ATOMS (A):
1665; 0.309; 0.200
REMARK 3 H-BOND (X . . . Y) REFINED ATOMS (A): 89; 0.168;
0.200
REMARK 3 SYMMETRY VDW REFINED ATOMS (A): 52; 0.228;
0.200
REMARK 3 SYMMETRY H-BOND REFINED ATOMS (A): 9; 0.218;
0.200
REMARK 3
REMARK 3 ISOTROPIC THERMAL FACTOR RESTRAINTS. COUNT RMS WEIGHT
REMARK 3 MAIN-CHAIN BOND REFINED ATOMS (A**2): 1660;
2.151; 3.000
REMARK 3 MAIN-CHAIN ANGLE REFINED ATOMS (A**2): 2588;
3.180; 5.000
REMARK 3 SIDE-CHAIN BOND REFINED ATOMS (A**2): 1065;
4.640; 7.000
REMARK 3 SIDE-CHAIN ANGLE REFINED ATOMS (A**2): 924;
5.442; 9.000
REMARK 3
REMARK 3 NCS RESTRAINTS STATISTICS
REMARK 3 NUMBER OF NCS GROUPS: NULL
REMARK 3
REMARK 3
REMARK 3 TLS DETAILS
REMARK 3 NUMBER OF TLS GROUPS: 2
REMARK 3 ATOM RECORD CONTAINS RESIDUAL B FACTORS
ONLY
REMARK 3
REMARK 3 TLS GROUP: 1
REMARK 3 NUMBER OF COMPONENTS GROUP: 1
REMARK 3 COMPONENTS C SSSEQI TO C SSSEQI
REMARK 3 RESIDUE RANGE: A 9 A 196
REMARK 3 ORIGIN FOR THE GROUP (A): 6.5459 29.3924 −8.9085
REMARK 3 T TENSOR
REMARK 3 T11: −0.0510 T22: −0.0163
REMARK 3 T33: 0.0412 T12: 0.0109
REMARK 3 T13: −0.0201 T23: 0.0639
REMARK 3 L TENSOR
REMARK 3 L11: 1.0238 L22: 1.0652
REMARK 3 L33: 0.1402 L12: −0.0578
REMARK 3 L13: 0.0466 L23: 0.0816
REMARK 3 S TENSOR
REMARK 3 S11: −0.0398 S12: 0.2633 S13: 0.0085
REMARK 3 S21: 0.0822 S22: 0.0447 S23: 0.2172
REMARK 3 S31: −0.0545 S32: 0.0708 S33: −0.0048
REMARK 3
REMARK 3 TLS GROUP: 2
REMARK 3 NUMBER OF COMPONENTS GROUP: 1
REMARK 3 COMPONENTS C SSSEQI TO C SSSEQI
REMARK 3 RESIDUE RANGE: B 31 B 167
REMARK 3 ORIGIN FOR THE GROUP (A): 24.0838 25.2120
12.7894
REMARK 3 T TENSOR
REMARK 3 T11: −0.0009 T22: −0.0420
REMARK 3 T33: −0.0654 T12: 0.0636
REMARK 3 T13: −0.0312 T23: 0.0420
REMARK 3 L TENSOR
REMARK 3 L11: 1.3724 L22: 1.0673
REMARK 3 L33: 2.6076 L12: 0.8437
REMARK 3 L13: 1.4287 L23: 0.6393
REMARK 3 S TENSOR
REMARK 3 S11: 0.1162 S12: 0.1266 S13: −0.1332
REMARK 3 S21: 0.2137 S22: 0.0292 S23: −0.0248
REMARK 3 S31: 0.1770 S32: 0.2825 S33: −0.1455
REMARK 3
REMARK 3
REMARK 3 BULK SOLVENT MODELLING.
REMARK 3 METHOD USED: MASK
REMARK 3 PARAMETERS FOR MASK CALCULATION
REMARK 3 VDW PROBE RADIUS: 1.20
REMARK 3 ION PROBE RADIUS: 0.80
REMARK 3 SHRINKAGE RADIUS: 0.80
REMARK 3
REMARK 3 OTHER REFINEMENT REMARKS:
REMARK 3 HYDROGENS HAVE BEEN ADDED IN THE RIDING
POSITIONS
REMARK 3
SSBOND 1 CYS A 61 CYS A 184
SSBOND 2 CYS A 97 CYS A 107
SSBOND 3 CYS B 65 CYS B 104
SSBOND 4 CYS B 92 CYS B 156
CISPEP 1 PHE A 35 PRO A 36 0.00
CISPEP 2 THR A 127 PRO A 128 0.00
CISPEP 3 ASN A 133 PRO A 134 0.00
CISPEP 4 GLY A 167 PRO A 168 0.00
CISPEP 5 ASP B 90 ARG B 91 0.00
CRYST1 81.085 81.085 50.945 90.00 90.00 90.00 P 41
SCALE1 0.012333 0.000000 0.000000 0.00000
SCALE2 0.000000 0.012333 0.000000 0.00000
SCALE3 0.000000 0.000000 0.019629 0.00000
ATOM	10	N	HIS	A	11	24.448	54.004	−27.877	1.00	49.00	N
ATOM	11	CA	HIS	A	11	23.039	54.322	−27.723	1.00	47.86	C
ATOM	12	CB	HIS	A	11	22.253	53.916	−28.974	1.00	48.48	C
ATOM	13	CG	HIS	A	11	22.560	54.756	−30.174	1.00	46.99	C
ATOM	14	ND1	HIS	A	11	21.891	55.929	−30.454	1.00	47.84	N
ATOM	15	CE1	HIS	A	11	22.369	56.455	−31.566	1.00	44.85	C
ATOM	16	NE2	HIS	A	11	23.333	55.672	−32.016	1.00	48.34	N
ATOM	17	CD2	HIS	A	11	23.473	54.602	−31.163	1.00	49.20	C
ATOM	18	C	HIS	A	11	22.494	53.661	−26.468	1.00	46.86	C
ATOM	19	O	HIS	A	11	22.657	52.455	−26.254	1.00	46.50	O
ATOM	20	N	HIS	A	12	21.858	54.459	−25.620	1.00	44.51	N
ATOM	21	CA	HIS	A	12	21.462	53.973	−24.313	1.00	43.01	C
ATOM	22	CB	HIS	A	12	22.056	54.854	−23.211	1.00	43.91	C
ATOM	23	CG	HIS	A	12	23.320	54.305	−22.635	1.00	46.33	C
ATOM	24	ND1	HIS	A	12	23.372	53.706	−21.396	1.00	47.69	N
ATOM	25	CE1	HIS	A	12	24.605	53.299	−21.160	1.00	52.21	C
ATOM	26	NE2	HIS	A	12	25.351	53.602	−22.207	1.00	51.06	N
ATOM	27	CD2	HIS	A	12	24.569	54.227	−23.145	1.00	49.90	C
ATOM	28	C	HIS	A	12	19.962	53.828	−24.139	1.00	40.46	C
ATOM	29	O	HIS	A	12	19.191	54.727	−24.500	1.00	41.03	O
ATOM	30	N	HIS	A	13	19.556	52.677	−23.624	1.00	39.88	N
ATOM	31	CA	HIS	A	13	18.184	52.506	−23.152	1.00	39.98	C
ATOM	32	CB	HIS	A	13	17.414	51.459	−23.973	1.00	39.69	C
ATOM	33	CG	HIS	A	13	15.982	51.315	−23.562	1.00	40.91	C
ATOM	34	ND1	HIS	A	13	15.410	50.100	−23.255	1.00	43.46	N
ATOM	35	CE1	HIS	A	13	14.154	50.287	−22.890	1.00	36.43	C
ATOM	36	NE2	HIS	A	13	13.895	51.579	−22.942	1.00	39.44	N
ATOM	37	CD2	HIS	A	13	15.021	52.242	−23.359	1.00	38.36	C
ATOM	38	C	HIS	A	13	18.174	52.172	−21.661	1.00	39.78	C
ATOM	39	O	HIS	A	13	18.660	51.131	−21.228	1.00	38.65	O
ATOM	40	N	HIS	A	14	17.617	53.068	−20.866	1.00	38.90	N
ATOM	41	CA	HIS	A	14	17.507	52.802	−19.451	1.00	39.71	C
ATOM	42	CB	HIS	A	14	17.974	54.017	−18.639	1.00	41.36	C
ATOM	43	C	HIS	A	14	16.049	52.499	−19.153	1.00	40.66	C
ATOM	44	O	HIS	A	14	15.159	53.220	−19.604	1.00	38.87	O
ATOM	45	N	HIS	A	15	15.797	51.424	−18.419	1.00	37.90	N
ATOM	46	CA	HIS	A	15	14.455	51.188	−17.913	1.00	39.77	C
ATOM	47	CB	HIS	A	15	13.713	50.239	−18.844	1.00	38.53	C
ATOM	48	CG	HIS	A	15	12.236	50.372	−18.753	1.00	36.65	C
ATOM	49	ND1	HIS	A	15	11.388	49.846	−19.698	1.00	36.72	N
ATOM	50	CE1	HIS	A	15	10.141	50.136	−19.372	1.00	37.69	C
ATOM	51	NE2	HIS	A	15	10.155	50.844	−18.256	1.00	36.35	N
ATOM	52	CD2	HIS	A	15	11.454	51.002	−17.845	1.00	37.33	C
ATOM	53	C	HIS	A	15	14.438	50.663	−16.465	1.00	42.34	C
ATOM	54	O	HIS	A	15	14.945	49.583	−16.197	1.00	45.21	O
ATOM	55	N	HIS	A	16	13.877	51.449	−15.542	1.00	42.50	N
ATOM	56	CA	HIS	A	16	13.849	51.102	−14.115	1.00	44.89	C
ATOM	57	CB	HIS	A	16	13.544	52.349	−13.269	1.00	46.52	C
ATOM	58	CG	HIS	A	16	14.588	53.417	−13.375	1.00	54.62	C
ATOM	59	ND1	HIS	A	16	14.398	54.577	−14.100	1.00	57.87	N
ATOM	60	CE1	HIS	A	16	15.486	55.323	−14.023	1.00	52.34	C
ATOM	61	NE2	HIS	A	16	16.378	54.684	−13.286	1.00	53.86	N
ATOM	62	CD2	HIS	A	16	15.843	53.488	−12.870	1.00	51.85	C
ATOM	63	C	HIS	A	16	12.856	49.985	−13.768	1.00	44.45	C
ATOM	64	O	HIS	A	16	11.720	50.017	−14.218	1.00	38.53	O
ATOM	65	N	GLU	A	17	13.296	49.033	−12.940	1.00	43.15	N
ATOM	66	CA	GLU	A	17	12.510	47.851	−12.579	1.00	45.72	C
ATOM	67	CB	GLU	A	17	13.325	46.576	−12.794	1.00	46.52	C
ATOM	68	CG	GLU	A	17	13.479	46.141	−14.242	1.00	45.21	C
ATOM	69	CD	GLU	A	17	14.404	44.935	−14.428	1.00	48.39	C
ATOM	70	OE1	GLU	A	17	14.909	44.363	−13.436	1.00	53.51	O
ATOM	71	OE2	GLU	A	17	14.645	44.557	−15.587	1.00	49.07	O
ATOM	72	C	GLU	A	17	12.077	47.943	−11.131	1.00	45.46	C
ATOM	73	O	GLU	A	17	12.914	48.171	−10.252	1.00	47.09	O
ATOM	74	N	GLU	A	18	10.775	47.812	−10.879	1.00	46.25	N
ATOM	75	CA	GLU	A	18	10.287	47.795	−9.500	1.00	47.01	C
ATOM	76	CB	GLU	A	18	9.270	48.907	−9.194	1.00	50.02	C
ATOM	77	CG	GLU	A	18	9.553	49.578	−7.827	1.00	53.61	C
ATOM	78	CD	GLU	A	18	8.322	50.164	−7.143	1.00	58.47	C
ATOM	79	OE1	GLU	A	18	7.339	49.415	−6.922	1.00	58.46	O
ATOM	80	OE2	GLU	A	18	8.356	51.370	−6.792	1.00	52.49	O
ATOM	81	C	GLU	A	18	9.737	46.439	−9.101	1.00	45.25	C
ATOM	82	O	GLU	A	18	8.859	45.885	−9.760	1.00	46.79	O
ATOM	83	N	THR	A	19	10.265	45.937	−7.993	1.00	43.60	N
ATOM	84	CA	THR	A	19	10.022	44.578	−7.547	1.00	40.92	C
ATOM	85	CB	THR	A	19	11.154	44.128	−6.611	1.00	40.82	C
ATOM	86	OG1	THR	A	19	12.355	43.937	−7.372	1.00	46.16	O
ATOM	87	CG2	THR	A	19	10.790	42.835	−5.855	1.00	41.51	C
ATOM	88	C	THR	A	19	8.719	44.532	−6.793	1.00	38.18	C
ATOM	89	O	THR	A	19	8.506	45.332	−5.877	1.00	38.71	O
ATOM	90	N	LEU	A	20	7.869	43.573	−7.155	1.00	35.11	N
ATOM	91	CA	LEU	A	20	6.598	43.341	−6.454	1.00	35.09	C
ATOM	92	CB	LEU	A	20	5.582	42.814	−7.455	1.00	32.21	C
ATOM	93	CG	LEU	A	20	5.228	43.763	−8.593	1.00	42.07	C
ATOM	94	CD1	LEU	A	20	4.775	43.011	−9.829	1.00	41.64	C
ATOM	95	CD2	LEU	A	20	4.192	44.745	−8.158	1.00	31.95	C
ATOM	96	C	LEU	A	20	6.783	42.315	−5.308	1.00	35.93	C
ATOM	97	O	LEU	A	20	6.192	42.424	−4.227	1.00	39.65	O
ATOM	98	N	LEU	A	21	7.647	41.347	−5.560	1.00	37.15	N
ATOM	99	CA	LEU	A	21	7.866	40.212	−4.662	1.00	36.59	C
ATOM	100	CB	LEU	A	21	6.704	39.210	−4.790	1.00	35.23	C
ATOM	101	CG	LEU	A	21	6.824	37.819	−4.076	1.00	30.98	C
ATOM	102	CD1	LEU	A	21	7.141	37.996	−2.622	1.00	42.83	C
ATOM	103	CD2	LEU	A	21	5.549	37.070	−4.163	1.00	31.48	C
ATOM	104	C	LEU	A	21	9.193	39.556	−5.034	1.00	37.39	C
ATOM	105	O	LEU	A	21	9.445	39.256	−6.193	1.00	39.08	O
ATOM	106	N	ASN	A	22	10.053	39.357	−4.050	1.00	39.54	N
ATOM	107	CA	ASN	A	22	11.326	38.676	−4.273	1.00	40.39	C
ATOM	108	CB	ASN	A	22	12.473	39.693	−4.295	1.00	36.59	C
ATOM	109	CG	ASN	A	22	13.795	39.073	−4.663	1.00	42.16	C
ATOM	110	OD1	ASN	A	22	13.963	37.854	−4.578	1.00	37.60	O
ATOM	111	ND2	ASN	A	22	14.759	39.910	−5.068	1.00	32.02	N
ATOM	112	C	ASN	A	22	11.525	37.720	−3.110	1.00	39.65	C
ATOM	113	O	ASN	A	22	11.721	38.195	−1.992	1.00	40.60	O
ATOM	114	N	THR	A	23	11.447	36.403	−3.362	1.00	43.19	N
ATOM	115	CA	THR	A	23	11.631	35.394	−2.304	1.00	39.47	C
ATOM	116	CB	THR	A	23	11.247	33.931	−2.746	1.00	39.83	C
ATOM	117	OG1	THR	A	23	12.103	33.496	−3.803	1.00	29.00	O
ATOM	118	CG2	THR	A	23	9.793	33.845	−3.201	1.00	37.70	C
ATOM	119	C	THR	A	23	13.062	35.354	−1.755	1.00	41.75	C
ATOM	120	O	THR	A	23	13.241	35.056	−0.571	1.00	39.34	O
ATOM	121	N	LYS	A	24	14.058	35.605	−2.613	1.00	42.15	N
ATOM	122	CA	LYS	A	24	15.497	35.577	−2.231	1.00	47.84	C
ATOM	123	CB	LYS	A	24	16.430	35.906	−3.417	1.00	44.41	C
ATOM	124	CG	LYS	A	24	16.713	34.791	−4.408	1.00	36.81	C
ATOM	125	CD	LYS	A	24	17.426	35.348	−5.632	1.00	51.46	C
ATOM	126	CE	LYS	A	24	16.468	36.179	−6.495	1.00	59.42	C
ATOM	127	NZ	LYS	A	24	17.187	37.004	−7.498	1.00	60.14	N
ATOM	128	C	LYS	A	24	15.843	36.550	−1.107	1.00	53.13	C
ATOM	129	O	LYS	A	24	16.809	36.334	−0.372	1.00	57.22	O
ATOM	130	N	LEU	A	25	15.069	37.619	−0.974	1.00	54.53	N
ATOM	131	CA	LEU	A	25	15.320	38.588	0.085	1.00	59.86	C
ATOM	132	CB	LEU	A	25	15.531	40.002	−0.491	1.00	60.08	C
ATOM	133	CG	LEU	A	25	16.786	40.121	−1.390	1.00	60.60	C
ATOM	134	CD1	LEU	A	25	16.740	41.310	−2.344	1.00	63.05	C
ATOM	135	CD2	LEU	A	25	18.090	40.118	−0.596	1.00	66.00	C
ATOM	136	C	LEU	A	25	14.269	38.521	1.205	1.00	62.83	C
ATOM	137	O	LEU	A	25	13.371	39.363	1.295	1.00	65.96	O
ATOM	138	N	GLU	A	26	14.417	37.481	2.034	1.00	63.60	N
ATOM	139	CA	GLU	A	26	13.557	37.151	3.180	1.00	64.36	C
ATOM	140	CB	GLU	A	26	12.164	36.740	2.703	1.00	65.26	C
ATOM	141	CG	GLU	A	26	11.181	36.462	3.840	1.00	68.35	C
ATOM	142	CD	GLU	A	26	10.195	35.365	3.503	1.00	69.03	C
ATOM	143	OE1	GLU	A	26	10.611	34.373	2.866	1.00	72.16	O
ATOM	144	OE2	GLU	A	26	9.006	35.483	3.885	1.00	70.04	O
ATOM	145	C	GLU	A	26	14.182	35.967	3.926	1.00	62.58	C
ATOM	146	O	GLU	A	26	14.503	34.958	3.303	1.00	61.58	O
ATOM	147	N	THR	A	27	14.358	36.078	5.244	1.00	62.75	N
ATOM	148	CA	THR	A	27	14.928	34.965	6.031	1.00	62.27	C
ATOM	149	CB	THR	A	27	16.365	35.278	6.593	1.00	62.72	C
ATOM	150	OG1	THR	A	27	17.247	35.654	5.526	1.00	60.03	O
ATOM	151	CG2	THR	A	27	16.959	34.054	7.245	1.00	56.16	C
ATOM	152	C	THR	A	27	13.979	34.389	7.117	1.00	62.81	C
ATOM	153	O	THR	A	27	14.427	33.864	8.148	1.00	63.93	O
ATOM	154	N	ALA	A	28	12.673	34.504	6.868	1.00	62.26	N
ATOM	155	CA	ALA	A	28	11.630	33.803	7.634	1.00	60.61	C
ATOM	156	CB	ALA	A	28	10.916	34.758	8.558	1.00	62.26	C
ATOM	157	C	ALA	A	28	10.646	33.186	6.647	1.00	58.58	C
ATOM	158	O	ALA	A	28	10.582	33.623	5.516	1.00	61.77	O
ATOM	159	N	ASP	A	29	9.867	32.197	7.080	1.00	57.43	N
ATOM	160	CA	ASP	A	29	9.059	31.336	6.188	1.00	51.76	C
ATOM	161	CB	ASP	A	29	8.248	30.372	7.029	1.00	52.60	C
ATOM	162	CG	ASP	A	29	9.024	29.852	8.206	1.00	54.73	C
ATOM	163	OD1	ASP	A	29	9.472	28.696	8.133	1.00	65.52	O
ATOM	164	OD2	ASP	A	29	9.221	30.597	9.195	1.00	57.50	O
ATOM	165	C	ASP	A	29	8.133	32.114	5.268	1.00	48.96	C
ATOM	166	O	ASP	A	29	7.583	33.121	5.686	1.00	50.09	O
ATOM	167	N	LEU	A	30	7.954	31.637	4.027	1.00	44.57	N
ATOM	168	CA	LEU	A	30	7.173	32.357	2.999	1.00	38.90	C
ATOM	169	CB	LEU	A	30	7.469	31.824	1.593	1.00	33.40	C
ATOM	170	CG	LEU	A	30	8.847	32.055	0.993	1.00	31.55	C
ATOM	171	CD1	LEU	A	30	9.081	30.975	−0.047	1.00	34.59	C
ATOM	172	CD2	LEU	A	30	8.873	33.455	0.382	1.00	35.00	C
ATOM	173	C	LEU	A	30	5.692	32.186	3.288	1.00	37.96	C
ATOM	174	O	LEU	A	30	4.886	33.060	2.968	1.00	38.81	O
ATOM	175	N	LYS	A	31	5.352	31.042	3.872	1.00	36.60	N
ATOM	176	CA	LYS	A	31	3.986	30.689	4.309	1.00	36.65	C
ATOM	177	CB	LYS	A	31	3.524	31.555	5.506	1.00	38.57	C
ATOM	178	CG	LYS	A	31	4.378	31.527	6.791	1.00	46.53	C
ATOM	179	CD	LYS	A	31	4.249	30.238	7.593	1.00	57.30	C
ATOM	180	CE	LYS	A	31	4.170	30.493	9.118	1.00	60.83	C
ATOM	181	NZ	LYS	A	31	5.181	31.459	9.679	1.00	65.93	N
ATOM	182	C	LYS	A	31	2.977	30.782	3.181	1.00	39.42	C
ATOM	183	O	LYS	A	31	1.858	31.305	3.381	1.00	41.43	O
ATOM	184	N	TRP	A	32	3.371	30.358	1.973	1.00	35.13	N
ATOM	185	CA	TRP	A	32	2.453	30.416	0.834	1.00	33.15	C
ATOM	186	CB	TRP	A	32	3.161	30.207	−0.500	1.00	28.95	C
ATOM	187	CG	TRP	A	32	4.039	31.317	−0.919	1.00	34.75	C
ATOM	188	CD1	TRP	A	32	4.205	32.537	−0.312	1.00	33.11	C
ATOM	189	NE1	TRP	A	32	5.093	33.291	−1.021	1.00	29.19	N
ATOM	190	CE2	TRP	A	32	5.511	32.583	−2.117	1.00	31.35	C
ATOM	191	CD2	TRP	A	32	4.872	31.332	−2.081	1.00	32.07	C
ATOM	192	CE3	TRP	A	32	5.140	30.397	−3.090	1.00	28.33	C
ATOM	193	CZ3	TRP	A	32	6.044	30.747	−4.096	1.00	29.85	C
ATOM	194	CH2	TRP	A	32	6.681	32.008	−4.088	1.00	33.09	C
ATOM	195	CZ2	TRP	A	32	6.443	32.928	−3.108	1.00	29.70	C
ATOM	196	C	TRP	A	32	1.381	29.360	1.045	1.00	34.03	C
ATOM	197	O	TRP	A	32	1.475	28.597	1.979	1.00	31.83	O
ATOM	198	N	VAL	A	33	0.387	29.316	0.166	1.00	36.83	N
ATOM	199	CA	VAL	A	33	−0.813	28.472	0.377	1.00	34.51	C
ATOM	200	CB	VAL	A	33	−2.075	29.329	0.158	1.00	39.47	C
ATOM	201	CG1	VAL	A	33	−3.367	28.480	0.048	1.00	38.42	C
ATOM	202	CG2	VAL	A	33	−2.180	30.345	1.283	1.00	29.62	C
ATOM	203	C	VAL	A	33	−0.811	27.254	−0.516	1.00	35.90	C
ATOM	204	O	VAL	A	33	−0.618	27.372	−1.721	1.00	35.14	O
ATOM	205	N	THR	A	34	−1.031	26.075	0.077	1.00	36.36	N
ATOM	206	CA	THR	A	34	−1.112	24.856	−0.726	1.00	36.51	C
ATOM	207	CB	THR	A	34	−0.110	23.848	−0.259	1.00	29.05	C
ATOM	208	OG1	THR	A	34	−0.276	23.679	1.146	1.00	30.25	O
ATOM	209	CG2	THR	A	34	1.324	24.336	−0.559	1.00	36.15	C
ATOM	210	C	THR	A	34	−2.504	24.202	−0.691	1.00	36.01	C
ATOM	211	O	THR	A	34	−3.244	24.330	0.293	1.00	39.89	O
ATOM	212	N	PHE	A	35	−2.836	23.508	−1.777	1.00	40.71	N
ATOM	213	CA	PHE	A	35	−4.038	22.661	−1.865	1.00	37.31	C
ATOM	214	CB	PHE	A	35	−5.242	23.488	−2.352	1.00	39.56	C
ATOM	215	CG	PHE	A	35	−6.458	22.656	−2.745	1.00	31.37	C
ATOM	216	CD1	PHE	A	35	−7.425	22.323	−1.800	1.00	38.00	C
ATOM	217	CE1	PHE	A	35	−8.536	21.564	−2.155	1.00	34.26	C
ATOM	218	CZ	PHE	A	35	−8.710	21.162	−3.467	1.00	41.72	C
ATOM	219	CE2	PHE	A	35	−7.770	21.507	−4.424	1.00	38.74	C
ATOM	220	CD2	PHE	A	35	−6.652	22.255	−4.061	1.00	37.81	C
ATOM	221	C	PHE	A	35	−3.799	21.477	−2.807	1.00	38.54	C
ATOM	222	O	PHE	A	35	−3.222	21.649	−3.876	1.00	41.98	O
ATOM	223	N	PRO	A	36	−4.272	20.275	−2.435	1.00	36.71	N
ATOM	224	CA	PRO	A	36	−4.947	19.954	−1.169	1.00	37.64	C
ATOM	225	CB	PRO	A	36	−5.768	18.692	−1.504	1.00	39.48	C
ATOM	226	CG	PRO	A	36	−5.523	18.410	−2.972	1.00	38.36	C
ATOM	227	CD	PRO	A	36	−4.236	19.098	−3.318	1.00	40.07	C
ATOM	228	C	PRO	A	36	−3.904	19.700	−0.087	1.00	40.22	C
ATOM	229	O	PRO	A	36	−2.750	19.379	−0.420	1.00	41.14	O
ATOM	230	N	GLN	A	37	−4.267	19.883	1.186	1.00	36.93	N
ATOM	231	CA	GLN	A	37	−3.271	19.770	2.261	1.00	39.87	C
ATOM	232	CB	GLN	A	37	−3.542	20.763	3.406	1.00	40.23	C
ATOM	233	CG	GLN	A	37	−2.965	22.128	3.109	1.00	42.03	C
ATOM	234	CD	GLN	A	37	−3.673	23.293	3.765	1.00	44.82	C
ATOM	235	OE1	GLN	A	37	−4.184	23.192	4.876	1.00	50.61	O
ATOM	236	NE2	GLN	A	37	−3.697	24.422	3.068	1.00	47.44	N
ATOM	237	C	GLN	A	37	−3.103	18.329	2.732	1.00	41.85	C
ATOM	238	O	GLN	A	37	−3.605	17.935	3.802	1.00	43.80	O
ATOM	239	N	VAL	A	38	−2.413	17.550	1.889	1.00	40.81	N
ATOM	240	CA	VAL	A	38	−2.108	16.133	2.121	1.00	40.56	C
ATOM	241	CB	VAL	A	38	−2.824	15.199	1.098	1.00	44.60	C
ATOM	242	CG1	VAL	A	38	−4.312	15.348	1.189	1.00	41.50	C
ATOM	243	CG2	VAL	A	38	−2.366	15.498	−0.335	1.00	46.63	C
ATOM	244	C	VAL	A	38	−0.623	15.866	1.983	1.00	40.11	C
ATOM	245	O	VAL	A	38	0.122	16.692	1.460	1.00	33.72	O
ATOM	246	N	ASP	A	39	−0.191	14.686	2.413	1.00	39.32	N
ATOM	247	CA	ASP	A	39	1.187	14.302	2.188	1.00	39.86	C
ATOM	248	CB	ASP	A	39	1.489	12.950	2.845	1.00	42.53	C
ATOM	249	CG	ASP	A	39	2.889	12.892	3.446	1.00	54.40	C
ATOM	250	OD1	ASP	A	39	3.849	13.397	2.806	1.00	56.20	O
ATOM	251	OD2	ASP	A	39	3.032	12.338	4.564	1.00	62.34	O
ATOM	252	C	ASP	A	39	1.494	14.312	0.682	1.00	38.22	C
ATOM	253	O	ASP	A	39	0.734	13.790	−0.121	1.00	39.89	O
ATOM	254	N	GLY	A	40	2.598	14.938	0.294	1.00	36.82	N
ATOM	255	CA	GLY	A	40	2.906	15.094	−1.115	1.00	36.32	C
ATOM	256	C	GLY	A	40	2.726	16.504	−1.637	1.00	36.89	C
ATOM	257	O	GLY	A	40	3.230	16.826	−2.713	1.00	40.19	O
ATOM	258	N	GLN	A	41	1.959	17.320	−0.910	1.00	34.90	N
ATOM	259	CA	GLN	A	41	1.794	18.743	−1.202	1.00	31.38	C
ATOM	260	CB	GLN	A	41	0.938	19.401	−0.098	1.00	34.79	C
ATOM	261	CG	GLN	A	41	1.706	19.597	1.237	1.00	31.27	C
ATOM	262	CD	GLN	A	41	0.855	19.958	2.420	1.00	32.64	C
ATOM	263	OE1	GLN	A	41	0.175	20.974	2.428	1.00	37.65	O
ATOM	264	NE2	GLN	A	41	0.921	19.135	3.456	1.00	36.27	N
ATOM	265	C	GLN	A	41	3.165	19.451	−1.292	1.00	32.83	C
ATOM	266	O	GLN	A	41	4.113	19.037	−0.633	1.00	30.94	O
ATOM	267	N	TRP	A	42	3.246	20.579	−2.015	1.00	27.39	N
ATOM	268	CA	TRP	A	42	4.499	21.331	−2.053	1.00	30.30	C
ATOM	269	CB	TRP	A	42	4.362	22.691	−2.791	1.00	30.12	C
ATOM	270	CG	TRP	A	42	4.056	22.655	−4.294	1.00	24.67	C
ATOM	271	CD1	TRP	A	42	2.866	22.342	−4.887	1.00	29.46	C
ATOM	272	NE1	TRP	A	42	2.993	22.421	−6.268	1.00	26.03	N
ATOM	273	CE2	TRP	A	42	4.270	22.836	−6.574	1.00	26.75	C
ATOM	274	CD2	TRP	A	42	4.969	22.988	−5.367	1.00	22.65	C
ATOM	275	CE3	TRP	A	42	6.310	23.374	−5.402	1.00	35.38	C
ATOM	276	CZ3	TRP	A	42	6.902	23.641	−6.633	1.00	25.44	C
ATOM	277	CH2	TRP	A	42	6.173	23.493	−7.821	1.00	33.53	C
ATOM	278	CZ2	TRP	A	42	4.838	23.106	−7.808	1.00	26.55	C
ATOM	279	C	TRP	A	42	4.829	21.626	−0.614	1.00	25.05	C
ATOM	280	O	TRP	A	42	3.940	21.655	0.198	1.00	26.88	O
ATOM	281	N	GLU	A	43	6.102	21.934	−0.351	1.00	28.52	N
ATOM	282	CA	GLU	A	43	6.648	22.065	0.960	1.00	28.30	C
ATOM	283	CB	GLU	A	43	7.221	20.708	1.368	0.50	29.79	C
ATOM	284	CG	GLU	A	43	7.855	20.711	2.685	0.50	27.80	C
ATOM	285	CD	GLU	A	43	7.621	19.437	3.393	0.50	29.66	C
ATOM	286	OE1	GLU	A	43	7.052	19.510	4.485	0.50	28.25	O
ATOM	287	OE2	GLU	A	43	7.976	18.362	2.850	0.50	33.51	O
ATOM	288	C	GLU	A	43	7.764	23.091	0.953	1.00	29.96	C
ATOM	289	O	GLU	A	43	8.672	23.045	0.108	1.00	30.23	O
ATOM	290	N	GLU	A	44	7.694	23.981	1.942	1.00	28.74	N
ATOM	291	CA	GLU	A	44	8.696	24.984	2.273	1.00	32.50	C
ATOM	292	CB	GLU	A	44	7.990	26.178	2.925	1.00	29.06	C
ATOM	293	CG	GLU	A	44	8.921	27.058	3.729	1.00	42.19	C
ATOM	294	CD	GLU	A	44	8.514	28.502	3.654	1.00	35.09	C
ATOM	295	OE1	GLU	A	44	7.329	28.813	3.928	1.00	45.10	O
ATOM	296	OE2	GLU	A	44	9.387	29.325	3.332	1.00	44.69	O
ATOM	297	C	GLU	A	44	9.898	24.539	3.154	1.00	27.75	C
ATOM	298	O	GLU	A	44	9.733	23.944	4.232	1.00	33.26	O
ATOM	299	N	LEU	A	45	11.102	24.921	2.734	1.00	28.38	N
ATOM	300	CA	LEU	A	45	12.330	24.400	3.255	1.00	33.31	C
ATOM	301	CB	LEU	A	45	12.556	23.055	2.501	1.00	37.82	C
ATOM	302	CG	LEU	A	45	13.623	21.985	2.685	1.00	45.75	C
ATOM	303	CD1	LEU	A	45	13.124	20.793	1.949	1.00	39.39	C
ATOM	304	CD2	LEU	A	45	14.894	22.391	2.058	1.00	47.39	C
ATOM	305	C	LEU	A	45	13.422	25.417	2.902	1.00	32.67	C
ATOM	306	O	LEU	A	45	13.383	26.031	1.850	1.00	31.80	O
ATOM	307	N	SER	A	46	14.375	25.625	3.804	0.50	25.99	N
ATOM	308	CA	SER	A	46	15.545	26.385	3.455	0.50	25.69	C
ATOM	309	CB	SER	A	46	16.319	26.790	4.722	0.50	21.08	C
ATOM	310	OG	SER	A	46	15.673	27.845	5.444	0.50	17.40	O
ATOM	311	C	SER	A	46	16.411	25.501	2.538	0.50	25.37	C
ATOM	312	O	SER	A	46	16.470	24.281	2.688	0.50	27.19	O
ATOM	313	N	GLY	A	47	17.042	26.131	1.567	1.00	35.25	N
ATOM	314	CA	GLY	A	47	18.069	25.515	0.770	1.00	37.20	C
ATOM	315	C	GLY	A	47	19.112	26.509	0.272	1.00	40.71	C
ATOM	316	O	GLY	A	47	19.031	27.723	0.479	1.00	37.07	O
ATOM	317	N	LEU	A	48	20.083	25.974	−0.444	1.00	42.16	N
ATOM	318	CA	LEU	A	48	21.090	26.788	−1.071	1.00	46.36	C
ATOM	319	CB	LEU	A	48	22.472	26.147	−0.882	1.00	47.59	C
ATOM	320	CG	LEU	A	48	23.420	26.858	0.095	1.00	46.13	C
ATOM	321	CD1	LEU	A	48	22.890	26.860	1.523	1.00	40.81	C
ATOM	322	CD2	LEU	A	48	24.840	26.268	0.015	1.00	45.26	C
ATOM	323	C	LEU	A	48	20.769	26.947	−2.526	1.00	47.20	C
ATOM	324	O	LEU	A	48	20.149	26.061	−3.134	1.00	47.47	O
ATOM	325	N	ASP	A	49	21.135	28.103	−3.069	1.00	48.27	N
ATOM	326	CA	ASP	A	49	21.056	28.332	−4.499	1.00	51.38	C
ATOM	327	CB	ASP	A	49	20.188	29.567	−4.845	1.00	50.70	C
ATOM	328	CG	ASP	A	49	20.680	30.869	−4.195	1.00	53.56	C
ATOM	329	OD1	ASP	A	49	21.425	30.828	−3.196	1.00	53.57	O
ATOM	330	OD2	ASP	A	49	20.299	31.962	−4.694	1.00	58.12	O
ATOM	331	C	ASP	A	49	22.474	28.435	−5.069	1.00	52.11	C
ATOM	332	O	ASP	A	49	23.446	28.314	−4.329	1.00	53.92	O
ATOM	333	N	GLU	A	50	22.576	28.657	−6.375	1.00	54.51	N
ATOM	334	CA	GLU	A	50	23.860	28.606	−7.063	1.00	56.83	C
ATOM	335	CB	GLU	A	50	23.663	28.272	−8.543	1.00	57.48	C
ATOM	336	CG	GLU	A	50	24.955	28.198	−9.341	1.00	58.63	C
ATOM	337	CD	GLU	A	50	24.747	28.485	−10.815	1.00	63.28	C
ATOM	338	OE1	GLU	A	50	23.826	29.261	−11.147	1.00	62.81	O
ATOM	339	OE2	GLU	A	50	25.505	27.935	−11.641	1.00	64.02	O
ATOM	340	C	GLU	A	50	24.615	29.924	−6.920	1.00	58.52	C
ATOM	341	O	GLU	A	50	25.752	30.052	−7.375	1.00	58.64	O
ATOM	342	N	GLU	A	51	24.016	30.884	−6.229	1.00	60.08	N
ATOM	343	CA	GLU	A	51	24.755	32.014	−5.680	1.00	61.33	C
ATOM	344	CB	GLU	A	51	23.862	33.246	−5.596	1.00	60.98	C
ATOM	345	CG	GLU	A	51	24.093	34.229	−6.720	1.00	65.33	C
ATOM	346	CD	GLU	A	51	25.552	34.338	−7.099	1.00	66.61	C
ATOM	347	OE1	GLU	A	51	26.153	33.321	−7.491	1.00	63.39	O
ATOM	348	OE2	GLU	A	51	26.100	35.448	−7.000	1.00	70.97	O
ATOM	349	C	GLU	A	51	25.355	31.726	−4.313	1.00	60.91	C
ATOM	350	O	GLU	A	51	26.225	32.444	−3.835	1.00	59.55	O
ATOM	351	N	GLN	A	52	24.893	30.666	−3.681	1.00	60.48	N
ATOM	352	CA	GLN	A	52	25.602	30.174	−2.532	1.00	60.49	C
ATOM	353	CB	GLN	A	52	25.917	28.705	−2.692	1.00	61.75	C
ATOM	354	C	GLN	A	52	24.854	30.424	−1.242	1.00	59.29	C
ATOM	355	O	GLN	A	52	25.237	29.908	−0.197	1.00	60.10	O
ATOM	356	N	HIS	A	53	23.804	31.235	−1.297	1.00	56.75	N
ATOM	357	CA	HIS	A	53	23.253	31.737	−0.044	1.00	54.55	C
ATOM	358	CB	HIS	A	53	23.006	33.245	−0.134	1.00	52.15	C
ATOM	359	CG	HIS	A	53	24.232	34.039	−0.458	1.00	59.55	C
ATOM	360	ND1	HIS	A	53	24.213	35.409	−0.608	1.00	58.63	N
ATOM	361	CE1	HIS	A	53	25.431	35.837	−0.890	1.00	60.64	C
ATOM	362	NE2	HIS	A	53	26.239	34.793	−0.929	1.00	65.96	N
ATOM	363	CD2	HIS	A	53	25.515	33.657	−0.662	1.00	62.27	C
ATOM	364	C	HIS	A	53	21.959	31.015	0.317	1.00	52.31	C
ATOM	365	O	HIS	A	53	21.175	30.649	−0.558	1.00	50.31	O
ATOM	366	N	SER	A	54	21.743	30.812	1.613	1.00	50.47	N
ATOM	367	CA	SER	A	54	20.530	30.169	2.094	1.00	47.56	C
ATOM	368	CB	SER	A	54	20.596	29.927	3.613	1.00	48.43	C
ATOM	369	OG	SER	A	54	19.286	29.843	4.172	1.00	45.67	O
ATOM	370	C	SER	A	54	19.287	30.986	1.758	1.00	45.87	C
ATOM	371	O	SER	A	54	19.123	32.128	2.237	1.00	48.05	O
ATOM	372	N	VAL	A	55	18.402	30.407	0.953	1.00	40.45	N
ATOM	373	CA	VAL	A	55	17.105	31.085	0.673	1.00	39.01	C
ATOM	374	CB	VAL	A	55	17.015	31.617	−0.788	1.00	36.82	C
ATOM	375	CG1	VAL	A	55	17.864	32.882	−0.951	1.00	44.80	C
ATOM	376	CG2	VAL	A	55	17.440	30.537	−1.781	1.00	37.51	C
ATOM	377	C	VAL	A	55	15.919	30.179	1.016	1.00	34.20	C
ATOM	378	O	VAL	A	55	16.091	28.989	1.260	1.00	37.43	O
ATOM	379	N	ARG	A	56	14.731	30.761	1.043	1.00	31.69	N
ATOM	380	CA	ARG	A	56	13.461	30.033	1.228	1.00	34.24	C
ATOM	381	CB	ARG	A	56	12.380	31.019	1.670	1.00	34.51	C
ATOM	382	CG	ARG	A	56	12.499	31.406	3.120	1.00	40.35	C
ATOM	383	CD	ARG	A	56	11.870	30.286	3.920	1.00	42.68	C
ATOM	384	NE	ARG	A	56	12.569	30.118	5.162	1.00	54.07	N
ATOM	385	CZ	ARG	A	56	12.264	29.246	6.110	1.00	45.17	C
ATOM	386	NH1	ARG	A	56	11.208	28.431	6.026	1.00	32.64	N
ATOM	387	NH2	ARG	A	56	13.020	29.249	7.184	1.00	43.41	N
ATOM	388	C	ARG	A	56	13.050	29.358	−0.068	1.00	36.72	C
ATOM	389	O	ARG	A	56	12.933	30.049	−1.074	1.00	37.99	O
ATOM	390	N	THR	A	57	12.898	28.028	−0.054	1.00	37.40	N
ATOM	391	CA	THR	A	57	12.555	27.264	−1.269	1.00	36.12	C
ATOM	392	CB	THR	A	57	13.657	26.239	−1.669	1.00	31.88	C
ATOM	393	OG1	THR	A	57	13.665	25.129	−0.746	1.00	32.23	O
ATOM	394	CG2	THR	A	57	15.055	26.937	−1.774	1.00	30.55	C
ATOM	395	C	THR	A	57	11.198	26.536	−1.150	1.00	30.38	C
ATOM	396	O	THR	A	57	10.690	26.366	−0.049	1.00	32.87	O
ATOM	397	N	TYR	A	58	10.671	26.073	−2.281	1.00	29.60	N
ATOM	398	CA	TYR	A	58	9.463	25.211	−2.336	1.00	25.84	C
ATOM	399	CB	TYR	A	58	8.204	25.927	−2.875	1.00	33.81	C
ATOM	400	CG	TYR	A	58	7.373	26.568	−1.769	1.00	32.75	C
ATOM	401	CD1	TYR	A	58	6.581	25.762	−0.919	1.00	36.07	C
ATOM	402	CE1	TYR	A	58	5.857	26.309	0.107	1.00	33.85	C
ATOM	403	CZ	TYR	A	58	5.909	27.681	0.318	1.00	28.13	C
ATOM	404	OH	TYR	A	58	5.143	28.196	1.340	1.00	39.16	O
ATOM	405	CE2	TYR	A	58	6.675	28.495	−0.494	1.00	32.86	C
ATOM	406	CD2	TYR	A	58	7.385	27.940	−1.549	1.00	30.61	C
ATOM	407	C	TYR	A	58	9.759	23.931	−3.119	1.00	27.75	C
ATOM	408	O	TYR	A	58	10.237	23.944	−4.251	1.00	30.30	O
ATOM	409	N	GLU	A	59	9.493	22.808	−2.518	1.00	26.84	N
ATOM	410	CA	GLU	A	59	9.743	21.517	−3.207	1.00	28.50	C
ATOM	411	CB	GLU	A	59	10.734	20.698	−2.395	1.00	25.37	C
ATOM	412	CG	GLU	A	59	12.194	21.194	−2.554	1.00	32.71	C
ATOM	413	CD	GLU	A	59	13.169	20.434	−1.708	1.00	35.65	C
ATOM	414	OE1	GLU	A	59	12.752	19.458	−1.043	1.00	42.68	O
ATOM	415	OE2	GLU	A	59	14.373	20.788	−1.734	1.00	38.99	O
ATOM	416	C	GLU	A	59	8.445	20.719	−3.429	1.00	29.63	C
ATOM	417	O	GLU	A	59	7.573	20.699	−2.581	1.00	29.86	O
ATOM	418	N	VAL	A	60	8.304	20.114	−4.597	1.00	32.15	N
ATOM	419	CA	VAL	A	60	7.342	19.043	−4.786	1.00	28.58	C
ATOM	420	CB	VAL	A	60	6.074	19.527	−5.482	1.00	30.98	C
ATOM	421	CG1	VAL	A	60	6.353	19.831	−6.910	1.00	23.51	C
ATOM	422	CG2	VAL	A	60	4.903	18.501	−5.270	1.00	28.38	C
ATOM	423	C	VAL	A	60	8.023	17.825	−5.495	1.00	32.59	C
ATOM	424	O	VAL	A	60	8.836	17.970	−6.418	1.00	31.84	O
ATOM	425	N	CYS	A	61	7.706	16.628	−5.036	1.00	32.96	N
ATOM	426	CA	CYS	A	61	8.172	15.412	−5.731	1.00	35.72	C
ATOM	427	CB	CYS	A	61	9.667	15.181	−5.499	1.00	36.99	C
ATOM	428	SG	CYS	A	61	10.357	13.789	−6.460	1.00	35.75	S
ATOM	429	C	CYS	A	61	7.320	14.168	−5.440	1.00	39.90	C
ATOM	430	O	CYS	A	61	7.784	13.212	−4.847	1.00	37.78	O
ATOM	431	N	ASP	A	62	6.070	14.192	−5.902	1.00	42.20	N
ATOM	432	CA	ASP	A	62	5.098	13.145	−5.583	1.00	46.74	C
ATOM	433	CB	ASP	A	62	3.882	13.839	−4.937	1.00	44.78	C
ATOM	434	CG	ASP	A	62	2.847	12.878	−4.360	1.00	47.88	C
ATOM	435	OD1	ASP	A	62	3.210	11.852	−3.750	1.00	41.91	O
ATOM	436	OD2	ASP	A	62	1.648	13.198	−4.502	1.00	40.24	O
ATOM	437	C	ASP	A	62	4.748	12.325	−6.856	1.00	50.85	C
ATOM	438	O	ASP	A	62	3.567	12.170	−7.223	1.00	49.30	O
ATOM	439	N	VAL	A	63	5.792	11.771	−7.494	1.00	51.88	N
ATOM	440	CA	VAL	A	63	5.747	11.308	−8.913	1.00	54.74	C
ATOM	441	CB	VAL	A	63	7.166	11.296	−9.566	1.00	54.31	C
ATOM	442	CG1	VAL	A	63	7.692	12.700	−9.757	1.00	51.43	C
ATOM	443	CG2	VAL	A	63	8.139	10.455	−8.736	1.00	54.86	C
ATOM	444	C	VAL	A	63	5.123	9.933	−9.169	1.00	59.46	C
ATOM	445	O	VAL	A	63	4.803	9.596	−10.319	1.00	59.09	O
ATOM	446	N	GLN	A	64	4.992	9.134	−8.108	1.00	62.97	N
ATOM	447	CA	GLN	A	64	4.441	7.787	−8.205	1.00	67.89	C
ATOM	448	CB	GLN	A	64	5.523	6.735	−7.964	1.00	69.08	C
ATOM	449	C	GLN	A	64	3.331	7.600	−7.193	1.00	70.54	C
ATOM	450	O	GLN	A	64	2.381	6.841	−7.433	1.00	71.49	O
ATOM	451	N	ARG	A	65	3.469	8.300	−6.065	1.00	72.75	N
ATOM	452	CA	ARG	A	65	2.538	8.217	−4.937	1.00	73.43	C
ATOM	453	CB	ARG	A	65	3.107	8.979	−3.739	1.00	73.53	C
ATOM	454	CG	ARG	A	65	4.643	8.994	−3.671	1.00	74.34	C
ATOM	455	CD	ARG	A	65	5.151	9.895	−2.553	1.00	74.16	C
ATOM	456	NE	ARG	A	65	6.539	9.612	−2.185	1.00	78.12	N
ATOM	457	CZ	ARG	A	65	6.912	8.709	−1.276	1.00	81.38	C
ATOM	458	NH1	ARG	A	65	8.203	8.535	−1.008	1.00	81.84	N
ATOM	459	NH2	ARG	A	65	6.001	7.979	−0.630	1.00	80.28	N
ATOM	460	C	ARG	A	65	1.175	8.781	−5.319	1.00	74.40	C
ATOM	461	O	ARG	A	65	0.137	8.308	−4.848	1.00	75.23	O
ATOM	462	N	ALA	A	66	1.187	9.752	−6.221	1.00	75.02	N
ATOM	463	CA	ALA	A	66	−0.022	10.410	−6.687	1.00	75.51	C
ATOM	464	CB	ALA	A	66	0.324	11.758	−7.268	1.00	74.75	C
ATOM	465	C	ALA	A	66	−0.772	9.571	−7.719	1.00	76.66	C
ATOM	466	O	ALA	A	66	−0.182	8.738	−8.406	1.00	75.96	O
ATOM	467	N	PRO	A	67	−2.081	9.805	−7.831	1.00	76.02	N
ATOM	468	CA	PRO	A	67	−2.860	9.213	−8.920	1.00	76.11	C
ATOM	469	CB	PRO	A	67	−3.444	7.964	−8.264	1.00	76.99	C
ATOM	470	CG	PRO	A	67	−3.465	8.286	−6.762	1.00	76.64	C
ATOM	471	CD	PRO	A	67	−2.737	9.576	−6.533	1.00	75.96	C
ATOM	472	C	PRO	A	67	−4.001	10.095	−9.427	1.00	73.84	C
ATOM	473	O	PRO	A	67	−5.117	9.990	−8.927	1.00	74.12	O
ATOM	474	N	GLY	A	68	−3.731	10.931	−10.422	1.00	71.47	N
ATOM	475	CA	GLY	A	68	−4.781	11.685	−11.088	1.00	68.41	C
ATOM	476	C	GLY	A	68	−4.893	13.125	−10.618	1.00	65.77	C
ATOM	477	O	GLY	A	68	−5.894	13.791	−10.859	1.00	65.68	O
ATOM	478	N	GLN	A	69	−3.854	13.607	−9.946	1.00	62.00	N
ATOM	479	CA	GLN	A	69	−4.019	14.608	−8.911	1.00	58.03	C
ATOM	480	CB	GLN	A	69	−3.807	13.999	−7.541	1.00	57.70	C
ATOM	481	CG	GLN	A	69	−4.617	14.674	−6.473	1.00	60.32	C
ATOM	482	CD	GLN	A	69	−3.768	15.263	−5.391	1.00	63.50	C
ATOM	483	OE1	GLN	A	69	−2.571	15.035	−5.343	1.00	69.20	O
ATOM	484	NE2	GLN	A	69	−4.383	16.027	−4.509	1.00	64.13	N
ATOM	485	C	GLN	A	69	−3.103	15.810	−9.075	1.00	54.71	C
ATOM	486	O	GLN	A	69	−2.022	15.710	−9.640	1.00	52.38	O
ATOM	487	N	ALA	A	70	−3.554	16.948	−8.567	1.00	50.26	N
ATOM	488	CA	ALA	A	70	−2.866	18.217	−8.769	1.00	45.28	C
ATOM	489	CB	ALA	A	70	−3.709	19.146	−9.653	1.00	46.12	C
ATOM	490	C	ALA	A	70	−2.513	18.911	−7.461	1.00	40.85	C
ATOM	491	O	ALA	A	70	−3.392	19.227	−6.667	1.00	40.28	O
ATOM	492	N	HIS	A	71	−1.226	19.190	−7.258	1.00	38.57	N
ATOM	493	CA	HIS	A	71	−0.776	19.932	−6.072	1.00	34.83	C
ATOM	494	CB	HIS	A	71	0.567	19.415	−5.531	1.00	33.42	C
ATOM	495	CG	HIS	A	71	0.567	17.965	−5.101	1.00	36.67	C
ATOM	496	ND1	HIS	A	71	−0.248	17.483	−4.094	1.00	42.49	N
ATOM	497	CE1	HIS	A	71	−0.032	16.189	−3.928	1.00	37.72	C
ATOM	498	NE2	HIS	A	71	0.924	15.816	−4.764	1.00	35.72	N
ATOM	499	CD2	HIS	A	71	1.314	16.912	−5.507	1.00	40.69	C
ATOM	500	C	HIS	A	71	−0.633	21.421	−6.445	1.00	36.72	C
ATOM	501	O	HIS	A	71	0.255	21.811	−7.240	1.00	30.07	O
ATOM	502	N	TRP	A	72	−1.458	22.244	−5.819	1.00	35.14	N
ATOM	503	CA	TRP	A	72	−1.437	23.690	−6.072	1.00	34.04	C
ATOM	504	CB	TRP	A	72	−2.853	24.250	−6.076	1.00	35.63	C
ATOM	505	CG	TRP	A	72	−3.670	23.874	−7.269	1.00	30.19	C
ATOM	506	CD1	TRP	A	72	−4.373	22.721	−7.443	1.00	37.72	C
ATOM	507	NE1	TRP	A	72	−4.994	22.715	−8.654	1.00	37.02	N
ATOM	508	CE2	TRP	A	72	−4.722	23.892	−9.300	1.00	41.37	C
ATOM	509	CD2	TRP	A	72	−3.877	24.648	−8.455	1.00	43.82	C
ATOM	510	CE3	TRP	A	72	−3.443	25.912	−8.885	1.00	41.53	C
ATOM	511	CZ3	TRP	A	72	−3.857	26.370	−10.124	1.00	37.00	C
ATOM	512	CH2	TRP	A	72	−4.701	25.594	−10.945	1.00	37.71	C
ATOM	513	CZ2	TRP	A	72	−5.139	24.352	−10.549	1.00	45.05	C
ATOM	514	C	TRP	A	72	−0.591	24.390	−5.020	1.00	32.97	C
ATOM	515	O	TRP	A	72	−0.574	23.956	−3.862	1.00	30.07	C
ATOM	516	N	LEU	A	73	0.198	25.379	−5.463	1.00	29.15	N
ATOM	517	CA	LEU	A	73	0.924	26.326	−4.587	1.00	28.01	C
ATOM	518	CB	LEU	A	73	2.450	26.140	−4.720	1.00	24.79	C
ATOM	519	CG	LEU	A	73	3.354	27.007	−3.870	1.00	28.60	C
ATOM	520	CD1	LEU	A	73	3.116	26.818	−2.389	1.00	28.15	C
ATOM	521	CD2	LEU	A	73	4.848	26.781	−4.220	1.00	30.48	C
ATOM	522	C	LEU	A	73	0.587	27.771	−4.989	1.00	28.82	C
ATOM	523	O	LEU	A	73	0.741	28.143	−6.166	1.00	32.47	O
ATOM	524	N	ARG	A	74	0.229	28.601	−4.016	1.00	26.25	N
ATOM	525	CA	ARG	A	74	−0.171	29.997	−4.349	1.00	31.34	C
ATOM	526	CB	ARG	A	74	−1.692	30.180	−4.242	1.00	32.48	C
ATOM	527	CG	ARG	A	74	−2.258	31.453	−4.942	1.00	30.02	C
ATOM	528	CD	ARG	A	74	−3.720	31.633	−4.574	1.00	36.24	C
ATOM	529	NE	ARG	A	74	−3.803	31.821	−3.132	1.00	39.56	N
ATOM	530	CZ	ARG	A	74	−4.863	31.571	−2.383	1.00	40.38	C
ATOM	531	NH1	ARG	A	74	−6.001	31.116	−2.916	1.00	38.53	N
ATOM	532	NH2	ARG	A	74	−4.767	31.798	−1.085	1.00	37.96	N
ATOM	533	C	ARG	A	74	0.553	31.020	−3.470	1.00	31.04	C
ATOM	534	O	ARG	A	74	0.638	30.847	−2.258	1.00	32.22	O
ATOM	535	N	THR	A	75	1.075	32.077	−4.084	1.00	33.16	N
ATOM	536	CA	THR	A	75	1.679	33.193	−3.289	1.00	34.65	C
ATOM	537	CB	THR	A	75	2.319	34.284	−4.147	1.00	34.94	C
ATOM	538	OG1	THR	A	75	1.299	34.906	−4.943	1.00	31.24	O
ATOM	539	CG2	THR	A	75	3.385	33.710	−5.035	1.00	38.97	C
ATOM	540	C	THR	A	75	0.649	33.872	−2.415	1.00	32.75	C
ATOM	541	O	THR	A	75	−0.566	33.639	−2.562	1.00	30.37	O
ATOM	542	N	GLY	A	76	1.134	34.708	−1.493	1.00	36.03	N
ATOM	543	CA	GLY	A	76	0.280	35.638	−0.751	1.00	34.99	C
ATOM	544	C	GLY	A	76	−0.168	36.709	−1.711	1.00	34.57	C
ATOM	545	O	GLY	A	76	0.262	36.700	−2.865	1.00	35.49	O
ATOM	546	N	TRP	A	77	−1.032	37.612	−1.238	1.00	32.47	N
ATOM	547	CA	TRP	A	77	−1.626	38.650	−2.085	1.00	34.91	C
ATOM	548	CB	TRP	A	77	−2.565	39.510	−1.255	1.00	33.83	C
ATOM	549	CG	TRP	A	77	−3.507	40.357	−2.092	1.00	38.76	C
ATOM	550	CD1	TRP	A	77	−4.293	39.951	−3.139	1.00	36.42	C
ATOM	551	NE1	TRP	A	77	−4.986	41.040	−3.659	1.00	35.07	N
ATOM	552	CE2	TRP	A	77	−4.662	42.153	−2.933	1.00	38.58	C
ATOM	553	CD2	TRP	A	77	−3.735	41.760	−1.937	1.00	42.72	C
ATOM	554	CE3	TRP	A	77	−3.244	42.726	−1.047	1.00	45.06	C
ATOM	555	CZ3	TRP	A	77	−3.675	44.034	−1.182	1.00	37.42	C
ATOM	556	CH2	TRP	A	77	−4.611	44.396	−2.177	1.00	39.82	C
ATOM	557	CZ2	TRP	A	77	−5.117	43.471	−3.055	1.00	41.18	C
ATOM	558	C	TRP	A	77	−0.528	39.545	−2.587	1.00	34.98	C
ATOM	559	O	TRP	A	77	0.240	40.023	−1.792	1.00	35.74	O
ATOM	560	N	VAL	A	78	−0.450	39.804	−3.888	1.00	38.30	N
ATOM	561	CA	VAL	A	78	0.580	40.746	−4.342	1.00	39.04	C
ATOM	562	CB	VAL	A	78	1.558	40.141	−5.392	1.00	39.37	C
ATOM	563	CG1	VAL	A	78	2.797	41.050	−5.563	1.00	39.09	C
ATOM	564	CG2	VAL	A	78	1.994	38.700	−4.983	1.00	33.31	C
ATOM	565	C	VAL	A	78	−0.020	42.079	−4.854	1.00	42.68	C
ATOM	566	O	VAL	A	78	−0.694	42.105	−5.910	1.00	41.94	O
ATOM	567	N	PRO	A	79	0.235	43.176	−4.110	1.00	42.96	N
ATOM	568	CA	PRO	A	79	−0.097	44.504	−4.588	1.00	46.35	C
ATOM	569	CB	PRO	A	79	0.378	45.420	−3.449	1.00	44.48	C
ATOM	570	CG	PRO	A	79	0.432	44.527	−2.236	1.00	38.83	C
ATOM	571	CD	PRO	A	79	0.876	43.222	−2.777	1.00	41.53	C
ATOM	572	C	PRO	A	79	0.611	44.806	−5.934	1.00	49.47	C
ATOM	573	O	PRO	A	79	1.832	44.949	−6.009	1.00	51.20	O
ATOM	574	N	ARG	A	80	−0.183	44.829	−6.997	1.00	53.14	N
ATOM	575	CA	ARG	A	80	0.249	45.329	−8.281	1.00	54.18	C
ATOM	576	CB	ARG	A	80	−0.769	44.923	−9.340	1.00	55.34	C
ATOM	577	CG	ARG	A	80	−0.888	45.833	−10.533	1.00	51.62	C
ATOM	578	CD	ARG	A	80	−2.346	45.943	−10.982	1.00	47.92	C
ATOM	579	NE	ARG	A	80	−3.010	47.189	−10.538	1.00	43.68	N
ATOM	580	CZ	ARG	A	80	−2.977	48.363	−11.174	1.00	53.21	C
ATOM	581	NH1	ARG	A	80	−2.282	48.541	−12.304	1.00	48.15	N
ATOM	582	NH2	ARG	A	80	−3.642	49.389	−10.660	1.00	50.73	N
ATOM	583	C	ARG	A	80	0.281	46.825	−8.058	1.00	56.38	C
ATOM	584	O	ARG	A	80	−0.765	47.478	−8.004	1.00	57.66	O
ATOM	585	N	ARG	A	81	1.476	47.362	−7.852	1.00	57.34	N
ATOM	586	CA	ARG	A	81	1.607	48.768	−7.490	1.00	58.23	C
ATOM	587	CB	ARG	A	81	3.054	49.083	−7.124	1.00	58.75	C
ATOM	588	CG	ARG	A	81	3.430	48.515	−5.765	1.00	57.81	C
ATOM	589	CD	ARG	A	81	4.811	47.914	−5.769	1.00	65.79	C
ATOM	590	NE	ARG	A	81	4.846	46.682	−4.989	1.00	69.25	N
ATOM	591	CZ	ARG	A	81	5.910	46.228	−4.334	1.00	71.96	C
ATOM	592	NH1	ARG	A	81	7.049	46.912	−4.349	1.00	73.08	N
ATOM	593	NH2	ARG	A	81	5.830	45.086	−3.655	1.00	75.90	N
ATOM	594	C	ARG	A	81	1.057	49.687	−8.584	1.00	59.36	C
ATOM	595	O	ARG	A	81	−0.012	50.285	−8.418	1.00	60.97	O
ATOM	596	N	GLY	A	82	1.775	49.786	−9.698	1.00	57.47	N
ATOM	597	CA	GLY	A	82	1.291	50.512	−10.849	1.00	56.99	C
ATOM	598	C	GLY	A	82	1.528	49.695	−12.092	1.00	56.65	C
ATOM	599	O	GLY	A	82	1.475	50.219	−13.206	1.00	56.18	O
ATOM	600	N	ALA	A	83	1.801	48.407	−11.892	1.00	55.51	N
ATOM	601	CA	ALA	A	83	2.078	47.474	−12.984	1.00	55.06	C
ATOM	602	CB	ALA	A	83	2.622	46.159	−12.439	1.00	53.08	C
ATOM	603	C	ALA	A	83	0.877	47.208	−13.868	1.00	54.91	C
ATOM	604	O	ALA	A	83	−0.272	47.183	−13.416	1.00	56.83	O
ATOM	605	N	VAL	A	84	1.156	46.989	−15.140	1.00	55.31	N
ATOM	606	CA	VAL	A	84	0.123	46.541	−16.053	1.00	56.06	C
ATOM	607	CB	VAL	A	84	−0.135	47.546	−17.203	1.00	56.51	C
ATOM	608	CG1	VAL	A	84	−0.933	46.892	−18.338	1.00	54.38	C
ATOM	609	CG2	VAL	A	84	−0.863	48.773	−16.661	1.00	51.88	C
ATOM	610	C	VAL	A	84	0.555	45.187	−16.569	1.00	56.01	C
ATOM	611	O	VAL	A	84	−0.244	44.242	−16.603	1.00	57.12	O
ATOM	612	N	HIS	A	85	1.818	45.103	−16.965	1.00	52.37	N
ATOM	613	CA	HIS	A	85	2.404	43.814	−17.268	1.00	52.72	C
ATOM	614	CB	HIS	A	85	2.900	43.727	−18.711	1.00	52.43	C
ATOM	615	CG	HIS	A	85	1.810	43.911	−19.713	1.00	54.23	C
ATOM	616	ND1	HIS	A	85	1.059	42.864	−20.195	1.00	50.36	N
ATOM	617	CE1	HIS	A	85	0.154	43.327	−21.038	1.00	53.21	C
ATOM	618	NE2	HIS	A	85	0.284	44.639	−21.109	1.00	54.30	N
ATOM	619	CD2	HIS	A	85	1.308	45.031	−20.283	1.00	52.00	C
ATOM	620	C	HIS	A	85	3.485	43.516	−16.267	1.00	49.96	C
ATOM	621	O	HIS	A	85	4.397	44.310	−16.049	1.00	51.17	O
ATOM	622	N	VAL	A	86	3.332	42.366	−15.630	1.00	47.91	N
ATOM	623	CA	VAL	A	86	4.242	41.911	−14.610	1.00	47.10	C
ATOM	624	CB	VAL	A	86	3.431	41.339	−13.414	1.00	49.81	C
ATOM	625	CG1	VAL	A	86	4.221	40.335	−12.580	1.00	46.34	C
ATOM	626	CG2	VAL	A	86	2.883	42.469	−12.557	1.00	49.43	C
ATOM	627	C	VAL	A	86	5.190	40.892	−15.246	1.00	43.83	C
ATOM	628	O	VAL	A	86	4.804	40.171	−16.172	1.00	42.11	O
ATOM	629	N	TYR	A	87	6.438	40.879	−14.781	1.00	39.95	N
ATOM	630	CA	TYR	A	87	7.384	39.865	−15.203	1.00	37.91	C
ATOM	631	CB	TYR	A	87	8.724	40.475	−15.541	1.00	35.88	C
ATOM	632	CG	TYR	A	87	8.811	41.281	−16.830	1.00	42.37	C
ATOM	633	CD1	TYR	A	87	9.646	40.873	−17.871	1.00	44.12	C
ATOM	634	CE1	TYR	A	87	9.779	41.618	−19.021	1.00	47.12	C
ATOM	635	CZ	TYR	A	87	9.074	42.791	−19.142	1.00	39.76	C
ATOM	636	OH	TYR	A	87	9.179	43.539	−20.295	1.00	50.68	O
ATOM	637	CE2	TYR	A	87	8.238	43.218	−18.129	1.00	35.52	C
ATOM	638	CD2	TYR	A	87	8.134	42.478	−16.972	1.00	42.43	C
ATOM	639	C	TYR	A	87	7.576	38.915	−14.037	1.00	31.73	C
ATOM	640	O	TYR	A	87	7.516	39.330	−12.899	1.00	32.92	O
ATOM	641	N	ALA	A	88	7.833	37.653	−14.327	1.00	35.28	N
ATOM	642	CA	ALA	A	88	7.884	36.654	−13.274	1.00	35.57	C
ATOM	643	CB	ALA	A	88	6.521	35.941	−13.123	1.00	35.79	C
ATOM	644	C	ALA	A	88	8.986	35.707	−13.607	1.00	35.70	C
ATOM	645	O	ALA	A	88	8.839	34.833	−14.436	1.00	37.89	O
ATOM	646	N	THR	A	89	10.126	35.931	−12.958	1.00	39.19	N
ATOM	647	CA	THR	A	89	11.313	35.161	−13.225	1.00	38.72	C
ATOM	648	CB	THR	A	89	12.560	36.058	−13.114	1.00	41.64	C
ATOM	649	OG1	THR	A	89	12.479	37.065	−14.125	1.00	39.96	O
ATOM	650	CG2	THR	A	89	13.850	35.262	−13.291	1.00	40.09	C
ATOM	651	C	THR	A	89	11.350	34.037	−12.208	1.00	38.27	C
ATOM	652	O	THR	A	89	11.327	34.284	−11.016	1.00	36.78	O
ATOM	653	N	LEU	A	90	11.391	32.810	−12.712	1.00	41.20	N
ATOM	654	CA	LEU	A	90	11.473	31.597	−11.899	1.00	37.67	C
ATOM	655	CB	LEU	A	90	10.400	30.599	−12.345	1.00	35.91	C
ATOM	656	CG	LEU	A	90	8.978	31.122	−12.557	1.00	42.98	C
ATOM	657	CD1	LEU	A	90	8.040	30.101	−13.249	1.00	37.76	C
ATOM	658	CD2	LEU	A	90	8.416	31.577	−11.249	1.00	37.89	C
ATOM	659	C	LEU	A	90	12.845	30.939	−12.031	1.00	35.29	C
ATOM	660	O	LEU	A	90	13.357	30.750	−13.129	1.00	34.84	O
ATOM	661	N	ARG	A	91	13.414	30.524	−10.908	1.00	32.23	N
ATOM	662	CA	ARG	A	91	14.578	29.704	−10.970	1.00	31.68	C
ATOM	663	CB	ARG	A	91	15.729	30.367	−10.213	1.00	29.26	C
ATOM	664	CG	ARG	A	91	16.186	31.702	−10.714	1.00	39.83	C
ATOM	665	CD	ARG	A	91	17.422	32.123	−9.918	1.00	48.82	C
ATOM	666	NE	ARG	A	91	18.182	33.162	−10.597	1.00	48.28	N
ATOM	667	CZ	ARG	A	91	19.207	32.929	−11.415	1.00	54.96	C
ATOM	668	NH1	ARG	A	91	19.832	33.957	−11.994	1.00	48.94	N
ATOM	669	NH2	ARG	A	91	19.607	31.674	−11.657	1.00	41.81	N
ATOM	670	C	ARG	A	91	14.230	28.388	−10.333	1.00	29.39	C
ATOM	671	O	ARG	A	91	13.650	28.379	−9.267	1.00	30.64	O
ATOM	672	N	PHE	A	92	14.603	27.283	−10.965	1.00	29.19	N
ATOM	673	CA	PHE	A	92	14.179	25.976	−10.483	1.00	28.13	C
ATOM	674	CB	PHE	A	92	12.672	25.695	−10.853	1.00	25.35	C
ATOM	675	CG	PHE	A	92	12.392	25.582	−12.330	1.00	31.38	C
ATOM	676	CD1	PHE	A	92	12.298	24.318	−12.957	1.00	30.18	C
ATOM	677	CE1	PHE	A	92	12.057	24.206	−14.311	1.00	29.16	C
ATOM	678	CZ	PHE	A	92	11.846	25.370	−15.072	1.00	39.78	C
ATOM	679	CE2	PHE	A	92	11.894	26.646	−14.463	1.00	28.29	C
ATOM	680	CD2	PHE	A	92	12.161	26.743	−13.098	1.00	36.30	C
ATOM	681	C	PHE	A	92	15.075	24.896	−10.979	1.00	28.40	C
ATOM	682	O	PHE	A	92	15.770	25.050	−11.991	1.00	33.15	O
ATOM	683	N	THR	A	93	15.024	23.775	−10.304	1.00	28.13	N
ATOM	684	CA	THR	A	93	15.649	22.555	−10.797	1.00	32.26	C
ATOM	685	CB	THR	A	93	16.770	22.043	−9.843	0.50	30.79	C
ATOM	686	OG1	THR	A	93	16.238	21.847	−8.539	0.50	24.15	O
ATOM	687	CG2	THR	A	93	17.892	23.084	−9.725	0.50	28.99	C
ATOM	688	C	THR	A	93	14.528	21.525	−11.044	1.00	35.09	C
ATOM	689	O	THR	A	93	13.461	21.541	−10.390	1.00	37.83	O
ATOM	690	N	MET	A	94	14.748	20.661	−12.022	1.00	37.88	N
ATOM	691	CA	MET	A	94	13.738	19.691	−12.440	1.00	34.08	C
ATOM	692	CB	MET	A	94	13.082	20.163	−13.741	1.00	37.68	C
ATOM	693	CG	MET	A	94	12.132	19.187	−14.384	1.00	31.33	C
ATOM	694	SD	MET	A	94	10.563	19.099	−13.517	1.00	37.28	S
ATOM	695	CE	MET	A	94	10.084	20.829	−13.643	1.00	24.37	C
ATOM	696	C	MET	A	94	14.466	18.376	−12.660	1.00	37.15	C
ATOM	697	O	MET	A	94	15.519	18.350	−13.326	1.00	37.61	O
ATOM	698	N	LEU	A	95	13.968	17.313	−12.049	1.00	32.63	N
ATOM	699	CA	LEU	A	95	14.611	16.001	−12.199	1.00	36.65	C
ATOM	700	CB	LEU	A	95	14.500	15.178	−10.912	1.00	35.07	C
ATOM	701	CG	LEU	A	95	15.630	15.458	−9.894	1.00	40.28	C
ATOM	702	CD1	LEU	A	95	15.447	16.766	−9.120	1.00	39.97	C
ATOM	703	CD2	LEU	A	95	15.799	14.331	−8.946	1.00	41.34	C
ATOM	704	C	LEU	A	95	14.126	15.196	−13.401	1.00	37.05	C
ATOM	705	O	LEU	A	95	12.951	15.165	−13.680	1.00	38.21	O
ATOM	706	N	GLU	A	96	15.064	14.546	−14.093	1.00	40.05	N
ATOM	707	CA	GLU	A	96	14.788	13.649	−15.213	1.00	39.08	C
ATOM	708	CB	GLU	A	96	16.103	13.106	−15.779	1.00	40.73	C
ATOM	709	CG	GLU	A	96	15.936	12.029	−16.850	1.00	41.96	C
ATOM	710	CD	GLU	A	96	17.259	11.583	−17.456	1.00	43.00	C
ATOM	711	OE1	GLU	A	96	18.244	11.364	−16.718	1.00	46.73	O
ATOM	712	OE2	GLU	A	96	17.299	11.443	−18.693	1.00	54.87	O
ATOM	713	C	GLU	A	96	13.931	12.497	−14.738	1.00	38.39	C
ATOM	714	O	GLU	A	96	14.320	11.774	−13.818	1.00	40.49	O
ATOM	715	N	CYS	A	97	12.764	12.313	−15.372	1.00	40.12	N
ATOM	716	CA	CYS	A	97	11.810	11.294	−14.934	1.00	39.96	C
ATOM	717	CB	CYS	A	97	10.527	11.350	−15.772	1.00	43.34	C
ATOM	718	SG	CYS	A	97	9.358	12.560	−15.204	1.00	46.32	S
ATOM	719	C	CYS	A	97	12.397	9.893	−14.973	1.00	41.63	C
ATOM	720	O	CYS	A	97	12.295	9.135	−13.992	1.00	41.45	O
ATOM	721	N	LEU	A	98	13.045	9.563	−16.089	1.00	45.11	N
ATOM	722	CA	LEU	A	98	13.628	8.226	−16.258	1.00	49.04	C
ATOM	723	CB	LEU	A	98	13.860	7.892	−17.743	1.00	51.09	C
ATOM	724	CG	LEU	A	98	12.548	7.587	−18.510	1.00	51.68	C
ATOM	725	CD1	LEU	A	98	12.708	7.541	−20.017	1.00	49.01	C
ATOM	726	CD2	LEU	A	98	11.843	6.315	−18.019	1.00	57.57	C
ATOM	727	C	LEU	A	98	14.859	7.951	−15.405	1.00	49.53	C
ATOM	728	O	LEU	A	98	15.338	6.828	−15.373	1.00	47.03	O
ATOM	729	N	SER	A	99	15.338	8.969	−14.688	1.00	52.06	N
ATOM	730	CA	SER	A	99	16.509	8.844	−13.803	1.00	53.05	C
ATOM	731	CB	SER	A	99	17.356	10.125	−13.826	1.00	53.42	C
ATOM	732	OG	SER	A	99	16.784	11.140	−12.992	1.00	59.05	O
ATOM	733	C	SER	A	99	16.081	8.591	−12.366	1.00	55.03	C
ATOM	734	O	SER	A	99	16.879	8.135	−11.542	1.00	53.98	O
ATOM	735	N	LEU	A	100	14.828	8.926	−12.060	1.00	57.16	N
ATOM	736	CA	LEU	A	100	14.355	8.903	−10.689	1.00	58.91	C
ATOM	737	CB	LEU	A	100	13.036	9.658	−10.554	1.00	57.21	C
ATOM	738	CG	LEU	A	100	12.907	11.112	−10.971	1.00	51.47	C
ATOM	739	CD1	LEU	A	100	11.448	11.472	−10.926	1.00	45.58	C
ATOM	740	CD2	LEU	A	100	13.689	12.003	−10.050	1.00	48.85	C
ATOM	741	C	LEU	A	100	14.147	7.471	−10.250	1.00	63.37	C
ATOM	742	O	LEU	A	100	13.775	6.629	−11.062	1.00	63.99	O
ATOM	743	N	PRO	A	101	14.391	7.187	−8.960	1.00	66.45	N
ATOM	744	CA	PRO	A	101	13.936	5.891	−8.477	1.00	67.84	C
ATOM	745	CB	PRO	A	101	14.775	5.656	−7.218	1.00	68.56	C
ATOM	746	CG	PRO	A	101	15.326	7.009	−6.814	1.00	68.23	C
ATOM	747	CD	PRO	A	101	15.054	7.995	−7.916	1.00	66.48	C
ATOM	748	C	PRO	A	101	12.440	5.954	−8.161	1.00	69.98	C
ATOM	749	O	PRO	A	101	11.956	6.967	−7.632	1.00	72.74	O
ATOM	750	N	ARG	A	102	11.721	4.899	−8.540	1.00	69.84	N
ATOM	751	CA	ARG	A	102	10.292	4.709	−8.226	1.00	69.18	C
ATOM	752	CB	ARG	A	102	10.066	4.608	−6.705	1.00	68.31	C
ATOM	753	C	ARG	A	102	9.309	5.706	−8.876	1.00	68.61	C
ATOM	754	O	ARG	A	102	8.196	5.884	−8.384	1.00	66.90	O
ATOM	755	N	ALA	A	103	9.712	6.321	−9.991	1.00	69.15	N
ATOM	756	CA	ALA	A	103	8.840	7.246	−10.735	1.00	68.27	C
ATOM	757	CB	ALA	A	103	9.659	8.135	−11.660	1.00	68.20	C
ATOM	758	C	ALA	A	103	7.751	6.512	−11.519	1.00	67.94	C
ATOM	759	O	ALA	A	103	8.043	5.742	−12.430	1.00	69.95	O
ATOM	760	N	GLY	A	104	6.496	6.761	−11.159	1.00	67.03	N
ATOM	761	CA	GLY	A	104	5.353	6.130	−11.813	1.00	65.29	C
ATOM	762	C	GLY	A	104	5.013	6.728	−13.168	1.00	64.79	C
ATOM	763	O	GLY	A	104	5.795	7.490	−13.734	1.00	64.68	O
ATOM	764	N	ARG	A	105	3.835	6.371	−13.681	1.00	64.75	N
ATOM	765	CA	ARG	A	105	3.313	6.884	−14.958	1.00	62.98	C
ATOM	766	CB	ARG	A	105	2.082	6.076	−15.373	1.00	63.28	C
ATOM	767	C	ARG	A	105	2.960	8.380	−14.900	1.00	60.94	C
ATOM	768	O	ARG	A	105	2.906	9.062	−15.932	1.00	61.36	O
ATOM	769	N	SER	A	106	2.738	8.884	−13.690	1.00	58.17	N
ATOM	770	CA	SER	A	106	2.346	10.276	−13.477	1.00	56.11	C
ATOM	771	CB	SER	A	106	1.752	10.438	−12.066	1.00	56.25	C
ATOM	772	OG	SER	A	106	1.128	11.702	−11.881	1.00	62.27	O
ATOM	773	C	SER	A	106	3.492	11.282	−13.733	1.00	52.57	C
ATOM	774	O	SER	A	106	3.240	12.458	−13.955	1.00	51.79	O
ATOM	775	N	CYS	A	107	4.736	10.802	−13.767	1.00	48.78	N
ATOM	776	CA	CYS	A	107	5.914	11.679	−13.824	1.00	45.90	C
ATOM	777	CB	CYS	A	107	7.197	10.838	−13.856	1.00	41.55	C
ATOM	778	SG	CYS	A	107	8.708	11.772	−13.436	1.00	45.62	S
ATOM	779	C	CYS	A	107	5.902	12.687	−14.992	1.00	44.80	C
ATOM	780	O	CYS	A	107	5.721	12.296	−16.133	1.00	45.74	O
ATOM	781	N	LYS	A	108	6.108	13.973	−14.680	1.00	42.56	N
ATOM	782	CA	LYS	A	108	6.171	15.074	−15.656	1.00	38.35	C
ATOM	783	CB	LYS	A	108	5.080	16.126	−15.390	1.00	38.46	C
ATOM	784	CG	LYS	A	108	3.617	15.631	−15.344	1.00	41.65	C
ATOM	785	CD	LYS	A	108	3.130	15.220	−16.728	1.00	48.57	C
ATOM	786	CE	LYS	A	108	1.623	15.055	−16.780	1.00	49.47	C
ATOM	787	NZ	LYS	A	108	1.183	13.739	−16.226	1.00	51.52	N
ATOM	788	C	LYS	A	108	7.512	15.802	−15.536	1.00	39.54	C
ATOM	789	O	LYS	A	108	8.128	15.818	−14.465	1.00	30.07	O
ATOM	790	N	GLU	A	109	7.944	16.427	−16.625	1.00	38.56	N
ATOM	791	CA	GLU	A	109	9.128	17.239	−16.574	1.00	38.64	C
ATOM	792	CB	GLU	A	109	10.181	16.730	−17.560	1.00	39.02	C
ATOM	793	CG	GLU	A	109	11.197	15.800	−16.920	1.00	38.15	C
ATOM	794	CD	GLU	A	109	11.851	14.822	−17.899	1.00	44.21	C
ATOM	795	OE1	GLU	A	109	11.980	15.168	−19.088	1.00	43.35	O
ATOM	796	OE2	GLU	A	109	12.272	13.717	−17.467	1.00	42.06	O
ATOM	797	C	GLU	A	109	8.712	18.710	−16.798	1.00	36.56	C
ATOM	798	O	GLU	A	109	9.471	19.530	−17.304	1.00	34.15	O
ATOM	799	N	THR	A	110	7.487	19.022	−16.383	1.00	38.64	N
ATOM	800	CA	THR	A	110	6.890	20.354	−16.584	1.00	36.73	C
ATOM	801	CB	THR	A	110	6.025	20.451	−17.885	1.00	39.68	C
ATOM	802	OG1	THR	A	110	4.742	19.859	−17.655	1.00	36.91	O
ATOM	803	CG2	THR	A	110	6.686	19.780	−19.096	1.00	41.93	C
ATOM	804	C	THR	A	110	5.997	20.727	−15.410	1.00	37.56	C
ATOM	805	O	THR	A	110	5.683	19.887	−14.551	1.00	38.82	O
ATOM	806	N	PHE	A	111	5.558	21.984	−15.397	1.00	34.68	N
ATOM	807	CA	PHE	A	111	4.613	22.485	−14.422	1.00	36.33	C
ATOM	808	CB	PHE	A	111	5.316	22.834	−13.062	1.00	30.29	C
ATOM	809	CG	PHE	A	111	6.288	24.008	−13.127	1.00	37.23	C
ATOM	810	CD1	PHE	A	111	5.861	25.295	−12.849	1.00	29.32	C
ATOM	811	CE1	PHE	A	111	6.719	26.368	−12.916	1.00	32.48	C
ATOM	812	CZ	PHE	A	111	8.045	26.184	−13.242	1.00	30.71	C
ATOM	813	CE2	PHE	A	111	8.505	24.895	−13.522	1.00	28.43	C
ATOM	814	CD2	PHE	A	111	7.604	23.816	−13.469	1.00	30.30	C
ATOM	815	C	PHE	A	111	3.880	23.675	−15.070	1.00	35.66	C
ATOM	816	O	PHE	A	111	4.361	24.226	−16.043	1.00	37.01	O
ATOM	817	N	THR	A	112	2.709	24.032	−14.559	1.00	34.15	N
ATOM	818	CA	THR	A	112	1.902	25.099	−15.158	1.00	38.08	C
ATOM	819	CB	THR	A	112	0.476	24.609	−15.513	1.00	33.33	C
ATOM	820	OG1	THR	A	112	0.534	23.264	−15.995	1.00	47.68	O
ATOM	821	CG2	THR	A	112	−0.151	25.509	−16.580	1.00	43.08	C
ATOM	822	C	THR	A	112	1.757	26.252	−14.190	1.00	33.68	C
ATOM	823	O	THR	A	112	1.636	26.024	−12.992	1.00	37.19	O
ATOM	824	N	VAL	A	113	1.739	27.477	−14.725	1.00	34.66	N
ATOM	825	CA	VAL	A	113	1.595	28.699	−13.935	1.00	34.20	C
ATOM	826	CB	VAL	A	113	2.762	29.695	−14.172	1.00	34.07	C
ATOM	827	CG1	VAL	A	113	2.620	30.929	−13.250	1.00	34.89	C
ATOM	828	CG2	VAL	A	113	4.084	29.039	−13.945	1.00	33.82	C
ATOM	829	C	VAL	A	113	0.278	29.398	−14.298	1.00	39.57	C
ATOM	830	O	VAL	A	113	−0.137	29.379	−15.457	1.00	42.20	O
ATOM	831	N	PHE	A	114	−0.343	30.032	−13.301	1.00	38.25	N
ATOM	832	CA	PHE	A	114	−1.679	30.608	−13.385	1.00	40.31	C
ATOM	833	CB	PHE	A	114	−2.721	29.729	−12.651	1.00	37.24	C
ATOM	834	CG	PHE	A	114	−3.128	28.487	−13.382	1.00	41.83	C
ATOM	835	CD1	PHE	A	114	−4.214	28.508	−14.269	1.00	36.65	C
ATOM	836	CE1	PHE	A	114	−4.609	27.380	−14.934	1.00	39.00	C
ATOM	837	CZ	PHE	A	114	−3.969	26.144	−14.676	1.00	45.82	C
ATOM	838	CE2	PHE	A	114	−2.897	26.096	−13.756	1.00	47.68	C
ATOM	839	CD2	PHE	A	114	−2.500	27.271	−13.113	1.00	46.54	C
ATOM	840	C	PHE	A	114	−1.569	31.905	−12.622	1.00	41.06	C
ATOM	841	O	PHE	A	114	−0.599	32.136	−11.923	1.00	38.95	O
ATOM	842	N	TYR	A	115	−2.559	32.774	−12.778	1.00	45.00	N
ATOM	843	CA	TYR	A	115	−2.713	33.895	−11.855	1.00	42.70	C
ATOM	844	CB	TYR	A	115	−1.955	35.146	−12.293	1.00	42.83	C
ATOM	845	CG	TYR	A	115	−2.521	35.945	−13.454	1.00	40.85	C
ATOM	846	CD1	TYR	A	115	−3.338	37.058	−13.234	1.00	41.69	C
ATOM	847	CE1	TYR	A	115	−3.841	37.820	−14.326	1.00	48.11	C
ATOM	848	CZ	TYR	A	115	−3.491	37.468	−15.640	1.00	49.33	C
ATOM	849	OH	TYR	A	115	−3.957	38.193	−16.727	1.00	51.63	O
ATOM	850	CE2	TYR	A	115	−2.657	36.384	−15.876	1.00	42.04	C
ATOM	851	CD2	TYR	A	115	−2.175	35.626	−14.771	1.00	46.72	C
ATOM	852	C	TYR	A	115	−4.167	34.175	−11.557	1.00	44.47	C
ATOM	853	O	TYR	A	115	−5.062	33.587	−12.167	1.00	44.61	O
ATOM	854	N	TYR	A	116	−4.389	35.025	−10.565	1.00	42.10	N
ATOM	855	CA	TYR	A	116	−5.712	35.412	−10.169	1.00	41.46	C
ATOM	856	CB	TYR	A	116	−6.248	34.439	−9.125	1.00	45.18	C
ATOM	857	CG	TYR	A	116	−7.594	34.821	−8.566	1.00	44.71	C
ATOM	858	CD1	TYR	A	116	−8.756	34.651	−9.322	1.00	48.20	C
ATOM	859	CE1	TYR	A	116	−9.997	34.998	−8.815	1.00	51.58	C
ATOM	860	CZ	TYR	A	116	−10.091	35.515	−7.532	1.00	48.34	C
ATOM	861	OH	TYR	A	116	−11.322	35.864	−7.042	1.00	50.58	O
ATOM	862	CE2	TYR	A	116	−8.953	35.692	−6.758	1.00	48.96	C
ATOM	863	CD2	TYR	A	116	−7.709	35.339	−7.279	1.00	43.17	C
ATOM	864	C	TYR	A	116	−5.627	36.809	−9.594	1.00	39.41	C
ATOM	865	O	TYR	A	116	−4.892	37.039	−8.643	1.00	39.20	O
ATOM	866	N	GLU	A	117	−6.354	37.755	−10.187	1.00	41.63	N
ATOM	867	CA	GLU	A	117	−6.451	39.109	−9.619	1.00	39.85	C
ATOM	868	CB	GLU	A	117	−6.656	40.172	−10.689	1.00	44.57	C
ATOM	869	CG	GLU	A	117	−5.696	40.238	−11.861	1.00	41.68	C
ATOM	870	CD	GLU	A	117	−5.987	41.478	−12.708	1.00	43.45	C
ATOM	871	OE1	GLU	A	117	−6.151	42.558	−12.099	1.00	39.22	O
ATOM	872	OE2	GLU	A	117	−6.076	41.379	−13.958	1.00	47.74	O
ATOM	873	C	GLU	A	117	−7.645	39.214	−8.703	1.00	40.05	C
ATOM	874	O	GLU	A	117	−8.720	38.631	−8.972	1.00	40.21	O
ATOM	875	N	SER	A	118	−7.496	40.010	−7.649	1.00	38.81	N
ATOM	876	CA	SER	A	118	−8.635	40.341	−6.784	1.00	40.06	C
ATOM	877	CB	SER	A	118	−8.714	39.353	−5.647	1.00	36.38	C
ATOM	878	OG	SER	A	118	−7.464	39.353	−4.975	1.00	41.44	O
ATOM	879	C	SER	A	118	−8.408	41.723	−6.204	1.00	41.25	C
ATOM	880	O	SER	A	118	−7.277	42.107	−5.969	1.00	41.14	O
ATOM	881	N	ASP	A	119	−9.476	42.466	−5.945	1.00	43.52	N
ATOM	882	CA	ASP	A	119	−9.331	43.849	−5.464	1.00	44.39	C
ATOM	883	CB	ASP	A	119	−10.632	44.642	−5.659	1.00	42.41	C
ATOM	884	CG	ASP	A	119	−10.730	45.267	−7.050	1.00	46.99	C
ATOM	885	OD1	ASP	A	119	−9.777	45.987	−7.479	1.00	44.22	O
ATOM	886	OD2	ASP	A	119	−11.768	45.046	−7.708	1.00	53.14	O
ATOM	887	C	ASP	A	119	−8.795	43.944	−4.011	1.00	45.57	C
ATOM	888	O	ASP	A	119	−8.150	44.928	−3.645	1.00	46.79	O
ATOM	889	N	ALA	A	120	−9.059	42.912	−3.208	1.00	42.24	N
ATOM	890	CA	ALA	A	120	−8.488	42.778	−1.873	1.00	41.91	C
ATOM	891	CB	ALA	A	120	−9.523	43.085	−0.814	1.00	41.29	C
ATOM	892	C	ALA	A	120	−7.958	41.342	−1.718	1.00	41.62	C
ATOM	893	O	ALA	A	120	−8.149	40.506	−2.605	1.00	41.95	O
ATOM	894	N	ASP	A	121	−7.279	41.080	−0.607	1.00	40.39	N
ATOM	895	CA	ASP	A	121	−6.760	39.750	−0.304	1.00	38.92	C
ATOM	896	CB	ASP	A	121	−5.603	39.842	0.695	1.00	39.88	C
ATOM	897	CG	ASP	A	121	−4.986	38.485	0.986	1.00	38.88	C
ATOM	898	OD1	ASP	A	121	−5.368	37.528	0.286	1.00	43.21	O
ATOM	899	OD2	ASP	A	121	−4.135	38.370	1.901	1.00	35.63	O
ATOM	900	C	ASP	A	121	−7.877	38.869	0.267	1.00	39.74	C
ATOM	901	O	ASP	A	121	−7.956	38.631	1.469	1.00	40.54	O
ATOM	902	N	THR	A	122	−8.724	38.356	−0.608	1.00	38.18	N
ATOM	903	CA	THR	A	122	−9.920	37.670	−0.167	1.00	42.04	C
ATOM	904	CB	THR	A	122	−11.102	38.158	−0.958	1.00	39.56	C
ATOM	905	OG1	THR	A	122	−10.799	38.009	−2.350	1.00	39.83	O
ATOM	906	CG2	THR	A	122	−11.348	39.643	−0.668	1.00	47.23	C
ATOM	907	C	THR	A	122	−9.819	36.149	−0.322	1.00	43.00	C
ATOM	908	O	THR	A	122	−10.737	35.417	0.059	1.00	45.82	O
ATOM	909	N	ALA	A	123	−8.712	35.668	−0.880	1.00	43.76	N
ATOM	910	CA	ALA	A	123	−8.527	34.207	−1.066	1.00	39.96	C
ATOM	911	CB	ALA	A	123	−7.500	33.946	−2.149	1.00	38.69	C
ATOM	912	C	ALA	A	123	−8.162	33.452	0.231	1.00	39.42	C
ATOM	913	O	ALA	A	123	−7.456	33.976	1.079	1.00	38.76	O
ATOM	914	N	THR	A	124	−8.630	32.207	0.354	1.00	37.16	N
ATOM	915	CA	THR	A	124	−8.381	31.380	1.544	1.00	30.14	C
ATOM	916	CB	THR	A	124	−9.759	31.027	2.267	1.00	27.28	C
ATOM	917	OG1	THR	A	124	−10.609	30.385	1.321	1.00	37.96	O
ATOM	918	CG2	THR	A	124	−10.449	32.264	2.782	1.00	34.09	C
ATOM	919	C	THR	A	124	−7.628	30.114	1.121	1.00	31.09	C
ATOM	920	O	THR	A	124	−7.161	29.992	−0.002	1.00	34.92	O
ATOM	921	N	ALA	A	125	−7.516	29.143	2.006	1.00	34.69	N
ATOM	922	CA	ALA	A	125	−6.966	27.857	1.594	1.00	35.09	C
ATOM	923	CB	ALA	A	125	−6.557	27.037	2.822	1.00	35.57	C
ATOM	924	C	ALA	A	125	−7.905	27.045	0.668	1.00	35.61	C
ATOM	925	O	ALA	A	125	−7.450	26.100	0.025	1.00	35.88	O
ATOM	926	N	LEU	A	126	−9.183	27.433	0.580	1.00	35.52	N
ATOM	927	CA	LEU	A	126	−10.170	26.725	−0.244	1.00	38.01	C
ATOM	928	CB	LEU	A	126	−11.158	25.926	0.629	1.00	40.30	C
ATOM	929	CG	LEU	A	126	−10.687	24.875	1.642	1.00	35.50	C
ATOM	930	CD1	LEU	A	126	−11.925	24.464	2.443	1.00	35.12	C
ATOM	931	CD2	LEU	A	126	−10.053	23.662	0.975	1.00	43.01	C
ATOM	932	C	LEU	A	126	−10.956	27.560	−1.259	1.00	39.41	C
ATOM	933	O	LEU	A	126	−11.697	26.987	−2.064	1.00	38.78	O
ATOM	934	N	THR	A	127	−10.819	28.892	−1.208	1.00	39.87	N
ATOM	935	CA	THR	A	127	−11.417	29.795	−2.201	1.00	40.08	C
ATOM	936	CB	THR	A	127	−12.495	30.751	−1.616	1.00	37.17	C
ATOM	937	OG1	THR	A	127	−11.920	31.565	−0.589	1.00	37.12	O
ATOM	938	CG2	THR	A	127	−13.710	29.964	−1.068	1.00	36.23	C
ATOM	939	C	THR	A	127	−10.309	30.639	−2.849	1.00	38.11	C
ATOM	940	O	THR	A	127	−9.397	31.072	−2.167	1.00	39.91	O
ATOM	941	N	PRO	A	128	−10.389	30.879	−4.160	1.00	38.97	N
ATOM	942	CA	PRO	A	128	−11.419	30.490	−5.120	1.00	38.25	C
ATOM	943	CB	PRO	A	128	−11.309	31.579	−6.193	1.00	37.19	C
ATOM	944	CG	PRO	A	128	−9.917	32.012	−6.167	1.00	36.47	C
ATOM	945	CD	PRO	A	128	−9.318	31.665	−4.813	1.00	41.36	C
ATOM	946	C	PRO	A	128	−11.145	29.112	−5.707	1.00	37.82	C
ATOM	947	O	PRO	A	128	−10.157	28.501	−5.356	1.00	39.53	O
ATOM	948	N	ALA	A	129	−12.025	28.630	−6.581	1.00	39.78	N
ATOM	949	CA	ALA	A	129	−11.854	27.318	−7.208	1.00	41.22	C
ATOM	950	CB	ALA	A	129	−12.845	27.149	−8.367	1.00	44.36	C
ATOM	951	C	ALA	A	129	−10.430	27.106	−7.684	1.00	41.46	C
ATOM	952	O	ALA	A	129	−9.931	27.854	−8.514	1.00	42.01	O
ATOM	953	N	TRP	A	130	−9.781	26.070	−7.148	1.00	41.79	N
ATOM	954	CA	TRP	A	130	−8.420	25.722	−7.528	1.00	40.28	C
ATOM	955	CB	TRP	A	130	−7.839	24.792	−6.481	1.00	40.07	C
ATOM	956	CG	TRP	A	130	−7.519	25.415	−5.177	1.00	37.59	C
ATOM	957	CD1	TRP	A	130	−8.231	25.310	−4.029	1.00	36.75	C
ATOM	958	NE1	TRP	A	130	−7.599	25.972	−3.007	1.00	41.38	N
ATOM	959	CE2	TRP	A	130	−6.447	26.532	−3.490	1.00	37.52	C
ATOM	960	CD2	TRP	A	130	−6.355	26.184	−4.859	1.00	39.29	C
ATOM	961	CE3	TRP	A	130	−5.265	26.625	−5.594	1.00	36.95	C
ATOM	962	CZ3	TRP	A	130	−4.283	27.382	−4.939	1.00	37.64	C
ATOM	963	CH2	TRP	A	130	−4.390	27.671	−3.578	1.00	27.48	C
ATOM	964	CZ2	TRP	A	130	−5.468	27.269	−2.837	1.00	38.20	C
ATOM	965	C	TRP	A	130	−8.357	25.051	−8.897	1.00	42.27	C
ATOM	966	O	TRP	A	130	−8.089	23.840	−9.012	1.00	43.07	O
ATOM	967	N	MET	A	131	−8.590	25.839	−9.940	1.00	42.81	N
ATOM	968	CA	MET	A	131	−8.682	25.324	−11.305	1.00	46.53	C
ATOM	969	CB	MET	A	131	−9.995	24.548	−11.502	1.00	44.82	C
ATOM	970	CG	MET	A	131	−11.234	25.302	−11.084	1.00	50.50	C
ATOM	971	SD	MET	A	131	−12.714	24.275	−10.951	1.00	56.25	S
ATOM	972	CE	MET	A	131	−12.308	23.173	−9.583	1.00	56.94	C
ATOM	973	C	MET	A	131	−8.664	26.499	−12.258	1.00	44.91	C
ATOM	974	O	MET	A	131	−9.043	27.602	−11.872	1.00	42.46	O
ATOM	975	N	GLU	A	132	−8.228	26.265	−13.491	1.00	46.13	N
ATOM	976	CA	GLU	A	132	−8.370	27.253	−14.554	1.00	47.13	C
ATOM	977	CB	GLU	A	132	−7.908	26.671	−15.892	1.00	47.45	C
ATOM	978	CG	GLU	A	132	−7.460	27.716	−16.901	1.00	47.99	C
ATOM	979	CD	GLU	A	132	−6.957	27.101	−18.192	1.00	49.03	C
ATOM	980	OE1	GLU	A	132	−6.709	25.877	−18.212	1.00	56.50	O
ATOM	981	OE2	GLU	A	132	−6.810	27.841	−19.187	1.00	59.16	O
ATOM	982	C	GLU	A	132	−9.811	27.741	−14.665	1.00	50.42	C
ATOM	983	O	GLU	A	132	−10.747	26.942	−14.675	1.00	49.36	O
ATOM	984	N	ASN	A	133	−9.980	29.056	−14.747	1.00	51.67	N
ATOM	985	CA	ASN	A	133	−11.273	29.680	−14.489	1.00	52.45	C
ATOM	986	CB	ASN	A	133	−12.287	29.272	−15.559	1.00	53.87	C
ATOM	987	CG	ASN	A	133	−12.849	30.462	−16.312	1.00	58.00	C
ATOM	988	OD1	ASN	A	133	−12.264	30.925	−17.291	1.00	55.56	O
ATOM	989	ND2	ASN	A	133	−13.991	30.965	−15.857	1.00	60.24	N
ATOM	990	C	ASN	A	133	−11.810	29.341	−13.102	1.00	51.46	C
ATOM	991	O	ASN	A	133	−12.643	28.449	−12.949	1.00	53.60	O
ATOM	992	N	PRO	A	134	−11.326	30.060	−12.094	1.00	48.44	N
ATOM	993	CA	PRO	A	134	−11.125	31.508	−12.207	1.00	46.49	C
ATOM	994	CB	PRO	A	134	−11.608	32.030	−10.853	1.00	48.19	C
ATOM	995	CG	PRO	A	134	−11.380	30.898	−9.917	1.00	44.82	C
ATOM	996	CD	PRO	A	134	−11.634	29.649	−10.713	1.00	45.15	C
ATOM	997	C	PRO	A	134	−9.656	31.862	−12.412	1.00	46.83	C
ATOM	998	O	PRO	A	134	−9.334	33.013	−12.705	1.00	42.89	O
ATOM	999	N	TYR	A	135	−8.778	30.876	−12.256	1.00	43.64	N
ATOM	1000	CA	TYR	A	135	−7.359	31.064	−12.529	1.00	41.33	C
ATOM	1001	CB	TYR	A	135	−6.551	29.927	−11.896	1.00	42.40	C
ATOM	1002	CG	TYR	A	135	−6.391	30.116	−10.420	1.00	38.37	C
ATOM	1003	CD1	TYR	A	135	−5.328	30.856	−9.917	1.00	43.89	C
ATOM	1004	CE1	TYR	A	135	−5.165	31.047	−8.565	1.00	35.67	C
ATOM	1005	CZ	TYR	A	135	−6.073	30.497	−7.686	1.00	40.40	C
ATOM	1006	OH	TYR	A	135	−5.892	30.710	−6.340	1.00	41.61	O
ATOM	1007	CE2	TYR	A	135	−7.143	29.734	−8.147	1.00	40.34	C
ATOM	1008	CD2	TYR	A	135	−7.289	29.543	−9.518	1.00	46.85	C
ATOM	1009	C	TYR	A	135	−7.035	31.247	−14.014	1.00	43.30	C
ATOM	1010	O	TYR	A	135	−7.694	30.675	−14.873	1.00	42.09	O
ATOM	1011	N	ILE	A	136	−6.031	32.078	−14.308	1.00	45.98	N
ATOM	1012	CA	ILE	A	136	−5.689	32.424	−15.693	1.00	45.22	C
ATOM	1013	CB	ILE	A	136	−5.611	33.966	−15.879	1.00	45.25	C
ATOM	1014	CG1	ILE	A	136	−6.674	34.667	−15.018	1.00	43.90	C
ATOM	1015	CD1	ILE	A	136	−6.852	36.169	−15.294	1.00	44.67	C
ATOM	1016	CG2	ILE	A	136	−5.625	34.329	−17.376	1.00	45.40	C
ATOM	1017	C	ILE	A	136	−4.360	31.802	−16.125	1.00	44.75	C
ATOM	1018	O	ILE	A	136	−3.317	32.244	−15.674	1.00	49.92	O
ATOM	1019	N	LYS	A	137	−4.405	30.788	−16.996	1.00	45.67	N
ATOM	1020	CA	LYS	A	137	−3.193	30.056	−17.437	1.00	45.23	C
ATOM	1021	CB	LYS	A	137	−3.550	29.029	−18.517	1.00	46.80	C
ATOM	1022	CG	LYS	A	137	−2.568	27.881	−18.636	1.00	51.30	C
ATOM	1023	CD	LYS	A	137	−2.822	27.038	−19.864	1.00	43.64	C
ATOM	1024	CE	LYS	A	137	−1.485	26.684	−20.499	1.00	52.43	C
ATOM	1025	NZ	LYS	A	137	−1.427	25.316	−21.121	1.00	52.54	N
ATOM	1026	C	LYS	A	137	−2.165	31.036	−17.974	1.00	44.80	C
ATOM	1027	O	LYS	A	137	−2.483	31.823	−18.865	1.00	44.54	O
ATOM	1028	N	VAL	A	138	−0.968	31.044	−17.371	1.00	44.85	N
ATOM	1029	CA	VAL	A	138	0.159	31.840	−17.855	1.00	42.62	C
ATOM	1030	CB	VAL	A	138	1.112	32.308	−16.722	1.00	44.21	C
ATOM	1031	CG1	VAL	A	138	2.292	33.090	−17.295	1.00	42.19	C
ATOM	1032	CG2	VAL	A	138	0.391	33.175	−15.727	1.00	39.45	C
ATOM	1033	C	VAL	A	138	0.926	31.034	−18.905	1.00	47.65	C
ATOM	1034	O	VAL	A	138	1.017	31.471	−20.063	1.00	50.24	O
ATOM	1035	N	ASP	A	139	1.449	29.855	−18.516	1.00	48.26	N
ATOM	1036	CA	ASP	A	139	2.147	28.942	−19.445	1.00	47.50	C
ATOM	1037	CB	ASP	A	139	3.486	29.565	−19.865	1.00	49.54	C
ATOM	1038	CG	ASP	A	139	3.863	29.271	−21.313	1.00	55.87	C
ATOM	1039	OD1	ASP	A	139	2.962	29.260	−22.189	1.00	55.59	O
ATOM	1040	OD2	ASP	A	139	5.078	29.094	−21.572	1.00	56.27	O
ATOM	1041	C	ASP	A	139	2.384	27.557	−18.816	1.00	46.73	C
ATOM	1042	O	ASP	A	139	2.370	27.425	−17.603	1.00	46.01	O
ATOM	1043	N	THR	A	140	2.571	26.533	−19.648	1.00	46.52	N
ATOM	1044	CA	THR	A	140	3.020	25.213	−19.200	1.00	46.71	C
ATOM	1045	CB	THR	A	140	2.359	24.089	−20.025	1.00	45.93	C
ATOM	1046	OG1	THR	A	140	0.941	24.093	−19.804	1.00	54.04	O
ATOM	1047	CG2	THR	A	140	2.891	22.720	−19.639	1.00	47.66	C
ATOM	1048	C	THR	A	140	4.552	25.235	−19.364	1.00	47.71	C
ATOM	1049	O	THR	A	140	5.044	25.308	−20.489	1.00	51.63	O
ATOM	1050	N	VAL	A	141	5.286	25.212	−18.245	1.00	45.47	N
ATOM	1051	CA	VAL	A	141	6.731	25.536	−18.205	1.00	43.47	C
ATOM	1052	CB	VAL	A	141	7.122	26.334	−16.913	1.00	43.73	C
ATOM	1053	CG1	VAL	A	141	8.620	26.701	−16.885	1.00	39.47	C
ATOM	1054	CG2	VAL	A	141	6.309	27.599	−16.782	1.00	41.94	C
ATOM	1055	C	VAL	A	141	7.551	24.264	−18.277	1.00	45.44	C
ATOM	1056	O	VAL	A	141	7.346	23.347	−17.484	1.00	42.78	O
ATOM	1057	N	ALA	A	142	8.479	24.214	−19.232	1.00	46.34	N
ATOM	1058	CA	ALA	A	142	9.357	23.061	−19.394	1.00	44.60	C
ATOM	1059	CB	ALA	A	142	9.303	22.534	−20.807	1.00	43.31	C
ATOM	1060	C	ALA	A	142	10.784	23.412	−19.003	1.00	44.91	C
ATOM	1061	O	ALA	A	142	11.166	24.586	−18.984	1.00	44.97	O
ATOM	1062	N	ALA	A	143	11.548	22.371	−18.673	1.00	45.80	N
ATOM	1063	CA	ALA	A	143	12.940	22.477	−18.238	1.00	43.20	C
ATOM	1064	CB	ALA	A	143	13.218	21.450	−17.176	1.00	42.14	C
ATOM	1065	C	ALA	A	143	13.871	22.258	−19.422	1.00	44.18	C
ATOM	1066	O	ALA	A	143	13.738	21.272	−20.138	1.00	44.34	O
ATOM	1067	N	GLU	A	144	14.822	23.174	−19.606	1.00	45.90	N
ATOM	1068	CA	GLU	A	144	15.860	23.046	−20.625	1.00	45.98	C
ATOM	1069	CB	GLU	A	144	16.443	24.409	−21.000	1.00	46.26	C
ATOM	1070	C	GLU	A	144	16.952	22.147	−20.105	1.00	46.83	C
ATOM	1071	O	GLU	A	144	17.680	21.548	−20.886	1.00	47.83	O
ATOM	1072	N	HIS	A	145	17.062	22.066	−18.771	1.00	47.47	N
ATOM	1073	CA	HIS	A	145	18.045	21.228	−18.103	1.00	43.60	C
ATOM	1074	CB	HIS	A	145	19.171	22.083	−17.531	1.00	41.41	C
ATOM	1075	CG	HIS	A	145	19.817	22.965	−18.550	1.00	49.97	C
ATOM	1076	ND1	HIS	A	145	20.679	22.482	−19.514	1.00	50.33	N
ATOM	1077	CE1	HIS	A	145	21.067	23.480	−20.288	1.00	55.83	C
ATOM	1078	NE2	HIS	A	145	20.470	24.585	−19.876	1.00	50.08	N
ATOM	1079	CD2	HIS	A	145	19.686	24.289	−18.790	1.00	50.75	C
ATOM	1080	C	HIS	A	145	17.436	20.361	−17.002	1.00	42.09	C
ATOM	1081	O	HIS	A	145	16.716	20.847	−16.135	1.00	39.62	O
ATOM	1082	N	LEU	A	146	17.765	19.075	−17.051	1.00	40.69	N
ATOM	1083	CA	LEU	A	146	17.326	18.092	−16.075	1.00	41.21	C
ATOM	1084	CB	LEU	A	146	16.898	16.793	−16.786	1.00	43.31	C
ATOM	1085	CG	LEU	A	146	15.739	16.923	−17.800	1.00	45.78	C
ATOM	1086	CD1	LEU	A	146	15.507	15.612	−18.551	1.00	52.48	C
ATOM	1087	CD2	LEU	A	146	14.444	17.386	−17.131	1.00	42.70	C
ATOM	1088	C	LEU	A	146	18.414	17.824	−15.032	1.00	39.66	C
ATOM	1089	O	LEU	A	146	19.626	17.831	−15.328	1.00	40.07	O
ATOM	1090	N	THR	A	147	17.986	17.616	−13.794	1.00	39.07	N
ATOM	1091	CA	THR	A	147	18.914	17.270	−12.723	1.00	36.70	C
ATOM	1092	CB	THR	A	147	18.558	18.011	−11.401	1.00	37.46	C
ATOM	1093	OG1	THR	A	147	18.771	19.419	−11.542	1.00	32.66	O
ATOM	1094	CG2	THR	A	147	19.418	17.501	−10.239	1.00	36.18	C
ATOM	1095	C	THR	A	147	18.847	15.737	−12.552	1.00	39.09	C
ATOM	1096	O	THR	A	147	17.742	15.142	−12.547	1.00	35.10	O
ATOM	1097	N	ARG	A	148	20.014	15.098	−12.483	1.00	37.07	N
ATOM	1098	CA	ARG	A	148	20.090	13.707	−12.031	1.00	37.30	C
ATOM	1099	CB	ARG	A	148	20.887	12.827	−13.001	1.00	36.01	C
ATOM	1100	CG	ARG	A	148	20.231	12.730	−14.351	1.00	42.87	C
ATOM	1101	CD	ARG	A	148	21.219	12.497	−15.435	1.00	46.15	C
ATOM	1102	NE	ARG	A	148	20.558	12.599	−16.732	1.00	49.73	N
ATOM	1103	CZ	ARG	A	148	20.535	13.696	−17.480	1.00	54.09	C
ATOM	1104	NH1	ARG	A	148	21.159	14.796	−17.073	1.00	55.32	N
ATOM	1105	NH2	ARG	A	148	19.886	13.687	−18.643	1.00	48.49	N
ATOM	1106	C	ARG	A	148	20.781	13.718	−10.689	1.00	37.62	C
ATOM	1107	O	ARG	A	148	21.837	14.357	−10.536	1.00	40.62	O
ATOM	1108	N	LYS	A	149	20.197	13.006	−9.729	1.00	33.82	N
ATOM	1109	CA	LYS	A	149	20.717	12.989	−8.374	1.00	38.43	C
ATOM	1110	CB	LYS	A	149	19.724	13.631	−7.391	1.00	36.45	C
ATOM	1111	CG	LYS	A	149	19.349	15.063	−7.677	1.00	39.04	C
ATOM	1112	CD	LYS	A	149	18.851	15.705	−6.408	1.00	31.27	C
ATOM	1113	CE	LYS	A	149	20.019	16.113	−5.543	1.00	33.52	C
ATOM	1114	NZ	LYS	A	149	19.519	16.702	−4.262	1.00	31.74	N
ATOM	1115	C	LYS	A	149	20.888	11.548	−7.968	1.00	39.40	C
ATOM	1116	O	LYS	A	149	20.194	10.675	−8.488	1.00	43.92	O
ATOM	1117	N	ARG	A	150	21.794	11.293	−7.032	1.00	38.52	N
ATOM	1118	CA	ARG	A	150	21.841	9.999	−6.426	1.00	37.72	C
ATOM	1119	CB	ARG	A	150	23.048	9.212	−6.913	1.00	39.83	C
ATOM	1120	CG	ARG	A	150	22.677	7.815	−7.416	1.00	40.68	C
ATOM	1121	CD	ARG	A	150	23.919	7.066	−7.884	1.00	50.69	C
ATOM	1122	NE	ARG	A	150	25.109	7.751	−7.419	1.00	48.61	N
ATOM	1123	CZ	ARG	A	150	25.889	7.366	−6.419	1.00	50.11	C
ATOM	1124	NH1	ARG	A	150	25.659	6.244	−5.744	1.00	40.80	N
ATOM	1125	NH2	ARG	A	150	26.919	8.124	−6.113	1.00	45.14	N
ATOM	1126	C	ARG	A	150	21.770	10.108	−4.899	1.00	41.36	C
ATOM	1127	O	ARG	A	150	22.707	10.607	−4.252	1.00	42.41	O
ATOM	1128	N	PRO	A	151	20.643	9.645	−4.314	1.00	40.04	N
ATOM	1129	CA	PRO	A	151	20.352	9.965	−2.926	1.00	43.16	C
ATOM	1130	CB	PRO	A	151	19.275	8.954	−2.566	1.00	44.97	C
ATOM	1131	CG	PRO	A	151	18.535	8.737	−3.854	1.00	42.32	C
ATOM	1132	CD	PRO	A	151	19.592	8.813	−4.923	1.00	40.05	C
ATOM	1133	C	PRO	A	151	21.600	9.831	−2.018	1.00	47.19	C
ATOM	1134	O	PRO	A	151	22.261	8.794	−2.040	1.00	45.98	O
ATOM	1135	N	GLY	A	152	21.922	10.913	−1.299	1.00	47.18	N
ATOM	1136	CA	GLY	A	152	22.973	10.945	−0.277	1.00	44.93	C
ATOM	1137	C	GLY	A	152	24.383	11.075	−0.813	1.00	43.32	C
ATOM	1138	O	GLY	A	152	25.353	11.273	−0.062	1.00	45.52	O
ATOM	1139	N	ALA	A	153	24.503	10.996	−2.122	1.00	42.03	N
ATOM	1140	CA	ALA	A	153	25.791	10.730	−2.711	1.00	42.81	C
ATOM	1141	CB	ALA	A	153	25.779	9.348	−3.358	1.00	41.08	C
ATOM	1142	C	ALA	A	153	26.205	11.781	−3.717	1.00	43.37	C
ATOM	1143	O	ALA	A	153	27.284	12.352	−3.606	1.00	45.89	O
ATOM	1144	N	GLU	A	154	25.372	12.042	−4.716	1.00	38.19	N
ATOM	1145	CA	GLU	A	154	25.889	12.780	−5.851	1.00	36.09	C
ATOM	1146	CB	GLU	A	154	26.600	11.797	−6.763	1.00	34.29	C
ATOM	1147	CG	GLU	A	154	27.493	12.370	−7.838	1.00	38.73	C
ATOM	1148	CD	GLU	A	154	28.005	11.307	−8.808	1.00	37.40	C
ATOM	1149	OE1	GLU	A	154	27.908	10.093	−8.512	1.00	44.61	O
ATOM	1150	OE2	GLU	A	154	28.460	11.691	−9.898	1.00	40.39	O
ATOM	1151	C	GLU	A	154	24.793	13.458	−6.631	1.00	40.06	C
ATOM	1152	O	GLU	A	154	23.649	12.986	−6.641	1.00	36.30	O
ATOM	1153	N	ALA	A	155	25.169	14.505	−7.359	1.00	38.96	N
ATOM	1154	CA	ALA	A	155	24.204	15.221	−8.171	1.00	37.58	C
ATOM	1155	CB	ALA	A	155	23.518	16.297	−7.339	1.00	41.18	C
ATOM	1156	C	ALA	A	155	24.837	15.832	−9.388	1.00	35.95	C
ATOM	1157	O	ALA	A	155	25.998	16.229	−9.358	1.00	38.79	O
ATOM	1158	N	THR	A	156	24.083	15.898	−10.476	1.00	36.21	N
ATOM	1159	CA	THR	A	156	24.470	16.730	−11.607	1.00	39.46	C
ATOM	1160	CB	THR	A	156	24.920	15.915	−12.849	1.00	41.34	C
ATOM	1161	OG1	THR	A	156	23.904	14.953	−13.171	1.00	43.78	O
ATOM	1162	CG2	THR	A	156	26.249	15.214	−12.622	1.00	38.27	C
ATOM	1163	C	THR	A	156	23.276	17.509	−12.046	1.00	39.87	C
ATOM	1164	O	THR	A	156	22.122	17.050	−11.933	1.00	37.90	O
ATOM	1165	N	GLY	A	157	23.529	18.690	−12.578	1.00	39.18	N
ATOM	1166	CA	GLY	A	157	22.428	19.490	−13.084	1.00	37.13	C
ATOM	1167	C	GLY	A	157	22.780	20.950	−13.226	1.00	35.38	C
ATOM	1168	O	GLY	A	157	23.866	21.396	−12.823	1.00	33.71	O
ATOM	1169	N	LYS	A	158	21.850	21.680	−13.825	1.00	37.34	N
ATOM	1170	CA	LYS	A	158	21.886	23.131	−13.921	1.00	37.93	C
ATOM	1171	CB	LYS	A	158	22.192	23.560	−15.358	1.00	40.53	C
ATOM	1172	C	LYS	A	158	20.519	23.694	−13.496	1.00	39.02	C
ATOM	1173	O	LYS	A	158	19.456	23.080	−13.744	1.00	37.62	O
ATOM	1174	N	VAL	A	159	20.553	24.859	−12.861	1.00	38.06	N
ATOM	1175	CA	VAL	A	159	19.336	25.622	−12.551	1.00	39.03	C
ATOM	1176	CB	VAL	A	159	19.653	26.888	−11.699	1.00	38.12	C
ATOM	1177	CG1	VAL	A	159	18.378	27.596	−11.228	1.00	31.20	C
ATOM	1178	CG2	VAL	A	159	20.479	26.510	−10.502	1.00	42.87	C
ATOM	1179	C	VAL	A	159	18.653	26.083	−13.829	1.00	38.78	C
ATOM	1180	O	VAL	A	159	19.295	26.642	−14.719	1.00	37.57	O
ATOM	1181	N	ASN	A	160	17.347	25.864	−13.911	1.00	37.96	N
ATOM	1182	CA	ASN	A	160	16.555	26.480	−14.968	1.00	40.09	C
ATOM	1183	CB	ASN	A	160	15.339	25.630	−15.291	1.00	37.65	C
ATOM	1184	CG	ASN	A	160	15.735	24.343	−15.924	1.00	41.03	C
ATOM	1185	OD1	ASN	A	160	16.012	24.295	−17.115	1.00	40.31	O
ATOM	1186	ND2	ASN	A	160	15.850	23.304	−15.127	1.00	39.22	N
ATOM	1187	C	ASN	A	160	16.195	27.909	−14.653	1.00	39.02	C
ATOM	1188	O	ASN	A	160	16.020	28.284	−13.504	1.00	40.50	O
ATOM	1189	N	VAL	A	161	16.152	28.736	−15.676	1.00	41.64	N
ATOM	1190	CA	VAL	A	161	15.680	30.090	−15.492	1.00	41.07	C
ATOM	1191	CB	VAL	A	161	16.807	31.143	−15.573	1.00	44.12	C
ATOM	1192	CG1	VAL	A	161	16.272	32.503	−15.082	1.00	42.61	C
ATOM	1193	CG2	VAL	A	161	18.065	30.722	−14.755	1.00	39.53	C
ATOM	1194	C	VAL	A	161	14.604	30.348	−16.546	1.00	42.83	C
ATOM	1195	O	VAL	A	161	14.835	30.185	−17.737	1.00	43.10	O
ATOM	1196	N	LYS	A	162	13.401	30.676	−16.090	1.00	43.32	N
ATOM	1197	CA	LYS	A	162	12.305	31.009	−17.004	1.00	44.78	C
ATOM	1198	CB	LYS	A	162	11.214	29.918	−17.004	1.00	42.48	C
ATOM	1199	CG	LYS	A	162	10.145	30.062	−18.115	1.00	45.76	C
ATOM	1200	CD	LYS	A	162	10.761	29.861	−19.514	1.00	47.76	C
ATOM	1201	CE	LYS	A	162	10.063	30.707	−20.577	1.00	45.12	C
ATOM	1202	NZ	LYS	A	162	10.982	30.966	−21.720	1.00	45.05	N
ATOM	1203	C	LYS	A	162	11.740	32.350	−16.563	1.00	43.17	C
ATOM	1204	O	LYS	A	162	11.532	32.581	−15.374	1.00	42.04	O
ATOM	1205	N	THR	A	163	11.538	33.254	−17.512	1.00	43.54	N
ATOM	1206	CA	THR	A	163	10.833	34.481	−17.193	1.00	39.40	C
ATOM	1207	CB	THR	A	163	11.658	35.711	−17.533	1.00	42.58	C
ATOM	1208	OG1	THR	A	163	12.816	35.742	−16.676	1.00	44.30	O
ATOM	1209	CG2	THR	A	163	10.846	37.006	−17.339	1.00	29.43	C
ATOM	1210	C	THR	A	163	9.516	34.409	−17.951	1.00	40.40	C
ATOM	1211	O	THR	A	163	9.499	34.187	−19.154	1.00	42.46	O
ATOM	1212	N	LEU	A	164	8.427	34.532	−17.211	1.00	39.29	N
ATOM	1213	CA	LEU	A	164	7.082	34.513	−17.756	1.00	41.09	C
ATOM	1214	CB	LEU	A	164	6.223	33.580	−16.903	1.00	37.65	C
ATOM	1215	CG	LEU	A	164	6.527	32.079	−17.062	1.00	34.39	C
ATOM	1216	CD1	LEU	A	164	5.534	31.295	−16.280	1.00	33.44	C
ATOM	1217	CD2	LEU	A	164	6.491	31.624	−18.505	1.00	30.97	C
ATOM	1218	C	LEU	A	164	6.520	35.944	−17.753	1.00	41.72	C
ATOM	1219	O	LEU	A	164	6.925	36.765	−16.935	1.00	41.65	O
ATOM	1220	N	ARG	A	165	5.618	36.240	−18.685	1.00	46.79	N
ATOM	1221	CA	ARG	A	165	4.950	37.552	−18.728	1.00	48.66	C
ATOM	1222	CB	ARG	A	165	5.210	38.285	−20.048	1.00	49.34	C
ATOM	1223	CG	ARG	A	165	4.630	39.706	−20.067	1.00	54.33	C
ATOM	1224	CD	ARG	A	165	5.512	40.673	−19.295	1.00	55.25	C
ATOM	1225	NE	ARG	A	165	6.735	40.850	−20.050	1.00	63.03	N
ATOM	1226	CZ	ARG	A	165	6.834	41.649	−21.098	1.00	59.03	C
ATOM	1227	NH1	ARG	A	165	5.794	42.374	−21.471	1.00	63.76	N
ATOM	1228	NH2	ARG	A	165	7.978	41.732	−21.761	1.00	63.22	N
ATOM	1229	C	ARG	A	165	3.452	37.432	−18.484	1.00	48.66	C
ATOM	1230	O	ARG	A	165	2.830	36.449	−18.860	1.00	52.45	O
ATOM	1231	N	LEU	A	166	2.871	38.466	−17.891	1.00	46.26	N
ATOM	1232	CA	LEU	A	166	1.573	38.344	−17.273	1.00	45.06	C
ATOM	1233	CB	LEU	A	166	1.798	37.906	−15.831	1.00	46.66	C
ATOM	1234	CG	LEU	A	166	0.794	37.731	−14.709	1.00	47.10	C
ATOM	1235	CD1	LEU	A	166	1.252	36.507	−13.939	1.00	47.69	C
ATOM	1236	CD2	LEU	A	166	0.767	38.977	−13.813	1.00	42.28	C
ATOM	1237	C	LEU	A	166	0.835	39.685	−17.337	1.00	44.50	C
ATOM	1238	O	LEU	A	166	1.422	40.738	−17.068	1.00	43.18	O
ATOM	1239	N	GLY	A	167	−0.444	39.627	−17.692	1.00	44.34	N
ATOM	1240	CA	GLY	A	167	−1.286	40.830	−17.818	1.00	46.04	C
ATOM	1241	C	GLY	A	167	−2.089	40.951	−19.117	1.00	46.16	C
ATOM	1242	O	GLY	A	167	−2.277	39.969	−19.851	1.00	48.83	O
ATOM	1243	N	PRO	A	168	−2.604	42.155	−19.404	1.00	44.04	N
ATOM	1244	CA	PRO	A	168	−2.568	43.359	−18.579	1.00	42.19	C
ATOM	1245	CB	PRO	A	168	−3.125	44.437	−19.517	1.00	42.07	C
ATOM	1246	CG	PRO	A	168	−3.995	43.694	−20.446	1.00	47.01	C
ATOM	1247	CD	PRO	A	168	−3.278	42.402	−20.690	1.00	45.76	C
ATOM	1248	C	PRO	A	168	−3.411	43.262	−17.308	1.00	40.54	C
ATOM	1249	O	PRO	A	168	−4.488	42.655	−17.313	1.00	38.18	O
ATOM	1250	N	LEU	A	169	−2.921	43.906	−16.250	1.00	43.31	N
ATOM	1251	CA	LEU	A	169	−3.546	43.889	−14.918	1.00	45.25	C
ATOM	1252	CB	LEU	A	169	−2.505	43.511	−13.880	1.00	45.68	C
ATOM	1253	CG	LEU	A	169	−1.920	42.103	−14.059	1.00	45.04	C
ATOM	1254	CD1	LEU	A	169	−0.397	42.117	−13.926	1.00	50.43	C
ATOM	1255	CD2	LEU	A	169	−2.553	41.196	−13.072	1.00	44.32	C
ATOM	1256	C	LEU	A	169	−4.225	45.212	−14.519	1.00	45.55	C
ATOM	1257	O	LEU	A	169	−3.719	46.295	−14.828	1.00	47.38	O
ATOM	1258	N	SER	A	170	−5.337	45.087	−13.794	1.00	43.84	N
ATOM	1259	CA	SER	A	170	−6.237	46.193	−13.435	1.00	48.14	C
ATOM	1260	CB	SER	A	170	−7.617	45.992	−14.085	1.00	44.83	C
ATOM	1261	OG	SER	A	170	−7.590	46.294	−15.470	1.00	50.91	O
ATOM	1262	C	SER	A	170	−6.484	46.371	−11.941	1.00	47.63	C
ATOM	1263	O	SER	A	170	−6.701	47.502	−11.490	1.00	47.42	O
ATOM	1264	N	LYS	A	171	−6.486	45.257	−11.195	1.00	44.02	N
ATOM	1265	CA	LYS	A	171	−6.991	45.256	−9.817	1.00	43.48	C
ATOM	1266	CB	LYS	A	171	−7.645	43.905	−9.455	1.00	43.41	C
ATOM	1267	CG	LYS	A	171	−8.737	43.410	−10.428	1.00	42.89	C
ATOM	1268	CD	LYS	A	171	−9.921	42.790	−9.677	1.00	45.77	C
ATOM	1269	CE	LYS	A	171	−10.862	42.045	−10.613	1.00	48.97	C
ATOM	1270	NZ	LYS	A	171	−10.337	40.673	−10.938	1.00	43.91	N
ATOM	1271	C	LYS	A	171	−5.904	45.615	−8.823	1.00	42.35	C
ATOM	1272	O	LYS	A	171	−4.744	45.750	−9.203	1.00	43.62	O
ATOM	1273	N	ALA	A	172	−6.262	45.775	−7.554	1.00	40.15	N
ATOM	1274	CA	ALA	A	172	−5.296	46.286	−6.592	1.00	40.64	C
ATOM	1275	CB	ALA	A	172	−5.963	46.540	−5.291	1.00	40.23	C
ATOM	1276	C	ALA	A	172	−4.120	45.317	−6.425	1.00	39.80	C
ATOM	1277	O	ALA	A	172	−2.984	45.726	−6.184	1.00	43.11	O
ATOM	1278	N	GLY	A	173	−4.399	44.031	−6.543	1.00	40.73	N
ATOM	1279	CA	GLY	A	173	−3.365	43.015	−6.434	1.00	37.01	C
ATOM	1280	C	GLY	A	173	−3.745	41.677	−7.017	1.00	38.09	C
ATOM	1281	O	GLY	A	173	−4.871	41.495	−7.536	1.00	35.36	O
ATOM	1282	N	PHE	A	174	−2.814	40.720	−6.921	1.00	30.39	N
ATOM	1283	CA	PHE	A	174	−3.020	39.450	−7.557	1.00	32.18	C
ATOM	1284	CB	PHE	A	174	−2.507	39.466	−9.014	1.00	31.00	C
ATOM	1285	CG	PHE	A	174	−1.004	39.557	−9.138	1.00	33.53	C
ATOM	1286	CD1	PHE	A	174	−0.220	38.387	−9.184	1.00	39.87	C
ATOM	1287	CE1	PHE	A	174	1.160	38.447	−9.279	1.00	40.76	C
ATOM	1288	CZ	PHE	A	174	1.804	39.678	−9.356	1.00	36.30	C
ATOM	1289	CE2	PHE	A	174	1.038	40.872	−9.305	1.00	40.79	C
ATOM	1290	CD2	PHE	A	174	−0.372	40.794	−9.206	1.00	34.74	C
ATOM	1291	C	PHE	A	174	−2.364	38.312	−6.746	1.00	30.68	C
ATOM	1292	O	PHE	A	174	−1.698	38.568	−5.748	1.00	34.70	O
ATOM	1293	N	TYR	A	175	−2.504	37.100	−7.254	1.00	34.65	N
ATOM	1294	CA	TYR	A	175	−1.825	35.917	−6.697	1.00	31.11	C
ATOM	1295	CB	TYR	A	175	−2.859	34.963	−6.139	1.00	36.87	C
ATOM	1296	CG	TYR	A	175	−3.695	35.498	−5.041	1.00	36.55	C
ATOM	1297	CD1	TYR	A	175	−3.246	35.442	−3.722	1.00	34.78	C
ATOM	1298	CE1	TYR	A	175	−4.004	35.942	−2.709	1.00	37.57	C
ATOM	1299	CZ	TYR	A	175	−5.241	36.488	−2.985	1.00	35.98	C
ATOM	1300	OH	TYR	A	175	−6.003	36.966	−1.953	1.00	34.98	O
ATOM	1301	CE2	TYR	A	175	−5.719	36.555	−4.281	1.00	39.64	C
ATOM	1302	CD2	TYR	A	175	−4.939	36.044	−5.306	1.00	34.73	C
ATOM	1303	C	TYR	A	175	−1.215	35.129	−7.800	1.00	34.83	C
ATOM	1304	O	TYR	A	175	−1.844	34.963	−8.839	1.00	36.19	O
ATOM	1305	N	LEU	A	176	−0.063	34.506	−7.533	1.00	34.99	N
ATOM	1306	CA	LEU	A	176	0.505	33.635	−8.516	1.00	36.02	C
ATOM	1307	CB	LEU	A	176	1.978	33.991	−8.765	1.00	32.58	C
ATOM	1308	CG	LEU	A	176	2.568	33.556	−10.093	1.00	33.93	C
ATOM	1309	CD1	LEU	A	176	1.971	34.305	−11.256	1.00	35.00	C
ATOM	1310	CD2	LEU	A	176	4.068	33.794	−10.077	1.00	34.45	C
ATOM	1311	C	LEU	A	176	0.340	32.206	−8.048	1.00	33.83	C
ATOM	1312	O	LEU	A	176	0.550	31.923	−6.871	1.00	34.45	O
ATOM	1313	N	ALA	A	177	−0.007	31.307	−8.961	1.00	31.16	N
ATOM	1314	CA	ALA	A	177	−0.165	29.924	−8.570	1.00	31.94	C
ATOM	1315	CB	ALA	A	177	−1.672	29.506	−8.480	1.00	33.96	C
ATOM	1316	C	ALA	A	177	0.632	28.995	−9.461	1.00	35.75	C
ATOM	1317	O	ALA	A	177	0.909	29.258	−10.658	1.00	35.44	O
ATOM	1318	N	PHE	A	178	1.033	27.900	−8.836	1.00	34.91	N
ATOM	1319	CA	PHE	A	178	1.835	26.896	−9.493	1.00	36.95	C
ATOM	1320	CB	PHE	A	178	3.173	26.699	−8.768	1.00	37.01	C
ATOM	1321	CG	PHE	A	178	4.025	27.931	−8.725	1.00	40.04	C
ATOM	1322	CD1	PHE	A	178	5.022	28.135	−9.690	1.00	34.45	C
ATOM	1323	CE1	PHE	A	178	5.826	29.267	−9.655	1.00	41.39	C
ATOM	1324	CZ	PHE	A	178	5.630	30.221	−8.645	1.00	38.98	C
ATOM	1325	CE2	PHE	A	178	4.617	30.043	−7.695	1.00	38.28	C
ATOM	1326	CD2	PHE	A	178	3.830	28.896	−7.727	1.00	31.99	C
ATOM	1327	C	PHE	A	178	1.019	25.652	−9.361	1.00	36.21	C
ATOM	1328	O	PHE	A	178	0.613	25.292	−8.255	1.00	37.32	O
ATOM	1329	N	GLN	A	179	0.771	25.001	−10.490	1.00	35.99	N
ATOM	1330	CA	GLN	A	179	0.151	23.696	−10.481	1.00	37.46	C
ATOM	1331	CB	GLN	A	179	−1.193	23.726	−11.248	1.00	37.59	C
ATOM	1332	CG	GLN	A	179	−1.779	22.345	−11.528	1.00	34.22	C
ATOM	1333	CD	GLN	A	179	−2.739	22.326	−12.728	1.00	39.93	C
ATOM	1334	OE1	GLN	A	179	−2.403	22.777	−13.817	1.00	45.97	O
ATOM	1335	NE2	GLN	A	179	−3.922	21.754	−12.529	1.00	45.45	N
ATOM	1336	C	GLN	A	179	1.068	22.583	−10.991	1.00	35.94	C
ATOM	1337	O	GLN	A	179	1.540	22.601	−12.105	1.00	33.60	O
ATOM	1338	N	ASP	A	180	1.271	21.592	−10.138	1.00	39.76	N
ATOM	1339	CA	ASP	A	180	2.028	20.410	−10.456	1.00	40.59	C
ATOM	1340	CB	ASP	A	180	2.898	20.092	−9.250	1.00	37.86	C
ATOM	1341	CG	ASP	A	180	3.454	18.706	−9.294	1.00	39.57	C
ATOM	1342	OD1	ASP	A	180	4.226	18.446	−10.237	1.00	39.93	O
ATOM	1343	OD2	ASP	A	180	3.141	17.893	−8.384	1.00	35.30	O
ATOM	1344	C	ASP	A	180	1.106	19.214	−10.744	1.00	40.58	C
ATOM	1345	O	ASP	A	180	0.119	19.009	−10.048	1.00	41.81	O
ATOM	1346	N	GLN	A	181	1.417	18.427	−11.769	1.00	41.23	N
ATOM	1347	CA	GLN	A	181	0.612	17.229	−12.057	1.00	40.16	C
ATOM	1348	CB	GLN	A	181	−0.197	17.361	−13.365	1.00	38.15	C
ATOM	1349	CG	GLN	A	181	−0.923	18.687	−13.561	1.00	41.10	C
ATOM	1350	CD	GLN	A	181	−1.592	18.821	−14.926	1.00	43.97	C
ATOM	1351	OE1	GLN	A	181	−1.923	17.826	−15.577	1.00	43.86	O
ATOM	1352	NE2	GLN	A	181	−1.807	20.066	−15.362	1.00	46.46	N
ATOM	1353	C	GLN	A	181	1.478	15.981	−12.087	1.00	37.45	C
ATOM	1354	O	GLN	A	181	1.018	14.916	−12.448	1.00	38.23	O
ATOM	1355	N	GLY	A	182	2.733	16.097	−11.679	1.00	35.03	N
ATOM	1356	CA	GLY	A	182	3.569	14.916	−11.563	1.00	31.33	C
ATOM	1357	C	GLY	A	182	5.061	15.219	−11.657	1.00	32.94	C
ATOM	1358	O	GLY	A	182	5.853	14.337	−11.965	1.00	33.01	O
ATOM	1359	N	ALA	A	183	5.455	16.446	−11.376	1.00	27.42	N
ATOM	1360	CA	ALA	A	183	6.916	16.789	−11.503	1.00	34.16	C
ATOM	1361	CB	ALA	A	183	7.084	18.245	−11.905	1.00	31.51	C
ATOM	1362	C	ALA	A	183	7.730	16.465	−10.224	1.00	36.88	C
ATOM	1363	O	ALA	A	183	7.165	16.305	−9.146	1.00	38.15	O
ATOM	1364	N	CYS	A	184	9.054	16.330	−10.362	1.00	38.55	N
ATOM	1365	CA	CYS	A	184	9.983	16.326	−9.232	1.00	37.77	C
ATOM	1366	CB	CYS	A	184	10.821	15.026	−9.216	1.00	40.69	C
ATOM	1367	SG	CYS	A	184	11.729	14.712	−7.696	1.00	37.47	S
ATOM	1368	C	CYS	A	184	10.866	17.571	−9.390	1.00	36.58	C
ATOM	1369	O	CYS	A	184	11.808	17.554	−10.162	1.00	34.19	O
ATOM	1370	N	MET	A	185	10.509	18.667	−8.705	1.00	35.34	N
ATOM	1371	CA	MET	A	185	11.161	19.976	−8.863	1.00	36.03	C
ATOM	1372	CB	MET	A	185	10.379	20.827	−9.856	1.00	34.42	C
ATOM	1373	CG	MET	A	185	8.902	21.024	−9.488	1.00	34.05	C
ATOM	1374	SD	MET	A	185	8.089	22.180	−10.598	1.00	36.69	S
ATOM	1375	CE	MET	A	185	8.821	23.708	−10.012	1.00	44.23	C
ATOM	1376	C	MET	A	185	11.317	20.774	−7.567	1.00	29.84	C
ATOM	1377	O	MET	A	185	10.536	20.592	−6.637	1.00	29.27	O
ATOM	1378	N	ALA	A	186	12.397	21.553	−7.464	1.00	30.72	N
ATOM	1379	CA	ALA	A	186	12.518	22.596	−6.450	1.00	27.77	C
ATOM	1380	CB	ALA	A	186	13.910	22.553	−5.745	1.00	25.18	C
ATOM	1381	C	ALA	A	186	12.336	23.979	−7.125	1.00	24.78	C
ATOM	1382	O	ALA	A	186	12.961	24.251	−8.150	1.00	31.56	O
ATOM	1383	N	LEU	A	187	11.565	24.864	−6.507	1.00	27.48	N
ATOM	1384	CA	LEU	A	187	11.519	26.299	−6.879	1.00	27.38	C
ATOM	1385	CB	LEU	A	187	10.101	26.887	−6.703	1.00	30.71	C
ATOM	1386	CG	LEU	A	187	9.980	28.385	−7.052	1.00	29.76	C
ATOM	1387	CD1	LEU	A	187	9.960	28.497	−8.550	1.00	25.31	C
ATOM	1388	CD2	LEU	A	187	8.780	29.029	−6.446	1.00	38.88	C
ATOM	1389	C	LEU	A	187	12.439	27.016	−5.931	1.00	26.96	C
ATOM	1390	O	LEU	A	187	12.136	27.168	−4.765	1.00	31.63	O
ATOM	1391	N	LEU	A	188	13.585	27.419	−6.445	1.00	23.82	N
ATOM	1392	CA	LEU	A	188	14.649	28.033	−5.680	1.00	22.42	C
ATOM	1393	CB	LEU	A	188	15.952	27.928	−6.492	1.00	18.60	C
ATOM	1394	CG	LEU	A	188	16.336	26.464	−6.872	1.00	22.31	C
ATOM	1395	CD1	LEU	A	188	17.713	26.386	−7.539	1.00	28.31	C
ATOM	1396	CD2	LEU	A	188	16.255	25.517	−5.679	1.00	28.43	C
ATOM	1397	C	LEU	A	188	14.302	29.477	−5.412	1.00	22.74	C
ATOM	1398	O	LEU	A	188	14.529	29.936	−4.329	1.00	28.62	O
ATOM	1399	N	SER	A	189	13.673	30.153	−6.382	1.00	27.21	N
ATOM	1400	CA	SER	A	189	13.270	31.519	−6.173	1.00	31.26	C
ATOM	1401	CB	SER	A	189	14.515	32.436	−6.114	1.00	36.03	C
ATOM	1402	OG	SER	A	189	15.019	32.681	−7.411	1.00	31.51	O
ATOM	1403	C	SER	A	189	12.252	32.016	−7.211	1.00	32.45	C
ATOM	1404	O	SER	A	189	12.127	31.446	−8.302	1.00	30.70	O
ATOM	1405	N	LEU	A	190	11.481	33.035	−6.801	1.00	33.70	N
ATOM	1406	CA	LEU	A	190	10.455	33.696	−7.616	1.00	35.24	C
ATOM	1407	CB	LEU	A	190	8.999	33.318	−7.175	1.00	33.65	C
ATOM	1408	CG	LEU	A	190	7.879	34.252	−7.704	1.00	37.98	C
ATOM	1409	CD1	LEU	A	190	7.758	34.196	−9.248	1.00	38.61	C
ATOM	1410	CD2	LEU	A	190	6.494	34.037	−7.064	1.00	34.04	C
ATOM	1411	C	LEU	A	190	10.680	35.193	−7.476	1.00	35.25	C
ATOM	1412	O	LEU	A	190	10.779	35.711	−6.376	1.00	33.56	O
ATOM	1413	N	HIS	A	191	10.780	35.893	−8.594	1.00	37.40	N
ATOM	1414	CA	HIS	A	191	10.920	37.330	−8.519	1.00	38.52	C
ATOM	1415	CB	HIS	A	191	12.402	37.758	−8.720	1.00	37.86	C
ATOM	1416	CG	HIS	A	191	12.617	39.246	−8.734	1.00	41.14	C
ATOM	1417	ND1	HIS	A	191	13.565	39.845	−9.531	1.00	38.74	N
ATOM	1418	CE1	HIS	A	191	13.539	41.156	−9.344	1.00	41.60	C
ATOM	1419	NE2	HIS	A	191	12.627	41.424	−8.430	1.00	40.15	N
ATOM	1420	CD2	HIS	A	191	12.039	40.244	−8.024	1.00	30.90	C
ATOM	1421	C	HIS	A	191	9.921	37.957	−9.487	1.00	39.05	C
ATOM	1422	O	HIS	A	191	9.977	37.744	−10.702	1.00	37.50	O
ATOM	1423	N	LEU	A	192	8.976	38.674	−8.890	1.00	38.54	N
ATOM	1424	CA	LEU	A	192	7.912	39.401	−9.592	1.00	40.13	C
ATOM	1425	CB	LEU	A	192	6.566	39.221	−8.876	1.00	39.90	C
ATOM	1426	CG	LEU	A	192	5.960	37.835	−8.772	1.00	36.90	C
ATOM	1427	CD1	LEU	A	192	4.835	37.864	−7.800	1.00	42.75	C
ATOM	1428	CD2	LEU	A	192	5.498	37.403	−10.150	1.00	33.58	C
ATOM	1429	C	LEU	A	192	8.274	40.859	−9.531	1.00	37.03	C
ATOM	1430	O	LEU	A	192	8.557	41.381	−8.457	1.00	36.49	O
ATOM	1431	N	PHE	A	193	8.241	41.502	−10.687	1.00	38.07	N
ATOM	1432	CA	PHE	A	193	8.650	42.894	−10.841	1.00	36.70	C
ATOM	1433	CB	PHE	A	193	10.216	43.035	−10.959	1.00	29.97	C
ATOM	1434	CG	PHE	A	193	10.802	42.363	−12.180	1.00	31.12	C
ATOM	1435	CD1	PHE	A	193	11.097	43.105	−13.328	1.00	37.50	C
ATOM	1436	CE1	PHE	A	193	11.596	42.500	−14.467	1.00	34.28	C
ATOM	1437	CZ	PHE	A	193	11.853	41.124	−14.481	1.00	45.74	C
ATOM	1438	CE2	PHE	A	193	11.563	40.350	−13.352	1.00	30.73	C
ATOM	1439	CD2	PHE	A	193	11.067	40.985	−12.190	1.00	37.59	C
ATOM	1440	C	PHE	A	193	7.950	43.450	−12.090	1.00	40.02	C
ATOM	1441	O	PHE	A	193	7.271	42.732	−12.840	1.00	44.09	O
ATOM	1442	N	TYR	A	194	8.097	44.747	−12.297	1.00	41.11	N
ATOM	1443	CA	TYR	A	194	7.673	45.348	−13.580	1.00	41.03	C
ATOM	1444	CB	TYR	A	194	6.236	45.880	−13.495	1.00	42.85	C
ATOM	1445	CG	TYR	A	194	6.023	47.133	−12.652	1.00	45.26	C
ATOM	1446	CD1	TYR	A	194	5.865	47.056	−11.268	1.00	45.47	C
ATOM	1447	CE1	TYR	A	194	5.635	48.201	−10.499	1.00	41.30	C
ATOM	1448	CZ	TYR	A	194	5.566	49.425	−11.108	1.00	41.62	C
ATOM	1449	OH	TYR	A	194	5.318	50.549	−10.355	1.00	41.25	O
ATOM	1450	CE2	TYR	A	194	5.703	49.532	−12.480	1.00	44.15	C
ATOM	1451	CD2	TYR	A	194	5.928	48.391	−13.248	1.00	45.95	C
ATOM	1452	C	TYR	A	194	8.650	46.430	−13.974	1.00	41.04	C
ATOM	1453	O	TYR	A	194	9.456	46.856	−13.147	1.00	40.79	O
ATOM	1454	N	LYS	A	195	8.592	46.864	−15.236	1.00	44.73	N
ATOM	1455	CA	LYS	A	195	9.456	47.945	−15.729	1.00	46.28	C
ATOM	1456	CB	LYS	A	195	10.152	47.561	−17.037	1.00	43.48	C
ATOM	1457	CG	LYS	A	195	10.979	46.305	−16.912	1.00	47.45	C
ATOM	1458	CD	LYS	A	195	11.676	45.924	−18.202	1.00	50.29	C
ATOM	1459	CE	LYS	A	195	12.404	44.596	−18.004	1.00	50.32	C
ATOM	1460	NZ	LYS	A	195	12.635	43.846	−19.282	1.00	59.34	N
ATOM	1461	C	LYS	A	195	8.624	49.217	−15.860	1.00	47.80	C
ATOM	1462	O	LYS	A	195	7.537	49.218	−16.454	1.00	45.96	O
ATOM	1463	N	LYS	A	196	9.144	50.290	−15.277	1.00	49.37	N
ATOM	1464	CA	LYS	A	196	8.323	51.432	−14.872	1.00	53.18	C
ATOM	1465	CB	LYS	A	196	9.160	52.333	−13.968	1.00	53.61	C
ATOM	1466	CG	LYS	A	196	8.409	52.877	−12.787	1.00	57.05	C
ATOM	1467	CD	LYS	A	196	9.326	52.905	−11.589	1.00	56.96	C
ATOM	1468	CE	LYS	A	196	9.150	54.183	−10.795	1.00	56.02	C
ATOM	1469	NZ	LYS	A	196	10.319	54.447	−9.912	1.00	49.28	N
ATOM	1470	C	LYS	A	196	7.673	52.246	−16.004	1.00	54.46	C
ATOM	1471	O	LYS	A	196	8.045	52.167	−17.184	1.00	52.26	O
ATOM	1472	OXT	LYS	A	196	6.733	53.018	−15.746	1.00	55.97	O
ATOM	1473	N	ILE	B	31	6.202	17.357	11.661	1.00	52.51	N
ATOM	1474	CA	ILE	B	31	6.652	17.466	13.083	1.00	51.68	C
ATOM	1475	CB	ILE	B	31	7.195	16.099	13.642	1.00	51.99	C
ATOM	1476	CG1	ILE	B	31	8.524	15.693	12.959	1.00	56.45	C
ATOM	1477	CD1	ILE	B	31	9.378	14.656	13.701	1.00	48.38	C
ATOM	1478	CG2	ILE	B	31	6.139	15.008	13.502	1.00	57.59	C
ATOM	1479	C	ILE	B	31	7.694	18.588	13.242	1.00	51.74	C
ATOM	1480	O	ILE	B	31	8.867	18.423	12.904	1.00	49.06	O
ATOM	1481	N	VAL	B	32	7.254	19.737	13.751	1.00	51.69	N
ATOM	1482	CA	VAL	B	32	8.155	20.860	13.927	1.00	49.76	C
ATOM	1483	CB	VAL	B	32	7.409	22.216	13.764	1.00	49.19	C
ATOM	1484	CG1	VAL	B	32	8.381	23.405	13.799	1.00	48.91	C
ATOM	1485	CG2	VAL	B	32	6.606	22.225	12.458	1.00	50.33	C
ATOM	1486	C	VAL	B	32	8.812	20.697	15.292	1.00	51.68	C
ATOM	1487	O	VAL	B	32	8.130	20.724	16.318	1.00	55.62	O
ATOM	1488	N	LEU	B	33	10.130	20.483	15.307	1.00	51.40	N
ATOM	1489	CA	LEU	B	33	10.881	20.426	16.570	1.00	49.84	C
ATOM	1490	CB	LEU	B	33	12.181	19.648	16.400	1.00	49.11	C
ATOM	1491	CG	LEU	B	33	12.026	18.219	15.866	1.00	50.26	C
ATOM	1492	CD1	LEU	B	33	13.092	17.915	14.844	1.00	45.27	C
ATOM	1493	CD2	LEU	B	33	12.059	17.216	17.001	1.00	49.51	C
ATOM	1494	C	LEU	B	33	11.157	21.838	17.081	1.00	51.22	C
ATOM	1495	O	LEU	B	33	10.961	22.817	16.350	1.00	51.79	O
ATOM	1496	N	GLU	B	34	11.587	21.956	18.334	1.00	48.63	N
ATOM	1497	CA	GLU	B	34	11.756	23.283	18.942	1.00	50.49	C
ATOM	1498	CB	GLU	B	34	11.951	23.178	20.458	1.00	52.60	C
ATOM	1499	C	GLU	B	34	12.914	24.043	18.303	1.00	47.30	C
ATOM	1500	O	GLU	B	34	14.019	23.514	18.216	1.00	45.62	O
ATOM	1501	N	PRO	B	35	12.651	25.282	17.841	1.00	46.68	N
ATOM	1502	CA	PRO	B	35	13.663	26.137	17.253	1.00	44.35	C
ATOM	1503	CB	PRO	B	35	12.961	27.492	17.191	1.00	46.18	C
ATOM	1504	CG	PRO	B	35	11.535	27.136	16.959	1.00	44.55	C
ATOM	1505	CD	PRO	B	35	11.319	25.926	17.817	1.00	46.72	C
ATOM	1506	C	PRO	B	35	14.940	26.229	18.079	1.00	46.44	C
ATOM	1507	O	PRO	B	35	14.912	26.212	19.326	1.00	46.98	O
ATOM	1508	N	ILE	B	36	16.058	26.291	17.377	1.00	47.07	N
ATOM	1509	CA	ILE	B	36	17.354	26.348	18.024	1.00	47.75	C
ATOM	1510	CB	ILE	B	36	18.272	25.214	17.548	1.00	45.95	C
ATOM	1511	CG1	ILE	B	36	17.727	23.879	18.073	1.00	46.11	C
ATOM	1512	CD1	ILE	B	36	18.656	22.714	17.974	1.00	48.49	C
ATOM	1513	CG2	ILE	B	36	19.708	25.452	18.031	1.00	52.98	C
ATOM	1514	C	ILE	B	36	17.994	27.717	17.845	1.00	47.45	C
ATOM	1515	O	ILE	B	36	18.367	28.116	16.739	1.00	47.44	O
ATOM	1516	N	TYR	B	37	18.090	28.444	18.951	1.00	48.70	N
ATOM	1517	CA	TYR	B	37	18.714	29.751	18.920	1.00	49.10	C
ATOM	1518	CB	TYR	B	37	18.089	30.679	19.948	1.00	48.08	C
ATOM	1519	CG	TYR	B	37	16.632	30.929	19.657	1.00	53.20	C
ATOM	1520	CD1	TYR	B	37	16.201	32.116	19.037	1.00	55.88	C
ATOM	1521	CE1	TYR	B	37	14.841	32.323	18.784	1.00	52.31	C
ATOM	1522	CZ	TYR	B	37	13.933	31.333	19.131	1.00	53.25	C
ATOM	1523	OH	TYR	B	37	12.585	31.480	18.900	1.00	55.81	O
ATOM	1524	CE2	TYR	B	37	14.343	30.168	19.727	1.00	49.90	C
ATOM	1525	CD2	TYR	B	37	15.675	29.969	19.988	1.00	55.92	C
ATOM	1526	C	TYR	B	37	20.208	29.644	19.095	1.00	48.06	C
ATOM	1527	O	TYR	B	37	20.705	29.188	20.135	1.00	47.00	O
ATOM	1528	N	TRP	B	38	20.902	30.081	18.055	1.00	44.34	N
ATOM	1529	CA	TRP	B	38	22.343	30.031	17.993	1.00	44.89	C
ATOM	1530	CB	TRP	B	38	22.794	29.823	16.533	1.00	45.89	C
ATOM	1531	CG	TRP	B	38	24.191	29.337	16.424	1.00	43.47	C
ATOM	1532	CD1	TRP	B	38	25.320	30.086	16.476	1.00	46.09	C
ATOM	1533	NE1	TRP	B	38	26.432	29.279	16.364	1.00	48.98	N
ATOM	1534	CE2	TRP	B	38	26.015	27.980	16.247	1.00	42.45	C
ATOM	1535	CD2	TRP	B	38	24.610	27.980	16.292	1.00	42.52	C
ATOM	1536	CE3	TRP	B	38	23.930	26.763	16.179	1.00	47.79	C
ATOM	1537	CZ3	TRP	B	38	24.653	25.621	16.043	1.00	46.68	C
ATOM	1538	CH2	TRP	B	38	26.051	25.649	16.007	1.00	47.89	C
ATOM	1539	CZ2	TRP	B	38	26.746	26.821	16.101	1.00	45.11	C
ATOM	1540	C	TRP	B	38	22.912	31.312	18.589	1.00	45.43	C
ATOM	1541	O	TRP	B	38	23.237	32.274	17.882	1.00	41.46	O
ATOM	1542	N	ASN	B	39	22.980	31.315	19.914	1.00	43.47	N
ATOM	1543	CA	ASN	B	39	23.587	32.390	20.669	1.00	47.07	C
ATOM	1544	CB	ASN	B	39	22.561	33.489	21.025	1.00	48.07	C
ATOM	1545	CG	ASN	B	39	21.403	32.981	21.887	1.00	48.17	C
ATOM	1546	OD1	ASN	B	39	21.589	32.193	22.806	1.00	61.41	O
ATOM	1547	ND2	ASN	B	39	20.207	33.467	21.607	1.00	56.57	N
ATOM	1548	C	ASN	B	39	24.274	31.798	21.893	1.00	47.83	C
ATOM	1549	O	ASN	B	39	23.880	30.722	22.380	1.00	48.70	O
ATOM	1550	N	SER	B	40	25.332	32.453	22.361	1.00	50.06	N
ATOM	1551	CA	SER	B	40	26.136	31.882	23.459	1.00	49.21	C
ATOM	1552	CB	SER	B	40	27.442	32.647	23.649	1.00	48.57	C
ATOM	1553	OG	SER	B	40	27.218	33.898	24.280	1.00	47.90	O
ATOM	1554	C	SER	B	40	25.336	31.785	24.776	1.00	50.37	C
ATOM	1555	O	SER	B	40	25.692	30.999	25.677	1.00	51.05	O
ATOM	1556	N	SER	B	41	24.249	32.554	24.875	1.00	48.80	N
ATOM	1557	CA	SER	B	41	23.325	32.428	26.008	1.00	52.76	C
ATOM	1558	CB	SER	B	41	22.504	33.714	26.211	1.00	51.67	C
ATOM	1559	OG	SER	B	41	21.575	33.924	25.161	1.00	57.98	O
ATOM	1560	C	SER	B	41	22.424	31.174	25.920	1.00	54.80	C
ATOM	1561	O	SER	B	41	21.563	30.955	26.782	1.00	55.52	O
ATOM	1562	N	ASN	B	42	22.665	30.329	24.914	1.00	53.48	N
ATOM	1563	CA	ASN	B	42	21.954	29.058	24.777	1.00	52.76	C
ATOM	1564	CB	ASN	B	42	21.929	28.601	23.303	1.00	52.32	C
ATOM	1565	CG	ASN	B	42	20.840	27.578	23.016	1.00	50.95	C
ATOM	1566	OD1	ASN	B	42	20.252	26.984	23.931	1.00	61.15	O
ATOM	1567	ND2	ASN	B	42	20.567	27.360	21.736	1.00	51.55	N
ATOM	1568	C	ASN	B	42	22.582	27.975	25.657	1.00	52.92	C
ATOM	1569	O	ASN	B	42	23.527	27.296	25.236	1.00	52.05	O
ATOM	1570	N	SER	B	43	22.051	27.813	26.868	1.00	52.45	N
ATOM	1571	CA	SER	B	43	22.571	26.817	27.819	1.00	54.85	C
ATOM	1572	CB	SER	B	43	22.026	27.063	29.231	1.00	53.84	C
ATOM	1573	OG	SER	B	43	20.659	26.694	29.333	1.00	57.96	O
ATOM	1574	C	SER	B	43	22.343	25.358	27.378	1.00	54.62	C
ATOM	1575	O	SER	B	43	22.959	24.447	27.926	1.00	56.78	O
ATOM	1576	N	LYS	B	44	21.479	25.152	26.378	1.00	53.79	N
ATOM	1577	CA	LYS	B	44	21.264	23.840	25.758	1.00	51.82	C
ATOM	1578	CB	LYS	B	44	20.148	23.919	24.720	1.00	52.94	C
ATOM	1579	C	LYS	B	44	22.530	23.276	25.109	1.00	50.94	C
ATOM	1580	O	LYS	B	44	22.605	22.071	24.860	1.00	50.22	O
ATOM	1581	N	PHE	B	45	23.504	24.152	24.821	1.00	49.62	N
ATOM	1582	CA	PHE	B	45	24.847	23.737	24.377	1.00	48.32	C
ATOM	1583	CB	PHE	B	45	25.553	24.826	23.572	1.00	47.65	C
ATOM	1584	CG	PHE	B	45	24.955	25.064	22.207	1.00	45.89	C
ATOM	1585	CD1	PHE	B	45	25.111	24.129	21.172	1.00	45.96	C
ATOM	1586	CE1	PHE	B	45	24.572	24.365	19.904	1.00	50.10	C
ATOM	1587	CZ	PHE	B	45	23.862	25.541	19.669	1.00	47.05	C
ATOM	1588	CE2	PHE	B	45	23.710	26.476	20.686	1.00	40.41	C
ATOM	1589	CD2	PHE	B	45	24.253	26.226	21.951	1.00	47.70	C
ATOM	1590	C	PHE	B	45	25.692	23.372	25.580	1.00	49.49	C
ATOM	1591	O	PHE	B	45	26.274	24.243	26.245	1.00	50.60	O
ATOM	1592	N	LEU	B	46	25.767	22.079	25.849	1.00	50.95	N
ATOM	1593	CA	LEU	B	46	26.364	21.592	27.087	1.00	51.22	C
ATOM	1594	CB	LEU	B	46	25.730	20.261	27.487	1.00	51.08	C
ATOM	1595	CG	LEU	B	46	24.203	20.190	27.619	1.00	46.10	C
ATOM	1596	CD1	LEU	B	46	23.796	18.761	27.883	1.00	43.82	C
ATOM	1597	CD2	LEU	B	46	23.662	21.111	28.694	1.00	48.08	C
ATOM	1598	C	LEU	B	46	27.878	21.452	26.985	1.00	54.27	C
ATOM	1599	O	LEU	B	46	28.397	21.095	25.924	1.00	55.19	O
ATOM	1600	N	PRO	B	47	28.592	21.756	28.088	1.00	55.99	N
ATOM	1601	CA	PRO	B	47	30.002	21.439	28.289	1.00	58.57	C
ATOM	1602	CB	PRO	B	47	30.085	21.210	29.807	1.00	58.59	C
ATOM	1603	CG	PRO	B	47	28.908	21.978	30.394	1.00	59.61	C
ATOM	1604	CD	PRO	B	47	28.053	22.487	29.245	1.00	55.29	C
ATOM	1605	C	PRO	B	47	30.423	20.159	27.568	1.00	60.23	C
ATOM	1606	O	PRO	B	47	29.753	19.124	27.703	1.00	60.06	O
ATOM	1607	N	GLY	B	48	31.512	20.242	26.801	1.00	60.39	N
ATOM	1608	CA	GLY	B	48	32.012	19.118	26.020	1.00	60.52	C
ATOM	1609	C	GLY	B	48	31.089	18.599	24.925	1.00	62.42	C
ATOM	1610	O	GLY	B	48	31.405	18.716	23.725	1.00	62.21	O
ATOM	1611	N	ALA	B	49	29.954	18.032	25.348	1.00	61.80	N
ATOM	1612	CA	ALA	B	49	28.988	17.361	24.474	1.00	61.62	C
ATOM	1613	CB	ALA	B	49	27.858	16.757	25.302	1.00	60.60	C
ATOM	1614	C	ALA	B	49	28.420	18.229	23.345	1.00	62.36	C
ATOM	1615	O	ALA	B	49	28.463	17.833	22.180	1.00	64.81	O
ATOM	1616	N	GLY	B	50	27.894	19.404	23.690	1.00	61.93	N
ATOM	1617	CA	GLY	B	50	27.206	20.263	22.722	1.00	60.75	C
ATOM	1618	C	GLY	B	50	25.706	20.038	22.758	1.00	59.01	C
ATOM	1619	O	GLY	B	50	25.154	19.714	23.818	1.00	58.98	O
ATOM	1620	N	LEU	B	51	25.051	20.190	21.607	1.00	56.06	N
ATOM	1621	CA	LEU	B	51	23.600	19.988	21.513	1.00	55.72	C
ATOM	1622	CB	LEU	B	51	22.923	21.197	20.861	1.00	55.78	C
ATOM	1623	CG	LEU	B	51	21.510	21.607	21.317	1.00	56.57	C
ATOM	1624	CD1	LEU	B	51	21.260	23.086	21.016	1.00	54.35	C
ATOM	1625	CD2	LEU	B	51	20.410	20.740	20.712	1.00	51.01	C
ATOM	1626	C	LEU	B	51	23.231	18.687	20.783	1.00	55.37	C
ATOM	1627	O	LEU	B	51	23.654	18.454	19.650	1.00	56.89	O
ATOM	1628	N	VAL	B	52	22.455	17.834	21.449	1.00	52.14	N
ATOM	1629	CA	VAL	B	52	22.091	16.532	20.898	1.00	49.64	C
ATOM	1630	CB	VAL	B	52	22.656	15.331	21.729	1.00	49.25	C
ATOM	1631	CG1	VAL	B	52	22.280	13.976	21.106	1.00	47.08	C
ATOM	1632	CG2	VAL	B	52	24.181	15.425	21.866	1.00	51.63	C
ATOM	1633	C	VAL	B	52	20.576	16.444	20.713	1.00	47.40	C
ATOM	1634	O	VAL	B	52	19.796	16.668	21.658	1.00	44.14	O
ATOM	1635	N	LEU	B	53	20.206	16.136	19.465	1.00	46.22	N
ATOM	1636	CA	LEU	B	53	18.839	16.015	18.990	1.00	46.52	C
ATOM	1637	CB	LEU	B	53	18.545	17.067	17.899	1.00	45.04	C
ATOM	1638	CG	LEU	B	53	18.416	18.522	18.330	1.00	49.63	C
ATOM	1639	CD1	LEU	B	53	18.373	19.404	17.093	1.00	41.47	C
ATOM	1640	CD2	LEU	B	53	17.178	18.711	19.223	1.00	46.52	C
ATOM	1641	C	LEU	B	53	18.710	14.674	18.333	1.00	46.61	C
ATOM	1642	O	LEU	B	53	19.693	14.160	17.789	1.00	45.23	O
ATOM	1643	N	ALA	B	54	17.488	14.136	18.377	1.00	48.27	N
ATOM	1644	CA	ALA	B	54	17.104	12.922	17.662	1.00	51.02	C
ATOM	1645	CB	ALA	B	54	16.871	11.748	18.636	1.00	54.27	C
ATOM	1646	C	ALA	B	54	15.841	13.229	16.845	1.00	52.58	C
ATOM	1647	O	ALA	B	54	14.711	13.093	17.344	1.00	50.37	O
ATOM	1648	N	PRO	B	55	16.035	13.722	15.606	1.00	51.74	N
ATOM	1649	CA	PRO	B	55	14.941	14.004	14.667	1.00	50.37	C
ATOM	1650	CB	PRO	B	55	15.546	15.065	13.753	1.00	48.25	C
ATOM	1651	CG	PRO	B	55	17.011	14.775	13.743	1.00	49.23	C
ATOM	1652	CD	PRO	B	55	17.352	14.098	15.044	1.00	51.76	C
ATOM	1653	C	PRO	B	55	14.538	12.782	13.846	1.00	49.88	C
ATOM	1654	O	PRO	B	55	15.357	11.906	13.592	1.00	49.10	O
ATOM	1655	N	GLN	B	56	13.281	12.748	13.422	1.00	50.05	N
ATOM	1656	CA	GLN	B	56	12.789	11.680	12.590	1.00	49.58	C
ATOM	1657	CB	GLN	B	56	11.439	11.207	13.119	1.00	49.76	C
ATOM	1658	CG	GLN	B	56	11.343	9.697	13.288	1.00	51.96	C
ATOM	1659	CD	GLN	B	56	12.022	9.182	14.553	1.00	53.57	C
ATOM	1660	OE1	GLN	B	56	12.667	9.934	15.296	1.00	48.95	O
ATOM	1661	NE2	GLN	B	56	11.867	7.884	14.805	1.00	44.22	N
ATOM	1662	C	GLN	B	56	12.647	12.193	11.165	1.00	50.12	C
ATOM	1663	O	GLN	B	56	12.295	13.349	10.967	1.00	49.01	O
ATOM	1664	N	ILE	B	57	12.940	11.338	10.185	1.00	50.19	N
ATOM	1665	CA	ILE	B	57	12.631	11.616	8.774	1.00	52.05	C
ATOM	1666	CB	ILE	B	57	12.797	10.340	7.884	1.00	50.70	C
ATOM	1667	CG1	ILE	B	57	14.270	9.879	7.814	1.00	52.97	C
ATOM	1668	CD1	ILE	B	57	15.269	10.917	7.322	1.00	50.34	C
ATOM	1669	CG2	ILE	B	57	12.200	10.527	6.505	1.00	55.73	C
ATOM	1670	C	ILE	B	57	11.211	12.192	8.661	1.00	53.21	C
ATOM	1671	O	ILE	B	57	10.235	11.604	9.151	1.00	52.05	O
ATOM	1672	N	GLY	B	58	11.116	13.365	8.041	1.00	54.38	N
ATOM	1673	CA	GLY	B	58	9.867	14.110	7.975	1.00	56.00	C
ATOM	1674	C	GLY	B	58	9.901	15.371	8.822	1.00	56.89	C
ATOM	1675	O	GLY	B	58	9.095	16.282	8.619	1.00	57.36	O
ATOM	1676	N	ASP	B	59	10.839	15.415	9.769	1.00	57.12	N
ATOM	1677	CA	ASP	B	59	10.966	16.522	10.724	1.00	55.47	C
ATOM	1678	CB	ASP	B	59	12.019	16.195	11.775	1.00	55.05	C
ATOM	1679	C	ASP	B	59	11.341	17.828	10.060	1.00	53.03	C
ATOM	1680	O	ASP	B	59	11.925	17.823	8.984	1.00	53.44	O
ATOM	1681	N	LYS	B	60	10.992	18.933	10.723	1.00	51.30	N
ATOM	1682	CA	LYS	B	60	11.409	20.285	10.345	1.00	47.93	C
ATOM	1683	CB	LYS	B	60	10.238	21.096	9.783	1.00	48.26	C
ATOM	1684	CG	LYS	B	60	9.889	20.884	8.297	1.00	46.39	C
ATOM	1685	CD	LYS	B	60	9.229	22.177	7.740	1.00	47.01	C
ATOM	1686	CE	LYS	B	60	8.534	21.992	6.395	1.00	52.74	C
ATOM	1687	NZ	LYS	B	60	7.991	23.324	5.847	1.00	44.78	N
ATOM	1688	C	LYS	B	60	11.979	20.988	11.586	1.00	46.25	C
ATOM	1689	O	LYS	B	60	11.384	20.949	12.655	1.00	45.18	O
ATOM	1690	N	LEU	B	61	13.142	21.608	11.435	1.00	45.65	N
ATOM	1691	CA	LEU	B	61	13.799	22.335	12.521	1.00	44.72	C
ATOM	1692	CB	LEU	B	61	14.975	21.527	13.077	1.00	45.50	C
ATOM	1693	CG	LEU	B	61	15.939	22.130	14.107	1.00	47.54	C
ATOM	1694	CD1	LEU	B	61	15.354	22.084	15.519	1.00	39.59	C
ATOM	1695	CD2	LEU	B	61	17.286	21.432	14.072	1.00	46.47	C
ATOM	1696	C	LEU	B	61	14.325	23.667	12.016	1.00	42.76	C
ATOM	1697	O	LEU	B	61	14.990	23.713	10.980	1.00	42.46	O
ATOM	1698	N	ASP	B	62	14.022	24.732	12.754	1.00	39.20	N
ATOM	1699	CA	ASP	B	62	14.588	26.045	12.507	1.00	40.51	C
ATOM	1700	CB	ASP	B	62	13.553	27.146	12.773	1.00	38.33	C
ATOM	1701	CG	ASP	B	62	12.304	27.020	11.914	1.00	43.05	C
ATOM	1702	OD1	ASP	B	62	11.233	27.448	12.381	1.00	53.67	O
ATOM	1703	OD2	ASP	B	62	12.363	26.508	10.779	1.00	50.75	O
ATOM	1704	C	ASP	B	62	15.791	26.280	13.419	1.00	40.29	C
ATOM	1705	O	ASP	B	62	15.676	26.176	14.649	1.00	44.71	O
ATOM	1706	N	ILE	B	63	16.941	26.612	12.824	1.00	39.54	N
ATOM	1707	CA	ILE	B	63	18.070	27.149	13.567	1.00	40.77	C
ATOM	1708	CB	ILE	B	63	19.371	26.483	13.157	1.00	41.56	C
ATOM	1709	CG1	ILE	B	63	19.243	24.966	13.300	1.00	38.50	C
ATOM	1710	CD1	ILE	B	63	20.358	24.219	12.616	1.00	50.40	C
ATOM	1711	CG2	ILE	B	63	20.556	27.016	13.981	1.00	41.42	C
ATOM	1712	C	ILE	B	63	18.112	28.688	13.321	1.00	40.07	C
ATOM	1713	O	ILE	B	63	18.179	29.139	12.167	1.00	42.17	O
ATOM	1714	N	ILE	B	64	18.039	29.468	14.402	1.00	40.38	N
ATOM	1715	CA	ILE	B	64	17.839	30.952	14.299	1.00	42.37	C
ATOM	1716	CB	ILE	B	64	16.539	31.409	15.011	1.00	44.09	C
ATOM	1717	CG1	ILE	B	64	15.325	30.676	14.458	1.00	40.39	C
ATOM	1718	CD1	ILE	B	64	15.048	29.389	15.178	1.00	47.96	C
ATOM	1719	CG2	ILE	B	64	16.338	32.965	14.883	1.00	40.44	C
ATOM	1720	C	ILE	B	64	18.945	31.742	14.953	1.00	45.33	C
ATOM	1721	O	ILE	B	64	19.215	31.530	16.138	1.00	44.27	O
ATOM	1722	N	CYS	B	65	19.576	32.658	14.212	1.00	47.81	N
ATOM	1723	CA	CYS	B	65	20.440	33.650	14.849	1.00	50.81	C
ATOM	1724	CB	CYS	B	65	21.625	34.041	13.976	1.00	52.46	C
ATOM	1725	SG	CYS	B	65	22.840	32.737	13.887	1.00	57.22	S
ATOM	1726	C	CYS	B	65	19.604	34.870	15.232	1.00	52.50	C
ATOM	1727	O	CYS	B	65	19.169	35.632	14.361	1.00	51.32	O
ATOM	1728	N	PRO	B	66	19.427	35.090	16.523	1.00	52.38	N
ATOM	1729	CA	PRO	B	66	18.436	36.051	17.007	1.00	56.14	C
ATOM	1730	CB	PRO	B	66	18.428	35.810	18.510	1.00	56.30	C
ATOM	1731	CG	PRO	B	66	18.947	34.448	18.672	1.00	55.10	C
ATOM	1732	CD	PRO	B	66	19.955	34.262	17.611	1.00	53.36	C
ATOM	1733	C	PRO	B	66	18.780	37.503	16.701	1.00	57.91	C
ATOM	1734	O	PRO	B	66	19.943	37.887	16.680	1.00	55.40	O
ATOM	1735	N	LYS	B	67	17.742	38.289	16.445	1.00	61.44	N
ATOM	1736	CA	LYS	B	67	17.760	39.738	16.596	1.00	63.19	C
ATOM	1737	CB	LYS	B	67	16.324	40.238	16.522	1.00	63.03	C
ATOM	1738	CG	LYS	B	67	16.105	41.449	15.671	1.00	63.45	C
ATOM	1739	CD	LYS	B	67	14.634	41.608	15.386	1.00	61.61	C
ATOM	1740	CE	LYS	B	67	14.307	43.020	14.962	1.00	65.44	C
ATOM	1741	NZ	LYS	B	67	13.998	43.916	16.102	1.00	65.01	N
ATOM	1742	C	LYS	B	67	18.341	40.152	17.937	1.00	65.68	C
ATOM	1743	O	LYS	B	67	17.926	39.645	18.972	1.00	66.30	O
ATOM	1744	N	VAL	B	68	19.271	41.098	17.938	1.00	66.29	N
ATOM	1745	CA	VAL	B	68	19.561	41.816	19.174	1.00	67.49	C
ATOM	1746	CB	VAL	B	68	20.942	41.501	19.750	1.00	66.82	C
ATOM	1747	CG1	VAL	B	68	21.073	40.009	20.042	1.00	66.77	C
ATOM	1748	CG2	VAL	B	68	22.021	41.977	18.826	1.00	63.95	C
ATOM	1749	C	VAL	B	68	19.320	43.312	19.154	1.00	68.26	C
ATOM	1750	O	VAL	B	68	20.061	44.068	18.532	1.00	68.98	O
ATOM	1751	N	ASP	B	69	18.285	43.722	19.874	1.00	69.20	N
ATOM	1752	CA	ASP	B	69	17.631	45.029	19.687	1.00	70.92	C
ATOM	1753	CB	ASP	B	69	16.119	44.881	19.934	1.00	69.99	C
ATOM	1754	CG	ASP	B	69	15.638	43.433	19.795	1.00	67.08	C
ATOM	1755	OD1	ASP	B	69	15.978	42.783	18.785	1.00	72.72	O
ATOM	1756	OD2	ASP	B	69	14.922	42.943	20.695	1.00	57.27	O
ATOM	1757	C	ASP	B	69	18.207	46.160	20.561	1.00	72.50	C
ATOM	1758	O	ASP	B	69	19.151	45.945	21.321	1.00	72.58	O
ATOM	1759	N	SER	B	70	17.640	47.363	20.434	1.00	74.73	N
ATOM	1760	CA	SER	B	70	18.004	48.508	21.287	1.00	77.16	C
ATOM	1761	C	SER	B	70	17.679	48.211	22.755	1.00	79.24	C
ATOM	1762	O	SER	B	70	18.492	48.469	23.649	1.00	78.89	O
ATOM	1763	N	LYS	B	71	16.472	47.687	22.980	1.00	81.34	N
ATOM	1764	CA	LYS	B	71	16.098	47.035	24.233	1.00	82.67	C
ATOM	1765	CB	LYS	B	71	14.669	47.409	24.636	1.00	82.35	C
ATOM	1766	C	LYS	B	71	16.220	45.520	24.021	1.00	84.04	C
ATOM	1767	O	LYS	B	71	15.557	44.961	23.145	1.00	84.71	O
ATOM	1768	N	THR	B	72	17.059	44.882	24.841	1.00	84.98	N
ATOM	1769	CA	THR	B	72	17.545	43.485	24.692	1.00	85.61	C
ATOM	1770	CB	THR	B	72	16.758	42.603	23.646	1.00	85.57	C
ATOM	1771	OG1	THR	B	72	15.358	42.607	23.953	1.00	85.29	O
ATOM	1772	CG2	THR	B	72	17.245	41.149	23.662	1.00	85.71	C
ATOM	1773	C	THR	B	72	19.066	43.520	24.425	1.00	85.75	C
ATOM	1774	O	THR	B	72	19.580	42.865	23.508	1.00	85.63	O
ATOM	1775	N	VAL	B	73	19.754	44.316	25.251	1.00	85.63	N
ATOM	1776	CA	VAL	B	73	21.222	44.480	25.269	1.00	85.19	C
ATOM	1777	CB	VAL	B	73	21.959	43.217	25.841	1.00	85.28	C
ATOM	1778	CG1	VAL	B	73	23.410	43.546	26.233	1.00	83.57	C
ATOM	1779	CG2	VAL	B	73	21.210	42.646	27.045	1.00	85.78	C
ATOM	1780	C	VAL	B	73	21.832	44.916	23.925	1.00	84.59	C
ATOM	1781	O	VAL	B	73	21.193	44.830	22.878	1.00	83.42	O
ATOM	1782	N	GLY	B	74	23.063	45.414	23.979	1.00	84.51	N
ATOM	1783	CA	GLY	B	74	23.854	45.647	22.777	1.00	84.58	C
ATOM	1784	C	GLY	B	74	24.647	44.398	22.419	1.00	84.25	C
ATOM	1785	O	GLY	B	74	24.482	43.338	23.053	1.00	85.08	O
ATOM	1786	N	GLN	B	75	25.505	44.526	21.403	1.00	81.57	N
ATOM	1787	CA	GLN	B	75	26.417	43.453	20.965	1.00	78.55	C
ATOM	1788	CB	GLN	B	75	27.350	42.999	22.102	1.00	78.75	C
ATOM	1789	CG	GLN	B	75	28.402	44.045	22.503	1.00	80.96	C
ATOM	1790	CD	GLN	B	75	28.668	44.097	24.009	1.00	83.13	C
ATOM	1791	OE1	GLN	B	75	27.757	43.914	24.820	1.00	84.28	O
ATOM	1792	NE2	GLN	B	75	29.919	44.367	24.384	1.00	81.04	N
ATOM	1793	C	GLN	B	75	25.697	42.268	20.311	1.00	74.88	C
ATOM	1794	O	GLN	B	75	24.789	41.663	20.884	1.00	75.60	O
ATOM	1795	N	TYR	B	76	26.122	41.964	19.091	1.00	70.64	N
ATOM	1796	CA	TYR	B	76	25.579	40.870	18.305	1.00	65.82	C
ATOM	1797	CB	TYR	B	76	25.256	41.387	16.895	1.00	62.96	C
ATOM	1798	CG	TYR	B	76	24.610	40.413	15.931	1.00	60.95	C
ATOM	1799	CD1	TYR	B	76	23.314	39.923	16.135	1.00	59.30	C
ATOM	1800	CE1	TYR	B	76	22.729	39.027	15.221	1.00	60.32	C
ATOM	1801	CZ	TYR	B	76	23.449	38.640	14.090	1.00	58.00	C
ATOM	1802	OH	TYR	B	76	22.931	37.778	13.142	1.00	58.90	O
ATOM	1803	CE2	TYR	B	76	24.721	39.138	13.879	1.00	60.57	C
ATOM	1804	CD2	TYR	B	76	25.285	40.017	14.784	1.00	54.01	C
ATOM	1805	C	TYR	B	76	26.608	39.745	18.286	1.00	63.37	C
ATOM	1806	O	TYR	B	76	27.806	39.995	18.413	1.00	62.55	O
ATOM	1807	N	GLU	B	77	26.138	38.508	18.149	1.00	59.87	N
ATOM	1808	CA	GLU	B	77	27.034	37.352	18.091	1.00	57.95	C
ATOM	1809	CB	GLU	B	77	26.501	36.220	18.980	1.00	58.47	C
ATOM	1810	C	GLU	B	77	27.268	36.895	16.648	1.00	54.89	C
ATOM	1811	O	GLU	B	77	26.396	36.283	16.024	1.00	53.41	O
ATOM	1812	N	TYR	B	78	28.445	37.217	16.117	1.00	52.94	N
ATOM	1813	CA	TYR	B	78	28.764	36.914	14.721	1.00	52.55	C
ATOM	1814	CB	TYR	B	78	29.841	37.877	14.187	1.00	53.56	C
ATOM	1815	CG	TYR	B	78	29.332	39.285	13.930	1.00	49.81	C
ATOM	1816	CD1	TYR	B	78	29.291	40.237	14.950	1.00	55.06	C
ATOM	1817	CE1	TYR	B	78	28.813	41.535	14.712	1.00	51.22	C
ATOM	1818	CZ	TYR	B	78	28.382	41.875	13.446	1.00	48.74	C
ATOM	1819	OH	TYR	B	78	27.919	43.147	13.187	1.00	53.04	O
ATOM	1820	CE2	TYR	B	78	28.427	40.953	12.419	1.00	46.58	C
ATOM	1821	CD2	TYR	B	78	28.904	39.670	12.660	1.00	51.58	C
ATOM	1822	C	TYR	B	78	29.184	35.451	14.537	1.00	55.29	C
ATOM	1823	O	TYR	B	78	30.229	35.031	15.035	1.00	55.26	O
ATOM	1824	N	TYR	B	79	28.352	34.674	13.835	1.00	54.89	N
ATOM	1825	CA	TYR	B	79	28.705	33.305	13.441	1.00	52.92	C
ATOM	1826	CB	TYR	B	79	27.939	32.276	14.265	1.00	53.97	C
ATOM	1827	CG	TYR	B	79	27.973	32.471	15.754	1.00	55.14	C
ATOM	1828	CD1	TYR	B	79	26.875	33.015	16.422	1.00	55.96	C
ATOM	1829	CE1	TYR	B	79	26.891	33.184	17.792	1.00	58.12	C
ATOM	1830	CZ	TYR	B	79	28.014	32.806	18.514	1.00	55.57	C
ATOM	1831	OH	TYR	B	79	28.030	32.989	19.863	1.00	57.86	O
ATOM	1832	CE2	TYR	B	79	29.121	32.269	17.875	1.00	56.26	C
ATOM	1833	CD2	TYR	B	79	29.091	32.099	16.501	1.00	53.27	C
ATOM	1834	C	TYR	B	79	28.420	32.995	11.981	1.00	54.07	C
ATOM	1835	O	TYR	B	79	27.498	33.556	11.392	1.00	52.83	O
ATOM	1836	N	LYS	B	80	29.220	32.085	11.415	1.00	53.13	N
ATOM	1837	CA	LYS	B	80	28.866	31.360	10.191	1.00	52.07	C
ATOM	1838	CB	LYS	B	80	29.990	31.406	9.149	1.00	51.71	C
ATOM	1839	CG	LYS	B	80	30.016	32.654	8.280	1.00	56.46	C
ATOM	1840	CD	LYS	B	80	31.021	32.499	7.152	1.00	55.08	C
ATOM	1841	CE	LYS	B	80	30.814	33.552	6.082	1.00	59.80	C
ATOM	1842	NZ	LYS	B	80	30.966	34.942	6.603	1.00	62.51	N
ATOM	1843	C	LYS	B	80	28.605	29.907	10.582	1.00	51.02	C
ATOM	1844	O	LYS	B	80	29.467	29.247	11.169	1.00	49.01	O
ATOM	1845	N	VAL	B	81	27.425	29.402	10.255	1.00	48.00	N
ATOM	1846	CA	VAL	B	81	27.048	28.066	10.703	1.00	48.41	C
ATOM	1847	CB	VAL	B	81	25.668	28.073	11.413	1.00	45.24	C
ATOM	1848	CG1	VAL	B	81	25.360	26.732	12.037	1.00	49.15	C
ATOM	1849	CG2	VAL	B	81	25.649	29.118	12.482	1.00	46.44	C
ATOM	1850	C	VAL	B	81	27.101	27.130	9.509	1.00	50.06	C
ATOM	1851	O	VAL	B	81	26.679	27.501	8.411	1.00	50.73	O
ATOM	1852	N	TYR	B	82	27.620	25.923	9.722	1.00	50.39	N
ATOM	1853	CA	TYR	B	82	27.909	24.998	8.622	1.00	51.80	C
ATOM	1854	CB	TYR	B	82	29.422	24.860	8.414	1.00	50.05	C
ATOM	1855	CG	TYR	B	82	30.088	26.033	7.741	1.00	55.29	C
ATOM	1856	CD1	TYR	B	82	30.609	27.094	8.492	1.00	60.37	C
ATOM	1857	CE1	TYR	B	82	31.237	28.183	7.871	1.00	59.32	C
ATOM	1858	CZ	TYR	B	82	31.357	28.209	6.486	1.00	60.82	C
ATOM	1859	OH	TYR	B	82	31.973	29.283	5.860	1.00	56.78	O
ATOM	1860	CE2	TYR	B	82	30.862	27.153	5.726	1.00	60.90	C
ATOM	1861	CD2	TYR	B	82	30.221	26.079	6.361	1.00	56.29	C
ATOM	1862	C	TYR	B	82	27.352	23.617	8.889	1.00	51.81	C
ATOM	1863	O	TYR	B	82	27.264	23.196	10.039	1.00	52.65	O
ATOM	1864	N	MET	B	83	26.999	22.916	7.815	1.00	52.67	N
ATOM	1865	CA	MET	B	83	26.743	21.484	7.884	1.00	54.74	C
ATOM	1866	CB	MET	B	83	25.601	21.099	6.941	1.00	55.19	C
ATOM	1867	CG	MET	B	83	25.406	19.614	6.751	1.00	55.78	C
ATOM	1868	SD	MET	B	83	24.629	18.846	8.168	1.00	62.13	S
ATOM	1869	CE	MET	B	83	22.912	18.982	7.717	1.00	53.46	C
ATOM	1870	C	MET	B	83	28.047	20.750	7.522	1.00	55.00	C
ATOM	1871	O	MET	B	83	28.531	20.846	6.387	1.00	53.90	O
ATOM	1872	N	VAL	B	84	28.621	20.054	8.505	1.00	55.21	N
ATOM	1873	CA	VAL	B	84	29.917	19.375	8.347	1.00	52.74	C
ATOM	1874	CB	VAL	B	84	30.977	19.860	9.389	1.00	50.47	C
ATOM	1875	CG1	VAL	B	84	31.411	21.268	9.096	1.00	46.44	C
ATOM	1876	CG2	VAL	B	84	30.466	19.738	10.816	1.00	49.60	C
ATOM	1877	C	VAL	B	84	29.801	17.856	8.434	1.00	55.22	C
ATOM	1878	O	VAL	B	84	28.712	17.308	8.613	1.00	55.27	O
ATOM	1879	N	ASP	B	85	30.946	17.194	8.289	1.00	57.58	N
ATOM	1880	CA	ASP	B	85	31.090	15.759	8.523	1.00	59.75	C
ATOM	1881	CB	ASP	B	85	32.035	15.146	7.471	1.00	61.05	C
ATOM	1882	CG	ASP	B	85	33.409	15.825	7.436	1.00	65.18	C
ATOM	1883	OD1	ASP	B	85	33.598	16.760	6.623	1.00	67.19	O
ATOM	1884	OD2	ASP	B	85	34.298	15.421	8.224	1.00	68.81	O
ATOM	1885	C	ASP	B	85	31.603	15.485	9.949	1.00	57.67	C
ATOM	1886	O	ASP	B	85	32.138	16.374	10.606	1.00	59.66	O
ATOM	1887	N	LYS	B	86	31.433	14.256	10.423	1.00	57.11	N
ATOM	1888	CA	LYS	B	86	31.936	13.859	11.738	1.00	54.53	C
ATOM	1889	CB	LYS	B	86	31.798	12.349	11.916	1.00	52.85	C
ATOM	1890	CG	LYS	B	86	32.434	11.817	13.179	1.00	44.47	C
ATOM	1891	CD	LYS	B	86	32.959	10.389	12.950	1.00	41.89	C
ATOM	1892	CE	LYS	B	86	32.765	9.541	14.174	1.00	38.48	C
ATOM	1893	NZ	LYS	B	86	33.495	10.036	15.379	1.00	47.23	N
ATOM	1894	C	LYS	B	86	33.389	14.294	12.000	1.00	55.95	C
ATOM	1895	O	LYS	B	86	33.713	14.762	13.093	1.00	55.26	O
ATOM	1896	N	ASP	B	87	34.253	14.147	10.999	1.00	57.71	N
ATOM	1897	CA	ASP	B	87	35.673	14.480	11.149	1.00	60.04	C
ATOM	1898	CB	ASP	B	87	36.528	13.745	10.107	1.00	59.81	C
ATOM	1899	CG	ASP	B	87	37.035	12.406	10.606	1.00	64.01	C
ATOM	1900	OD1	ASP	B	87	37.633	12.362	11.709	1.00	62.33	O
ATOM	1901	OD2	ASP	B	87	36.847	11.399	9.882	1.00	62.56	O
ATOM	1902	C	ASP	B	87	35.941	15.980	11.078	1.00	60.97	C
ATOM	1903	O	ASP	B	87	36.953	16.449	11.581	1.00	61.10	O
ATOM	1904	N	GLN	B	88	35.057	16.738	10.446	1.00	61.32	N
ATOM	1905	CA	GLN	B	88	35.265	18.178	10.363	1.00	63.39	C
ATOM	1906	CB	GLN	B	88	34.473	18.784	9.208	1.00	63.94	C
ATOM	1907	C	GLN	B	88	34.837	18.810	11.667	1.00	64.84	C
ATOM	1908	O	GLN	B	88	35.222	19.929	11.983	1.00	65.42	O
ATOM	1909	N	ALA	B	89	34.040	18.061	12.417	1.00	65.49	N
ATOM	1910	CA	ALA	B	89	33.424	18.533	13.644	1.00	65.15	C
ATOM	1911	CB	ALA	B	89	31.989	18.034	13.731	1.00	65.66	C
ATOM	1912	C	ALA	B	89	34.212	18.022	14.824	1.00	64.18	C
ATOM	1913	O	ALA	B	89	34.544	18.765	15.735	1.00	63.09	O
ATOM	1914	O	ASP	B	90	36.855	17.048	17.406	1.00	20.00	O
ATOM	1915	N	ASP	B	90	34.503	16.731	14.795	1.00	20.00	N
ATOM	1916	CA	ASP	B	90	35.305	16.114	15.829	1.00	20.00	C
ATOM	1917	C	ASP	B	90	36.371	17.098	16.280	1.00	20.00	C
ATOM	1918	CB	ASP	B	90	35.928	14.827	15.303	1.00	20.00	C
ATOM	1919	CG	ASP	B	90	35.238	13.602	15.839	1.00	20.00	C
ATOM	1920	OD1	ASP	B	90	34.100	13.741	16.329	1.00	20.00	O
ATOM	1921	OD2	ASP	B	90	35.838	12.510	15.788	1.00	20.00	O
ATOM	1922	O	ARG	B	91	38.909	20.743	14.930	1.00	20.00	O
ATOM	1923	N	ARG	B	91	36.693	18.021	15.390	1.00	20.00	N
ATOM	1924	CA	ARG	B	91	38.029	18.543	15.278	1.00	20.00	C
ATOM	1925	C	ARG	B	91	37.934	19.999	14.865	1.00	20.00	C
ATOM	1926	CB	ARG	B	91	38.794	17.757	14.225	1.00	20.00	C
ATOM	1927	N	CYS	B	92	36.744	20.402	14.436	1.00	65.62	N
ATOM	1928	CA	CYS	B	92	36.377	21.803	14.449	1.00	63.54	C
ATOM	1929	CB	CYS	B	92	36.658	22.414	15.813	1.00	62.30	C
ATOM	1930	SG	CYS	B	92	35.415	22.029	17.030	1.00	61.91	S
ATOM	1931	C	CYS	B	92	37.103	22.560	13.364	1.00	63.64	C
ATOM	1932	O	CYS	B	92	37.751	23.557	13.622	1.00	62.94	O
ATOM	1933	N	THR	B	93	36.973	22.076	12.139	1.00	66.00	N
ATOM	1934	CA	THR	B	93	37.644	22.682	10.998	1.00	69.32	C
ATOM	1935	CB	THR	B	93	38.992	21.965	10.653	1.00	69.46	C
ATOM	1936	OG1	THR	B	93	39.501	22.457	9.406	1.00	71.08	O
ATOM	1937	CG2	THR	B	93	38.813	20.447	10.563	1.00	67.96	C
ATOM	1938	C	THR	B	93	36.711	22.682	9.798	1.00	70.96	C
ATOM	1939	O	THR	B	93	36.174	21.638	9.422	1.00	72.14	O
ATOM	1940	N	ILE	B	94	36.500	23.868	9.231	1.00	72.37	N
ATOM	1941	CA	ILE	B	94	35.749	24.019	7.985	1.00	73.47	C
ATOM	1942	CB	ILE	B	94	34.519	24.973	8.129	1.00	72.37	C
ATOM	1943	CG1	ILE	B	94	34.943	26.416	8.425	1.00	71.50	C
ATOM	1944	CD1	ILE	B	94	34.846	27.339	7.244	1.00	65.08	C
ATOM	1945	CG2	ILE	B	94	33.571	24.464	9.211	1.00	72.82	C
ATOM	1946	C	ILE	B	94	36.699	24.430	6.851	1.00	74.87	C
ATOM	1947	O	ILE	B	94	36.281	24.598	5.701	1.00	74.36	O
ATOM	1948	N	LYS	B	95	37.979	24.587	7.201	1.00	76.69	N
ATOM	1949	CA	LYS	B	95	39.050	24.828	6.236	1.00	78.11	C
ATOM	1950	CB	LYS	B	95	40.345	25.209	6.955	1.00	77.98	C
ATOM	1951	C	LYS	B	95	39.231	23.555	5.414	1.00	79.85	C
ATOM	1952	O	LYS	B	95	40.318	22.964	5.359	1.00	80.52	O
ATOM	1953	N	LYS	B	96	38.132	23.164	4.770	1.00	80.67	N
ATOM	1954	CA	LYS	B	96	37.946	21.878	4.109	1.00	80.88	C
ATOM	1955	CB	LYS	B	96	38.263	20.732	5.106	1.00	80.35	C
ATOM	1956	CG	LYS	B	96	37.430	19.457	5.056	1.00	79.50	C
ATOM	1957	CD	LYS	B	96	36.505	19.334	6.265	1.00	77.17	C
ATOM	1958	CE	LYS	B	96	35.924	20.675	6.665	1.00	77.09	C
ATOM	1959	NZ	LYS	B	96	34.524	20.596	7.133	1.00	76.80	N
ATOM	1960	C	LYS	B	96	36.494	21.937	3.589	1.00	81.93	C
ATOM	1961	O	LYS	B	96	35.881	23.011	3.640	1.00	82.40	O
ATOM	1962	N	GLU	B	97	35.953	20.832	3.071	1.00	82.44	N
ATOM	1963	CA	GLU	B	97	34.574	20.804	2.541	1.00	82.95	C
ATOM	1964	CB	GLU	B	97	34.245	19.415	1.978	1.00	82.71	C
ATOM	1965	C	GLU	B	97	33.513	21.250	3.575	1.00	82.95	C
ATOM	1966	O	GLU	B	97	33.406	20.664	4.663	1.00	83.36	O
ATOM	1967	N	ASN	B	98	32.746	22.291	3.233	1.00	81.59	N
ATOM	1968	CA	ASN	B	98	31.794	22.911	4.171	1.00	79.66	C
ATOM	1969	CB	ASN	B	98	32.549	23.709	5.239	1.00	80.02	C
ATOM	1970	C	ASN	B	98	30.731	23.801	3.511	1.00	78.31	C
ATOM	1971	O	ASN	B	98	31.048	24.644	2.660	1.00	77.79	O
ATOM	1972	N	THR	B	99	29.478	23.620	3.932	1.00	76.30	N
ATOM	1973	CA	THR	B	99	28.321	24.312	3.327	1.00	74.52	C
ATOM	1974	CB	THR	B	99	27.334	23.301	2.663	1.00	74.67	C
ATOM	1975	OG1	THR	B	99	27.823	21.957	2.811	1.00	73.98	O
ATOM	1976	CG2	THR	B	99	27.139	23.624	1.182	1.00	73.78	C
ATOM	1977	C	THR	B	99	27.570	25.185	4.363	1.00	72.17	C
ATOM	1978	O	THR	B	99	26.920	24.645	5.274	1.00	72.60	O
ATOM	1979	N	PRO	B	100	27.641	26.530	4.214	1.00	68.26	N
ATOM	1980	CA	PRO	B	100	27.251	27.464	5.286	1.00	65.84	C
ATOM	1981	CB	PRO	B	100	28.052	28.743	4.960	1.00	65.48	C
ATOM	1982	CG	PRO	B	100	28.612	28.545	3.556	1.00	66.33	C
ATOM	1983	CD	PRO	B	100	28.070	27.252	3.005	1.00	68.07	C
ATOM	1984	C	PRO	B	100	25.752	27.753	5.352	1.00	62.59	C
ATOM	1985	O	PRO	B	100	25.240	28.596	4.605	1.00	63.79	O
ATOM	1986	N	LEU	B	101	25.071	27.056	6.259	1.00	59.41	N
ATOM	1987	CA	LEU	B	101	23.617	27.127	6.403	1.00	56.35	C
ATOM	1988	CB	LEU	B	101	23.105	25.985	7.290	1.00	56.25	C
ATOM	1989	CG	LEU	B	101	23.449	24.556	6.871	1.00	53.36	C
ATOM	1990	CD1	LEU	B	101	22.629	23.566	7.659	1.00	57.33	C
ATOM	1991	CD2	LEU	B	101	23.255	24.344	5.374	1.00	48.21	C
ATOM	1992	C	LEU	B	101	23.126	28.455	6.951	1.00	56.12	C
ATOM	1993	O	LEU	B	101	22.025	28.905	6.620	1.00	55.96	O
ATOM	1994	N	LEU	B	102	23.923	29.074	7.812	1.00	54.26	N
ATOM	1995	CA	LEU	B	102	23.641	30.435	8.253	1.00	52.03	C
ATOM	1996	CB	LEU	B	102	23.173	30.459	9.708	1.00	52.13	C
ATOM	1997	CG	LEU	B	102	21.954	29.702	10.235	1.00	50.45	C
ATOM	1998	CD1	LEU	B	102	22.041	29.695	11.719	1.00	55.04	C
ATOM	1999	CD2	LEU	B	102	20.692	30.392	9.827	1.00	60.55	C
ATOM	2000	C	LEU	B	102	24.870	31.323	8.140	1.00	52.59	C
ATOM	2001	O	LEU	B	102	25.984	30.933	8.523	1.00	51.55	O
ATOM	2002	N	ASN	B	103	24.655	32.521	7.621	1.00	53.64	N
ATOM	2003	CA	ASN	B	103	25.600	33.615	7.793	1.00	54.00	C
ATOM	2004	CB	ASN	B	103	25.998	34.252	6.467	1.00	54.78	C
ATOM	2005	CG	ASN	B	103	26.931	35.436	6.665	1.00	58.33	C
ATOM	2006	OD1	ASN	B	103	28.084	35.271	7.084	1.00	58.48	O
ATOM	2007	ND2	ASN	B	103	26.424	36.643	6.399	1.00	45.80	N
ATOM	2008	C	ASN	B	103	25.015	34.670	8.720	1.00	53.18	C
ATOM	2009	O	ASN	B	103	24.442	35.657	8.267	1.00	54.82	O
ATOM	2010	N	CYS	B	104	25.172	34.463	10.023	1.00	52.46	N
ATOM	2011	CA	CYS	B	104	24.649	35.394	11.007	1.00	51.44	C
ATOM	2012	CB	CYS	B	104	24.466	34.700	12.341	1.00	53.41	C
ATOM	2013	SG	CYS	B	104	23.832	33.036	12.178	1.00	49.61	S
ATOM	2014	C	CYS	B	104	25.604	36.556	11.139	1.00	53.20	C
ATOM	2015	O	CYS	B	104	26.565	36.513	11.915	1.00	51.74	O
ATOM	2016	N	ALA	B	105	25.335	37.578	10.338	1.00	52.80	N
ATOM	2017	CA	ALA	B	105	26.121	38.783	10.298	1.00	52.86	C
ATOM	2018	CB	ALA	B	105	27.202	38.669	9.219	1.00	53.20	C
ATOM	2019	C	ALA	B	105	25.188	39.945	10.006	1.00	53.19	C
ATOM	2020	O	ALA	B	105	25.501	40.812	9.184	1.00	54.31	O
ATOM	2021	N	ARG	B	106	24.030	39.929	10.668	1.00	54.23	N
ATOM	2022	CA	ARG	B	106	23.018	40.988	10.559	1.00	53.54	C
ATOM	2023	CB	ARG	B	106	21.984	40.637	9.480	1.00	53.56	C
ATOM	2024	C	ARG	B	106	22.319	41.211	11.900	1.00	53.50	C
ATOM	2025	O	ARG	B	106	21.322	40.545	12.206	1.00	53.50	O
ATOM	2026	N	PRO	B	107	22.847	42.136	12.715	1.00	53.15	N
ATOM	2027	CA	PRO	B	107	22.255	42.466	14.024	1.00	54.11	C
ATOM	2028	CB	PRO	B	107	23.089	43.666	14.488	1.00	55.59	C
ATOM	2029	CG	PRO	B	107	24.428	43.483	13.797	1.00	51.19	C
ATOM	2030	CD	PRO	B	107	24.091	42.894	12.459	1.00	52.06	C
ATOM	2031	C	PRO	B	107	20.745	42.804	14.041	1.00	56.24	C
ATOM	2032	O	PRO	B	107	20.048	42.480	15.012	1.00	57.46	O
ATOM	2033	N	ASP	B	108	20.245	43.423	12.978	1.00	56.84	N
ATOM	2034	CA	ASP	B	108	18.905	44.009	13.004	1.00	56.83	C
ATOM	2035	CB	ASP	B	108	18.933	45.389	12.354	1.00	58.06	C
ATOM	2036	CG	ASP	B	108	17.754	46.242	12.761	1.00	60.68	C
ATOM	2037	OD1	ASP	B	108	17.196	46.004	13.857	1.00	64.10	O
ATOM	2038	OD2	ASP	B	108	17.386	47.154	11.988	1.00	66.86	O
ATOM	2039	C	ASP	B	108	17.823	43.138	12.362	1.00	56.19	C
ATOM	2040	O	ASP	B	108	16.689	43.573	12.151	1.00	53.32	O
ATOM	2041	N	GLN	B	109	18.170	41.887	12.085	1.00	56.39	N
ATOM	2042	CA	GLN	B	109	17.298	41.022	11.324	1.00	55.55	C
ATOM	2043	CB	GLN	B	109	17.632	41.124	9.827	1.00	55.41	C
ATOM	2044	CG	GLN	B	109	17.483	39.837	9.023	1.00	58.46	C
ATOM	2045	CD	GLN	B	109	17.142	40.063	7.561	1.00	61.57	C
ATOM	2046	OE1	GLN	B	109	17.045	41.204	7.089	1.00	66.19	O
ATOM	2047	NE2	GLN	B	109	16.949	38.971	6.831	1.00	64.69	N
ATOM	2048	C	GLN	B	109	17.368	39.593	11.852	1.00	57.37	C
ATOM	2049	O	GLN	B	109	18.452	39.029	12.060	1.00	57.65	O
ATOM	2050	N	ASP	B	110	16.192	39.038	12.100	1.00	56.55	N
ATOM	2051	CA	ASP	B	110	16.039	37.669	12.534	1.00	57.00	C
ATOM	2052	CB	ASP	B	110	14.552	37.452	12.871	1.00	58.93	C
ATOM	2053	CG	ASP	B	110	14.329	36.698	14.179	1.00	61.20	C
ATOM	2054	OD1	ASP	B	110	15.110	36.866	15.149	1.00	64.56	O
ATOM	2055	OD2	ASP	B	110	13.335	35.946	14.236	1.00	62.44	O
ATOM	2056	C	ASP	B	110	16.481	36.773	11.360	1.00	55.17	C
ATOM	2057	O	ASP	B	110	15.835	36.771	10.316	1.00	56.87	O
ATOM	2058	N	VAL	B	111	17.581	36.039	11.523	1.00	51.13	N
ATOM	2059	CA	VAL	B	111	18.119	35.158	10.471	1.00	47.12	C
ATOM	2060	CB	VAL	B	111	19.647	35.389	10.217	1.00	48.87	C
ATOM	2061	CG1	VAL	B	111	20.219	34.352	9.227	1.00	53.14	C
ATOM	2062	CG2	VAL	B	111	19.938	36.818	9.728	1.00	42.07	C
ATOM	2063	C	VAL	B	111	17.921	33.693	10.852	1.00	46.36	C
ATOM	2064	O	VAL	B	111	18.266	33.289	11.975	1.00	42.74	O
ATOM	2065	N	LYS	B	112	17.400	32.898	9.915	1.00	43.12	N
ATOM	2066	CA	LYS	B	112	17.032	31.485	10.162	1.00	43.58	C
ATOM	2067	CB	LYS	B	112	15.546	31.455	10.558	1.00	42.82	C
ATOM	2068	CG	LYS	B	112	14.766	30.199	10.270	1.00	44.74	C
ATOM	2069	CD	LYS	B	112	13.271	30.542	10.259	1.00	48.96	C
ATOM	2070	CE	LYS	B	112	12.691	30.498	11.670	1.00	45.37	C
ATOM	2071	NZ	LYS	B	112	11.754	31.661	11.947	1.00	45.29	N
ATOM	2072	C	LYS	B	112	17.346	30.504	9.003	1.00	42.43	C
ATOM	2073	O	LYS	B	112	17.477	30.921	7.847	1.00	45.59	O
ATOM	2074	N	PHE	B	113	17.513	29.216	9.327	1.00	40.79	N
ATOM	2075	CA	PHE	B	113	17.572	28.148	8.331	1.00	38.79	C
ATOM	2076	CB	PHE	B	113	18.998	27.550	8.153	1.00	39.14	C
ATOM	2077	CG	PHE	B	113	19.104	26.543	6.997	1.00	34.85	C
ATOM	2078	CD1	PHE	B	113	19.549	26.945	5.741	1.00	35.55	C
ATOM	2079	CE1	PHE	B	113	19.640	26.015	4.697	1.00	38.24	C
ATOM	2080	CZ	PHE	B	113	19.250	24.709	4.892	1.00	34.91	C
ATOM	2081	CE2	PHE	B	113	18.807	24.299	6.148	1.00	40.75	C
ATOM	2082	CD2	PHE	B	113	18.737	25.208	7.177	1.00	44.17	C
ATOM	2083	C	PHE	B	113	16.634	27.073	8.800	1.00	39.23	C
ATOM	2084	O	PHE	B	113	16.731	26.593	9.956	1.00	43.15	O
ATOM	2085	N	THR	B	114	15.728	26.686	7.916	1.00	36.48	N
ATOM	2086	CA	THR	B	114	14.768	25.619	8.184	1.00	36.83	C
ATOM	2087	CB	THR	B	114	13.384	25.985	7.687	1.00	40.83	C
ATOM	2088	OG1	THR	B	114	12.968	27.231	8.286	1.00	37.54	O
ATOM	2089	CG2	THR	B	114	12.394	24.877	7.993	1.00	36.72	C
ATOM	2090	C	THR	B	114	15.214	24.313	7.502	1.00	38.84	C
ATOM	2091	O	THR	B	114	15.307	24.201	6.286	1.00	40.09	O
ATOM	2092	N	ILE	B	115	15.501	23.317	8.311	1.00	38.37	N
ATOM	2093	CA	ILE	B	115	15.934	22.042	7.802	1.00	38.31	C
ATOM	2094	CB	ILE	B	115	16.914	21.365	8.790	1.00	38.74	C
ATOM	2095	OG1	ILE	B	115	18.233	22.145	8.874	1.00	40.45	C
ATOM	2096	CD1	ILE	B	115	19.179	21.628	9.988	1.00	41.07	C
ATOM	2097	CG2	ILE	B	115	17.189	19.957	8.376	1.00	37.17	C
ATOM	2098	C	ILE	B	115	14.696	21.197	7.693	1.00	39.26	C
ATOM	2099	O	ILE	B	115	13.905	21.146	8.626	1.00	40.19	O
ATOM	2100	N	LYS	B	116	14.508	20.566	6.539	1.00	38.88	N
ATOM	2101	CA	LYS	B	116	13.586	19.455	6.452	1.00	39.98	C
ATOM	2102	CB	LYS	B	116	12.647	19.601	5.253	1.00	39.37	C
ATOM	2103	CG	LYS	B	116	11.972	18.305	4.805	1.00	40.21	C
ATOM	2104	CD	LYS	B	116	10.761	18.025	5.630	1.00	40.79	C
ATOM	2105	CE	LYS	B	116	9.630	17.361	4.844	1.00	47.35	C
ATOM	2106	NZ	LYS	B	116	10.037	16.252	3.926	1.00	43.81	N
ATOM	2107	C	LYS	B	116	14.408	18.162	6.350	1.00	41.05	C
ATOM	2108	O	LYS	B	116	15.163	17.961	5.393	1.00	40.58	O
ATOM	2109	N	PHE	B	117	14.250	17.299	7.347	1.00	40.29	N
ATOM	2110	CA	PHE	B	117	14.894	15.997	7.368	1.00	40.81	C
ATOM	2111	CB	PHE	B	117	14.958	15.425	8.801	1.00	41.73	C
ATOM	2112	CG	PHE	B	117	15.737	16.291	9.761	1.00	39.87	C
ATOM	2113	CD1	PHE	B	117	15.091	17.297	10.487	1.00	40.27	C
ATOM	2114	CE1	PHE	B	117	15.791	18.118	11.354	1.00	36.48	C
ATOM	2115	CZ	PHE	B	117	17.174	17.971	11.468	1.00	40.12	C
ATOM	2116	CE2	PHE	B	117	17.845	16.976	10.706	1.00	36.80	C
ATOM	2117	CD2	PHE	B	117	17.121	16.151	9.874	1.00	34.89	C
ATOM	2118	C	PHE	B	117	14.109	15.078	6.451	1.00	42.46	C
ATOM	2119	O	PHE	B	117	13.074	14.534	6.839	1.00	42.34	O
ATOM	2120	N	GLN	B	118	14.599	14.956	5.220	1.00	43.34	N
ATOM	2121	CA	GLN	B	118	14.001	14.143	4.168	1.00	42.93	C
ATOM	2122	CB	GLN	B	118	13.223	15.038	3.177	1.00	47.34	C
ATOM	2123	CG	GLN	B	118	14.085	16.077	2.491	1.00	34.74	C
ATOM	2124	CD	GLN	B	118	13.336	16.995	1.531	1.00	41.59	C
ATOM	2125	OE1	GLN	B	118	13.710	18.137	1.385	1.00	41.26	O
ATOM	2126	NE2	GLN	B	118	12.277	16.508	0.896	1.00	37.39	N
ATOM	2127	C	GLN	B	118	15.137	13.401	3.453	1.00	43.86	C
ATOM	2128	O	GLN	B	118	16.281	13.882	3.422	1.00	40.85	O
ATOM	2129	N	GLU	B	119	14.817	12.239	2.873	1.00	45.99	N
ATOM	2130	CA	GLU	B	119	15.833	11.342	2.277	1.00	46.54	C
ATOM	2131	CB	GLU	B	119	15.266	9.924	2.128	1.00	49.19	C
ATOM	2132	CG	GLU	B	119	16.253	8.817	2.513	1.00	54.11	C
ATOM	2133	CD	GLU	B	119	15.932	8.188	3.859	1.00	62.40	C
ATOM	2134	OE1	GLU	B	119	14.732	8.144	4.211	1.00	69.97	O
ATOM	2135	OE2	GLU	B	119	16.864	7.725	4.560	1.00	62.46	O
ATOM	2136	C	GLU	B	119	16.375	11.802	0.913	1.00	45.75	C
ATOM	2137	O	GLU	B	119	17.486	11.447	0.523	1.00	46.08	O
ATOM	2138	N	PHE	B	120	15.579	12.606	0.212	1.00	41.97	N
ATOM	2139	CA	PHE	B	120	15.842	13.014	−1.161	1.00	41.19	C
ATOM	2140	CB	PHE	B	120	15.190	11.988	−2.102	1.00	41.38	C
ATOM	2141	CG	PHE	B	120	15.342	12.284	−3.568	1.00	44.79	C
ATOM	2142	CD1	PHE	B	120	16.433	11.791	−4.276	1.00	46.25	C
ATOM	2143	CE1	PHE	B	120	16.573	12.041	−5.639	1.00	48.01	C
ATOM	2144	CZ	PHE	B	120	15.597	12.780	−6.311	1.00	48.10	C
ATOM	2145	CE2	PHE	B	120	14.491	13.269	−5.614	1.00	48.86	C
ATOM	2146	CD2	PHE	B	120	14.363	13.008	−4.251	1.00	47.10	C
ATOM	2147	C	PHE	B	120	15.235	14.411	−1.339	1.00	38.45	C
ATOM	2148	O	PHE	B	120	14.098	14.642	−0.939	1.00	39.71	O
ATOM	2149	N	SER	B	121	16.001	15.338	−1.908	1.00	38.75	N
ATOM	2150	CA	SER	B	121	15.503	16.687	−2.222	1.00	35.73	C
ATOM	2151	CB	SER	B	121	16.336	17.720	−1.482	1.00	41.04	C
ATOM	2152	OG	SER	B	121	16.075	19.038	−1.979	1.00	32.57	O
ATOM	2153	C	SER	B	121	15.630	16.928	−3.713	1.00	36.73	C
ATOM	2154	O	SER	B	121	16.697	16.644	−4.245	1.00	37.53	O
ATOM	2155	N	PRO	B	122	14.549	17.421	−4.414	1.00	35.00	N
ATOM	2156	CA	PRO	B	122	14.686	17.884	−5.794	1.00	31.41	C
ATOM	2157	CB	PRO	B	122	13.251	18.193	−6.211	1.00	33.87	C
ATOM	2158	CG	PRO	B	122	12.549	18.466	−4.956	1.00	36.13	C
ATOM	2159	CD	PRO	B	122	13.128	17.460	−4.018	1.00	31.71	C
ATOM	2160	C	PRO	B	122	15.605	19.080	−6.037	1.00	34.20	C
ATOM	2161	O	PRO	B	122	15.924	19.376	−7.206	1.00	28.62	O
ATOM	2162	N	ASN	B	123	16.063	19.713	−4.952	1.00	35.06	N
ATOM	2163	CA	ASN	B	123	17.077	20.740	−5.053	1.00	35.87	C
ATOM	2164	CB	ASN	B	123	17.094	21.655	−3.821	1.00	36.31	C
ATOM	2165	CG	ASN	B	123	18.043	22.880	−3.984	1.00	33.87	C
ATOM	2166	OD1	ASN	B	123	18.656	23.093	−5.032	1.00	32.22	O
ATOM	2167	ND2	ASN	B	123	18.121	23.693	−2.943	1.00	35.68	N
ATOM	2168	C	ASN	B	123	18.448	20.112	−5.270	1.00	34.15	C
ATOM	2169	O	ASN	B	123	18.928	19.291	−4.469	1.00	33.65	O
ATOM	2170	N	LEU	B	124	19.039	20.510	−6.383	1.00	33.29	N
ATOM	2171	CA	LEU	B	124	20.394	20.196	−6.723	1.00	37.26	C
ATOM	2172	CB	LEU	B	124	20.804	21.083	−7.895	1.00	35.44	C
ATOM	2173	CG	LEU	B	124	22.203	20.963	−8.484	1.00	40.34	C
ATOM	2174	CD1	LEU	B	124	22.338	19.636	−9.207	1.00	35.24	C
ATOM	2175	CD2	LEU	B	124	22.360	22.114	−9.433	1.00	38.11	C
ATOM	2176	C	LEU	B	124	21.341	20.364	−5.524	1.00	36.68	C
ATOM	2177	O	LEU	B	124	22.267	19.587	−5.378	1.00	38.26	O
ATOM	2178	N	TRP	B	125	21.088	21.354	−4.662	1.00	37.81	N
ATOM	2179	CA	TRP	B	125	21.878	21.556	−3.442	1.00	41.99	C
ATOM	2180	CB	TRP	B	125	22.371	22.993	−3.331	1.00	44.52	C
ATOM	2181	CG	TRP	B	125	23.266	23.394	−4.426	1.00	48.30	C
ATOM	2182	CD1	TRP	B	125	24.609	23.183	−4.507	1.00	48.48	C
ATOM	2183	NE1	TRP	B	125	25.100	23.701	−5.680	1.00	46.89	N
ATOM	2184	CE2	TRP	B	125	24.065	24.261	−6.381	1.00	48.31	C
ATOM	2185	CD2	TRP	B	125	22.892	24.093	−5.611	1.00	48.46	C
ATOM	2186	CE3	TRP	B	125	21.675	24.579	−6.110	1.00	51.01	C
ATOM	2187	CZ3	TRP	B	125	21.674	25.222	−7.336	1.00	47.38	C
ATOM	2188	CH2	TRP	B	125	22.857	25.380	−8.074	1.00	47.99	C
ATOM	2189	CZ2	TRP	B	125	24.062	24.917	−7.611	1.00	47.47	C
ATOM	2190	C	TRP	B	125	21.117	21.240	−2.181	1.00	41.23	C
ATOM	2191	O	TRP	B	125	21.540	21.611	−1.091	1.00	44.51	O
ATOM	2192	N	GLY	B	126	20.007	20.538	−2.321	1.00	40.47	N
ATOM	2193	CA	GLY	B	126	19.175	20.183	−1.183	1.00	40.35	C
ATOM	2194	C	GLY	B	126	19.900	19.357	−0.144	1.00	41.68	C
ATOM	2195	O	GLY	B	126	20.904	18.705	−0.452	1.00	41.73	O
ATOM	2196	N	LEU	B	127	19.384	19.378	1.086	1.00	41.78	N
ATOM	2197	CA	LEU	B	127	19.928	18.578	2.187	1.00	43.54	C
ATOM	2198	CB	LEU	B	127	19.885	19.371	3.502	1.00	45.56	C
ATOM	2199	CG	LEU	B	127	20.829	20.562	3.715	1.00	45.47	C
ATOM	2200	CD1	LEU	B	127	20.761	21.056	5.145	1.00	47.06	C
ATOM	2201	CD2	LEU	B	127	22.269	20.227	3.361	1.00	52.41	C
ATOM	2202	C	LEU	B	127	19.169	17.251	2.317	1.00	46.47	C
ATOM	2203	O	LEU	B	127	17.932	17.223	2.246	1.00	45.51	O
ATOM	2204	N	GLU	B	128	19.914	16.151	2.486	1.00	49.01	N
ATOM	2205	CA	GLU	B	128	19.358	14.785	2.392	1.00	50.26	C
ATOM	2206	CB	GLU	B	128	19.662	14.201	1.002	1.00	50.78	C
ATOM	2207	CG	GLU	B	128	19.339	15.167	−0.175	1.00	52.96	C
ATOM	2208	CD	GLU	B	128	19.395	14.518	−1.561	1.00	52.08	C
ATOM	2209	OE1	GLU	B	128	20.089	13.484	−1.727	1.00	54.11	O
ATOM	2210	OE2	GLU	B	128	18.733	15.050	−2.500	1.00	44.98	O
ATOM	2211	C	GLU	B	128	19.870	13.866	3.541	1.00	51.60	C
ATOM	2212	O	GLU	B	128	21.053	13.901	3.882	1.00	51.94	O
ATOM	2213	N	PHE	B	129	18.984	13.064	4.143	1.00	50.16	N
ATOM	2214	CA	PHE	B	129	19.301	12.410	5.428	1.00	50.35	C
ATOM	2215	CB	PHE	B	129	18.616	13.148	6.579	1.00	49.69	C
ATOM	2216	CG	PHE	B	129	19.000	14.602	6.689	1.00	53.84	C
ATOM	2217	CD1	PHE	B	129	18.143	15.602	6.218	1.00	53.48	C
ATOM	2218	CE1	PHE	B	129	18.497	16.963	6.321	1.00	50.73	C
ATOM	2219	CZ	PHE	B	129	19.718	17.324	6.879	1.00	51.56	C
ATOM	2220	CE2	PHE	B	129	20.589	16.329	7.349	1.00	56.53	C
ATOM	2221	CD2	PHE	B	129	20.223	14.982	7.253	1.00	53.44	C
ATOM	2222	C	PHE	B	129	18.985	10.907	5.487	1.00	52.61	C
ATOM	2223	O	PHE	B	129	17.967	10.449	4.950	1.00	51.12	O
ATOM	2224	N	GLN	B	130	19.849	10.151	6.172	1.00	56.51	N
ATOM	2225	CA	GLN	B	130	19.828	8.674	6.124	1.00	59.82	C
ATOM	2226	CB	GLN	B	130	21.247	8.116	5.889	1.00	60.33	C
ATOM	2227	CG	GLN	B	130	22.020	8.753	4.713	1.00	61.86	C
ATOM	2228	CD	GLN	B	130	23.338	8.053	4.385	1.00	60.72	C
ATOM	2229	OE1	GLN	B	130	23.752	7.113	5.069	1.00	69.64	O
ATOM	2230	NE2	GLN	B	130	23.997	8.508	3.322	1.00	59.67	N
ATOM	2231	C	GLN	B	130	19.170	7.969	7.328	1.00	60.84	C
ATOM	2232	O	GLN	B	130	19.206	8.461	8.465	1.00	59.63	O
ATOM	2233	N	ALA	B	131	18.610	6.790	7.038	1.00	63.58	N
ATOM	2234	CA	ALA	B	131	17.841	5.932	7.965	1.00	64.07	C
ATOM	2235	CB	ALA	B	131	17.808	4.489	7.434	1.00	64.33	C
ATOM	2236	C	ALA	B	131	18.239	5.947	9.453	1.00	63.60	C
ATOM	2237	O	ALA	B	131	17.463	6.390	10.298	1.00	64.85	O
ATOM	2238	N	ASN	B	132	19.426	5.437	9.765	1.00	61.85	N
ATOM	2239	CA	ASN	B	132	19.939	5.450	11.134	1.00	58.11	C
ATOM	2240	CB	ASN	B	132	19.985	4.033	11.716	1.00	57.70	C
ATOM	2241	CG	ASN	B	132	19.258	3.917	13.056	1.00	57.57	C
ATOM	2242	OD1	ASN	B	132	19.863	4.027	14.125	1.00	52.75	O
ATOM	2243	ND2	ASN	B	132	17.953	3.688	12.998	1.00	56.67	N
ATOM	2244	C	ASN	B	132	21.325	6.091	11.097	1.00	56.55	C
ATOM	2245	O	ASN	B	132	22.347	5.409	11.243	1.00	54.32	O
ATOM	2246	N	LYS	B	133	21.343	7.408	10.876	1.00	52.59	N
ATOM	2247	CA	LYS	B	133	22.584	8.143	10.583	1.00	51.69	C
ATOM	2248	CB	LYS	B	133	22.726	8.277	9.055	1.00	52.35	C
ATOM	2249	CG	LYS	B	133	23.788	9.235	8.509	1.00	54.30	C
ATOM	2250	CD	LYS	B	133	25.209	8.685	8.590	1.00	55.71	C
ATOM	2251	CE	LYS	B	133	26.123	9.361	7.560	1.00	56.13	C
ATOM	2252	NZ	LYS	B	133	26.218	10.847	7.729	1.00	55.26	N
ATOM	2253	C	LYS	B	133	22.690	9.507	11.316	1.00	50.35	C
ATOM	2254	O	LYS	B	133	21.680	10.157	11.581	1.00	45.66	O
ATOM	2255	N	ASP	B	134	23.925	9.906	11.646	1.00	50.68	N
ATOM	2256	CA	ASP	B	134	24.219	11.149	12.375	1.00	51.33	C
ATOM	2257	CB	ASP	B	134	25.246	10.914	13.497	1.00	53.85	C
ATOM	2258	CG	ASP	B	134	24.881	9.760	14.403	1.00	54.97	C
ATOM	2259	OD1	ASP	B	134	23.787	9.792	15.001	1.00	61.14	O
ATOM	2260	OD2	ASP	B	134	25.692	8.818	14.521	1.00	63.22	O
ATOM	2261	C	ASP	B	134	24.781	12.214	11.446	1.00	51.63	C
ATOM	2262	O	ASP	B	134	25.579	11.910	10.546	1.00	50.16	O
ATOM	2263	N	TYR	B	135	24.368	13.464	11.678	1.00	51.47	N
ATOM	2264	CA	TYR	B	135	24.844	14.617	10.903	1.00	50.95	C
ATOM	2265	CB	TYR	B	135	23.765	15.107	9.945	1.00	51.81	C
ATOM	2266	CG	TYR	B	135	23.375	14.080	8.901	1.00	53.87	C
ATOM	2267	CD1	TYR	B	135	22.302	13.228	9.120	1.00	55.22	C
ATOM	2268	CE1	TYR	B	135	21.930	12.280	8.175	1.00	55.50	C
ATOM	2269	CZ	TYR	B	135	22.633	12.174	6.991	1.00	55.59	C
ATOM	2270	OH	TYR	B	135	22.241	11.219	6.075	1.00	55.74	O
ATOM	2271	CE2	TYR	B	135	23.716	13.008	6.738	1.00	55.39	C
ATOM	2272	CD2	TYR	B	135	24.082	13.961	7.697	1.00	50.04	C
ATOM	2273	C	TYR	B	135	25.222	15.724	11.857	1.00	50.07	C
ATOM	2274	O	TYR	B	135	24.666	15.811	12.959	1.00	47.79	O
ATOM	2275	N	TYR	B	136	26.169	16.559	11.444	1.00	52.35	N
ATOM	2276	CA	TYR	B	136	26.726	17.566	12.352	1.00	53.64	C
ATOM	2277	CB	TYR	B	136	28.187	17.242	12.691	1.00	56.73	C
ATOM	2278	CG	TYR	B	136	28.423	15.870	13.310	1.00	60.71	C
ATOM	2279	CD1	TYR	B	136	28.328	14.701	12.541	1.00	63.40	C
ATOM	2280	CE1	TYR	B	136	28.547	13.453	13.099	1.00	63.12	C
ATOM	2281	CZ	TYR	B	136	28.892	13.353	14.431	1.00	61.25	C
ATOM	2282	OH	TYR	B	136	29.120	12.116	14.984	1.00	61.58	O
ATOM	2283	CE2	TYR	B	136	29.008	14.494	15.216	1.00	64.20	C
ATOM	2284	CD2	TYR	B	136	28.772	15.743	14.654	1.00	59.76	C
ATOM	2285	C	TYR	B	136	26.636	18.985	11.820	1.00	52.48	C
ATOM	2286	O	TYR	B	136	26.701	19.225	10.613	1.00	52.71	O
ATOM	2287	N	ILE	B	137	26.509	19.926	12.750	1.00	51.25	N
ATOM	2288	CA	ILE	B	137	26.430	21.344	12.443	1.00	48.75	C
ATOM	2289	CB	ILE	B	137	24.975	21.849	12.481	1.00	51.09	C
ATOM	2290	CG1	ILE	B	137	24.223	21.481	11.180	1.00	50.13	C
ATOM	2291	CD1	ILE	B	137	22.704	21.633	11.274	1.00	47.53	C
ATOM	2292	CG2	ILE	B	137	24.941	23.358	12.811	1.00	40.73	C
ATOM	2293	C	ILE	B	137	27.240	22.060	13.510	1.00	48.65	C
ATOM	2294	O	ILE	B	137	26.978	21.897	14.709	1.00	46.02	O
ATOM	2295	N	ILE	B	138	28.208	22.864	13.067	1.00	46.40	N
ATOM	2296	CA	ILE	B	138	29.125	23.546	13.969	1.00	44.96	C
ATOM	2297	CB	ILE	B	138	30.534	22.873	13.957	1.00	46.61	C
ATOM	2298	CG1	ILE	B	138	31.170	22.955	12.558	1.00	44.58	C
ATOM	2299	CD1	ILE	B	138	32.693	22.657	12.515	1.00	36.53	C
ATOM	2300	CG2	ILE	B	138	30.468	21.423	14.466	1.00	48.73	C
ATOM	2301	C	ILE	B	138	29.285	24.999	13.548	1.00	46.45	C
ATOM	2302	O	ILE	B	138	28.681	25.433	12.583	1.00	45.73	O
ATOM	2303	N	SER	B	139	30.093	25.756	14.283	1.00	46.68	N
ATOM	2304	CA	SER	B	139	30.615	27.033	13.767	1.00	50.66	C
ATOM	2305	CB	SER	B	139	29.706	28.215	14.146	1.00	51.05	C
ATOM	2306	OG	SER	B	139	30.290	29.441	13.717	1.00	52.58	O
ATOM	2307	C	SER	B	139	32.023	27.264	14.314	1.00	50.78	C
ATOM	2308	O	SER	B	139	32.239	27.119	15.520	1.00	51.39	O
ATOM	2309	N	THR	B	140	32.964	27.625	13.438	1.00	50.11	N
ATOM	2310	CA	THR	B	140	34.352	27.920	13.864	1.00	54.13	C
ATOM	2311	CB	THR	B	140	35.409	27.282	12.924	1.00	52.12	C
ATOM	2312	OG1	THR	B	140	35.051	27.513	11.560	1.00	51.29	O
ATOM	2313	CG2	THR	B	140	35.493	25.775	13.164	1.00	56.06	C
ATOM	2314	C	THR	B	140	34.629	29.421	14.072	1.00	53.66	C
ATOM	2315	O	THR	B	140	35.762	29.833	14.319	1.00	54.84	O
ATOM	2316	N	SER	B	141	33.568	30.220	13.978	1.00	53.68	N
ATOM	2317	CA	SER	B	141	33.640	31.661	14.128	1.00	52.39	C
ATOM	2318	CB	SER	B	141	32.400	32.311	13.503	1.00	54.33	C
ATOM	2319	OG	SER	B	141	32.157	31.779	12.205	1.00	47.17	O
ATOM	2320	C	SER	B	141	33.722	31.968	15.609	1.00	54.75	C
ATOM	2321	O	SER	B	141	33.090	31.288	16.428	1.00	57.16	O
ATOM	2322	N	ASN	B	142	34.509	32.969	15.975	1.00	52.29	N
ATOM	2323	CA	ASN	B	142	34.741	33.204	17.392	1.00	51.16	C
ATOM	2324	CB	ASN	B	142	36.220	33.539	17.661	1.00	50.07	C
ATOM	2325	CG	ASN	B	142	36.473	34.996	17.869	1.00	55.16	C
ATOM	2326	OD1	ASN	B	142	36.678	35.743	16.915	1.00	61.85	O
ATOM	2327	ND2	ASN	B	142	36.509	35.414	19.136	1.00	51.49	N
ATOM	2328	C	ASN	B	142	33.736	34.157	18.063	1.00	51.20	C
ATOM	2329	O	ASN	B	142	33.895	34.521	19.238	1.00	51.08	O
ATOM	2330	N	GLY	B	143	32.719	34.570	17.299	1.00	50.47	N
ATOM	2331	CA	GLY	B	143	31.643	35.424	17.795	1.00	50.52	C
ATOM	2332	C	GLY	B	143	31.764	36.925	17.590	1.00	51.28	C
ATOM	2333	O	GLY	B	143	30.825	37.669	17.903	1.00	50.26	O
ATOM	2334	N	SER	B	144	32.898	37.376	17.056	1.00	53.07	N
ATOM	2335	CA	SER	B	144	33.265	38.799	17.086	1.00	55.66	C
ATOM	2336	CB	SER	B	144	34.725	38.939	17.504	1.00	55.64	C
ATOM	2337	OG	SER	B	144	35.557	38.164	16.662	1.00	55.12	O
ATOM	2338	C	SER	B	144	33.037	39.605	15.805	1.00	57.74	C
ATOM	2339	O	SER	B	144	32.699	40.803	15.873	1.00	58.24	O
ATOM	2340	N	LEU	B	145	33.237	38.964	14.651	1.00	58.51	N
ATOM	2341	CA	LEU	B	145	33.204	39.638	13.329	1.00	59.93	C
ATOM	2342	CB	LEU	B	145	32.877	41.138	13.436	1.00	59.99	C
ATOM	2343	CG	LEU	B	145	32.790	42.022	12.187	1.00	58.59	C
ATOM	2344	CD1	LEU	B	145	31.717	41.539	11.235	1.00	56.85	C
ATOM	2345	CD2	LEU	B	145	32.557	43.492	12.576	1.00	60.03	C
ATOM	2346	C	LEU	B	145	34.515	39.443	12.583	1.00	60.20	C
ATOM	2347	O	LEU	B	145	34.543	38.819	11.524	1.00	60.65	O
ATOM	2348	N	GLU	B	146	35.604	39.974	13.134	1.00	61.34	N
ATOM	2349	CA	GLU	B	146	36.928	39.772	12.538	1.00	62.60	C
ATOM	2350	CB	GLU	B	146	37.998	40.590	13.266	1.00	61.85	C
ATOM	2351	CG	GLU	B	146	38.123	42.030	12.766	1.00	64.43	C
ATOM	2352	CD	GLU	B	146	37.060	42.965	13.338	1.00	67.41	C
ATOM	2353	OE1	GLU	B	146	37.408	43.791	14.212	1.00	68.51	O
ATOM	2354	OE2	GLU	B	146	35.884	42.880	12.916	1.00	67.92	O
ATOM	2355	C	GLU	B	146	37.292	38.287	12.520	1.00	62.26	C
ATOM	2356	O	GLU	B	146	38.134	37.850	11.723	1.00	62.28	O
ATOM	2357	N	GLY	B	147	36.635	37.522	13.393	1.00	60.53	N
ATOM	2358	CA	GLY	B	147	36.785	36.077	13.424	1.00	58.38	C
ATOM	2359	C	GLY	B	147	35.703	35.336	12.662	1.00	57.21	C
ATOM	2360	O	GLY	B	147	35.808	34.128	12.464	1.00	56.76	O
ATOM	2361	N	LEU	B	148	34.675	36.069	12.229	1.00	57.52	N
ATOM	2362	CA	LEU	B	148	33.487	35.517	11.552	1.00	55.98	C
ATOM	2363	CB	LEU	B	148	32.674	36.661	10.914	1.00	56.73	C
ATOM	2364	OG	LEU	B	148	31.380	36.448	10.111	1.00	54.78	C
ATOM	2365	CD1	LEU	B	148	30.401	35.463	10.759	1.00	47.97	C
ATOM	2366	CD2	LEU	B	148	30.710	37.791	9.842	1.00	53.84	C
ATOM	2367	C	LEU	B	148	33.817	34.432	10.524	1.00	56.07	C
ATOM	2368	O	LEU	B	148	33.181	33.388	10.489	1.00	55.33	O
ATOM	2369	N	ASP	B	149	34.832	34.674	9.704	1.00	57.37	N
ATOM	2370	CA	ASP	B	149	35.228	33.712	8.675	1.00	57.71	C
ATOM	2371	CB	ASP	B	149	35.433	34.427	7.333	1.00	58.37	C
ATOM	2372	CG	ASP	B	149	35.787	35.901	7.504	1.00	59.20	C
ATOM	2373	OD1	ASP	B	149	36.457	36.258	8.508	1.00	58.54	O
ATOM	2374	OD2	ASP	B	149	35.383	36.700	6.635	1.00	60.63	O
ATOM	2375	C	ASP	B	149	36.466	32.893	9.080	1.00	58.10	C
ATOM	2376	O	ASP	B	149	37.213	32.410	8.220	1.00	57.61	O
ATOM	2377	N	ASN	B	150	36.680	32.742	10.390	1.00	56.91	N
ATOM	2378	CA	ASN	B	150	37.712	31.834	10.874	1.00	56.84	C
ATOM	2379	CB	ASN	B	150	37.912	31.931	12.396	1.00	55.39	C
ATOM	2380	CG	ASN	B	150	38.659	33.192	12.799	1.00	54.03	C
ATOM	2381	OD1	ASN	B	150	39.183	33.914	11.946	1.00	53.83	O
ATOM	2382	ND2	ASN	B	150	38.698	33.473	14.099	1.00	56.00	N
ATOM	2383	C	ASN	B	150	37.367	30.430	10.447	1.00	57.87	C
ATOM	2384	O	ASN	B	150	36.336	29.880	10.840	1.00	58.19	O
ATOM	2385	N	GLN	B	151	38.222	29.876	9.599	1.00	57.57	N
ATOM	2386	CA	GLN	B	151	38.005	28.551	9.045	1.00	58.65	C
ATOM	2387	CB	GLN	B	151	38.760	28.417	7.716	1.00	59.29	C
ATOM	2388	CG	GLN	B	151	38.337	29.449	6.648	1.00	55.33	C
ATOM	2389	CD	GLN	B	151	37.597	28.832	5.475	1.00	61.37	C
ATOM	2390	OE1	GLN	B	151	38.109	27.918	4.824	1.00	63.82	O
ATOM	2391	NE2	GLN	B	151	36.394	29.340	5.184	1.00	50.29	N
ATOM	2392	C	GLN	B	151	38.365	27.428	10.036	1.00	59.36	C
ATOM	2393	O	GLN	B	151	38.176	26.237	9.730	1.00	58.04	O
ATOM	2394	N	GLU	B	152	38.862	27.810	11.223	1.00	59.43	N
ATOM	2395	CA	GLU	B	152	39.181	26.833	12.272	1.00	60.25	C
ATOM	2396	CB	GLU	B	152	40.602	26.256	12.078	1.00	61.48	C
ATOM	2397	CG	GLU	B	152	41.747	27.124	12.625	1.00	66.64	C
ATOM	2398	CD	GLU	B	152	42.467	27.885	11.504	1.00	68.50	C
ATOM	2399	OE1	GLU	B	152	43.153	27.227	10.670	1.00	70.55	O
ATOM	2400	OE2	GLU	B	152	42.360	29.142	11.471	1.00	70.22	O
ATOM	2401	C	GLU	B	152	38.979	27.296	13.735	1.00	59.91	C
ATOM	2402	O	GLU	B	152	39.092	28.489	14.055	1.00	57.60	O
ATOM	2403	N	GLY	B	153	38.670	26.328	14.603	1.00	59.88	N
ATOM	2404	CA	GLY	B	153	38.611	26.530	16.052	1.00	61.08	C
ATOM	2405	C	GLY	B	153	37.320	27.083	16.638	1.00	62.49	C
ATOM	2406	O	GLY	B	153	36.298	26.389	16.676	1.00	61.87	O
ATOM	2407	N	GLY	B	154	37.397	28.340	17.090	1.00	63.05	N
ATOM	2408	CA	GLY	B	154	36.402	29.036	17.933	1.00	62.98	C
ATOM	2409	C	GLY	B	154	34.981	28.521	18.070	1.00	62.97	C
ATOM	2410	O	GLY	B	154	34.373	28.096	17.087	1.00	64.66	O
ATOM	2411	N	VAL	B	155	34.452	28.571	19.295	1.00	61.10	N
ATOM	2412	CA	VAL	B	155	33.051	28.238	19.574	1.00	57.44	C
ATOM	2413	CB	VAL	B	155	32.086	29.191	18.770	1.00	59.75	C
ATOM	2414	CG1	VAL	B	155	30.869	28.479	18.148	1.00	53.52	C
ATOM	2415	CG2	VAL	B	155	31.694	30.398	19.640	1.00	59.92	C
ATOM	2416	C	VAL	B	155	32.774	26.725	19.473	1.00	56.32	C
ATOM	2417	O	VAL	B	155	32.358	26.102	20.454	1.00	55.79	O
ATOM	2418	N	CYS	B	156	33.067	26.126	18.319	1.00	54.93	N
ATOM	2419	CA	CYS	B	156	33.049	24.667	18.173	1.00	54.61	C
ATOM	2420	CB	CYS	B	156	33.494	24.270	16.754	1.00	52.18	C
ATOM	2421	SG	CYS	B	156	33.580	22.483	16.410	1.00	54.42	S
ATOM	2422	C	CYS	B	156	33.909	23.990	19.278	1.00	54.64	C
ATOM	2423	O	CYS	B	156	33.407	23.164	20.052	1.00	54.63	O
ATOM	2424	N	GLN	B	157	35.187	24.360	19.371	1.00	55.54	N
ATOM	2425	CA	GLN	B	157	36.065	23.825	20.426	1.00	56.56	C
ATOM	2426	CB	GLN	B	157	37.535	23.863	19.983	1.00	56.95	C
ATOM	2427	C	GLN	B	157	35.892	24.528	21.791	1.00	56.30	C
ATOM	2428	O	GLN	B	157	35.845	23.877	22.843	1.00	57.99	O
ATOM	2429	N	THR	B	158	35.780	25.856	21.755	1.00	54.56	N
ATOM	2430	CA	THR	B	158	35.832	26.703	22.947	1.00	51.87	C
ATOM	2431	CB	THR	B	158	36.082	28.197	22.528	1.00	53.75	C
ATOM	2432	OG1	THR	B	158	37.496	28.431	22.411	1.00	49.36	O
ATOM	2433	CG2	THR	B	158	35.470	29.201	23.512	1.00	52.72	C
ATOM	2434	C	THR	B	158	34.632	26.566	23.900	1.00	51.82	C
ATOM	2435	O	THR	B	158	34.800	26.579	25.128	1.00	52.22	O
ATOM	2436	N	ARG	B	159	33.441	26.403	23.335	1.00	49.63	N
ATOM	2437	CA	ARG	B	159	32.187	26.495	24.078	1.00	49.75	C
ATOM	2438	CB	ARG	B	159	31.544	27.873	23.850	1.00	47.71	C
ATOM	2439	C	ARG	B	159	31.223	25.388	23.657	1.00	50.64	C
ATOM	2440	O	ARG	B	159	30.016	25.478	23.906	1.00	52.26	O
ATOM	2441	N	ALA	B	160	31.780	24.338	23.045	1.00	49.93	N
ATOM	2442	CA	ALA	B	160	31.031	23.199	22.492	1.00	48.16	C
ATOM	2443	CB	ALA	B	160	30.681	22.213	23.589	1.00	47.09	C
ATOM	2444	C	ALA	B	160	29.781	23.593	21.693	1.00	47.13	C
ATOM	2445	O	ALA	B	160	28.729	22.967	21.837	1.00	46.20	O
ATOM	2446	N	MET	B	161	29.897	24.650	20.888	1.00	48.64	N
ATOM	2447	CA	MET	B	161	28.791	25.123	20.060	1.00	50.67	C
ATOM	2448	CB	MET	B	161	28.928	26.603	19.706	1.00	52.39	C
ATOM	2449	CG	MET	B	161	28.155	27.506	20.613	1.00	51.45	C
ATOM	2450	SD	MET	B	161	27.427	28.867	19.687	1.00	55.07	S
ATOM	2451	CE	MET	B	161	26.010	29.168	20.740	1.00	54.49	C
ATOM	2452	C	MET	B	161	28.658	24.300	18.803	1.00	49.34	C
ATOM	2453	O	MET	B	161	29.151	24.659	17.730	1.00	48.03	O
ATOM	2454	N	LYS	B	162	27.994	23.170	18.953	1.00	49.25	N
ATOM	2455	CA	LYS	B	162	27.692	22.303	17.820	1.00	48.55	C
ATOM	2456	CB	LYS	B	162	28.860	21.354	17.556	1.00	51.62	C
ATOM	2457	CG	LYS	B	162	29.575	20.893	18.800	1.00	49.28	C
ATOM	2458	CD	LYS	B	162	31.087	20.929	18.634	1.00	50.58	C
ATOM	2459	CE	LYS	B	162	31.753	20.166	19.772	1.00	50.05	C
ATOM	2460	NZ	LYS	B	162	33.254	20.284	19.818	1.00	49.37	N
ATOM	2461	C	LYS	B	162	26.373	21.547	18.060	1.00	49.72	C
ATOM	2462	O	LYS	B	162	25.916	21.410	19.222	1.00	43.36	O
ATOM	2463	N	ILE	B	163	25.736	21.121	16.963	1.00	47.99	N
ATOM	2464	CA	ILE	B	163	24.568	20.251	17.040	1.00	47.17	C
ATOM	2465	CB	ILE	B	163	23.306	20.835	16.329	1.00	46.99	C
ATOM	2466	CG1	ILE	B	163	22.952	22.213	16.880	1.00	46.43	C
ATOM	2467	CD1	ILE	B	163	21.965	22.944	16.019	1.00	56.53	C
ATOM	2468	CG2	ILE	B	163	22.082	19.898	16.490	1.00	43.12	C
ATOM	2469	C	ILE	B	163	24.929	18.931	16.392	1.00	47.16	C
ATOM	2470	O	ILE	B	163	25.505	18.905	15.299	1.00	47.77	O
ATOM	2471	N	LEU	B	164	24.586	17.844	17.085	1.00	47.94	N
ATOM	2472	CA	LEU	B	164	24.639	16.492	16.538	1.00	47.40	C
ATOM	2473	CB	LEU	B	164	25.458	15.602	17.485	1.00	48.90	C
ATOM	2474	CG	LEU	B	164	25.515	14.084	17.312	1.00	48.11	C
ATOM	2475	CD1	LEU	B	164	25.891	13.674	15.901	1.00	52.59	C
ATOM	2476	CD2	LEU	B	164	26.497	13.532	18.324	1.00	46.10	C
ATOM	2477	C	LEU	B	164	23.210	15.947	16.335	1.00	48.56	C
ATOM	2478	O	LEU	B	164	22.455	15.805	17.301	1.00	47.48	O
ATOM	2479	N	MET	B	165	22.836	15.666	15.078	1.00	49.17	N
ATOM	2480	CA	MET	B	165	21.500	15.120	14.757	1.00	48.85	C
ATOM	2481	CB	MET	B	165	20.840	15.899	13.620	1.00	48.68	C
ATOM	2482	CG	MET	B	165	20.442	17.324	14.038	1.00	51.96	C
ATOM	2483	SD	MET	B	165	20.732	18.576	12.780	1.00	52.67	S
ATOM	2484	CE	MET	B	165	22.520	18.375	12.593	1.00	54.06	C
ATOM	2485	C	MET	B	165	21.509	13.624	14.460	1.00	47.92	C
ATOM	2486	O	MET	B	165	22.112	13.162	13.481	1.00	43.94	O
ATOM	2487	N	LYS	B	166	20.820	12.893	15.332	1.00	49.57	N
ATOM	2488	CA	LYS	B	166	20.791	11.437	15.337	1.00	50.86	C
ATOM	2489	CB	LYS	B	166	21.118	10.881	16.748	1.00	50.14	C
ATOM	2490	CG	LYS	B	166	22.499	11.269	17.311	1.00	44.29	C
ATOM	2491	CD	LYS	B	166	22.993	10.265	18.367	1.00	51.13	C
ATOM	2492	CE	LYS	B	166	24.398	9.728	18.020	1.00	44.96	C
ATOM	2493	NZ	LYS	B	166	25.262	9.450	19.224	1.00	51.45	N
ATOM	2494	C	LYS	B	166	19.437	10.891	14.869	1.00	52.27	C
ATOM	2495	O	LYS	B	166	18.388	11.185	15.452	1.00	49.95	O
ATOM	2496	N	VAL	B	167	19.466	10.116	13.793	1.00	53.68	N
ATOM	2497	CA	VAL	B	167	18.484	9.043	13.659	1.00	55.69	C
ATOM	2498	CB	VAL	B	167	17.754	8.987	12.300	1.00	53.78	C
ATOM	2499	CG1	VAL	B	167	16.393	8.309	12.485	1.00	51.87	C
ATOM	2500	CG2	VAL	B	167	17.564	10.378	11.706	1.00	60.81	C
ATOM	2501	C	VAL	B	167	19.221	7.728	13.947	1.00	56.53	C
ATOM	2502	O	VAL	B	167	20.288	7.731	14.582	1.00	55.95	O
ATOM	2503	O	HOH	C	1	−1.068	19.700	−2.247	1.00	20.00	O
ATOM	2504	O	HOH	D	2	15.644	38.458	−11.327	1.00	20.00	O
ATOM	2505	O	HOH	D	3	−8.095	49.449	−9.306	1.00	20.00	O
ATOM	2506	O	HOH	D	4	14.879	14.522	19.283	1.00	20.00	O
ATOM	2507	O	HOH	D	5	19.086	43.782	7.312	1.00	20.00	O
ATOM	2508	O	HOH	D	6	3.762	36.483	−0.689	1.00	20.00	O
ATOM	2509	O	HOH	D	7	5.977	28.240	−23.712	1.00	20.00	O
ATOM	2510	O	HOH	D	9	38.280	30.933	15.129	1.00	20.00	O
ATOM	2511	O	HOH	D	10	−2.614	8.973	−12.882	1.00	20.00	O
ATOM	2512	O	HOH	D	11	33.557	12.755	6.451	1.00	20.00	O
ATOM	2513	O	HOH	D	12	13.880	42.897	11.851	1.00	20.00	O
ATOM	2514	O	HOH	D	13	19.942	29.901	−7.927	1.00	20.00	O
ATOM	2515	O	HOH	D	14	20.613	48.185	26.172	1.00	20.00	O
ATOM	2516	O	HOH	D	15	23.384	36.996	17.915	1.00	20.00	O
ATOM	2517	O	HOH	D	16	12.029	8.173	11.014	1.00	20.00	O
ATOM	2518	O	HOH	D	18	17.554	21.123	−23.737	1.00	20.00	O
ATOM	2519	O	HOH	D	19	34.755	13.969	18.956	1.00	20.00	O
ATOM	2520	O	HOH	D	20	19.454	17.871	−19.578	1.00	20.00	O
ATOM	2521	O	HOH	D	21	16.241	30.564	5.560	1.00	20.00	O
ATOM	2522	O	HOH	D	22	4.906	11.442	0.110	1.00	20.00	O
ATOM	2523	O	HOH	D	23	0.407	21.483	−3.061	1.00	20.00	O
ATOM	2524	O	HOH	D	24	11.613	15.180	−2.107	1.00	20.00	O
ATOM	2525	O	HOH	D	25	3.322	26.535	2.926	1.00	20.00	O
ATOM	2526	O	HOH	D	26	0.515	33.846	2.133	1.00	20.00	O
ATOM	2527	O	HOH	D	27	20.755	10.411	1.428	1.00	20.00	O
ATOM	2528	O	HOH	D	28	17.637	11.370	−10.183	1.00	20.00	O
ATOM	2529	O	HOH	D	29	25.321	5.436	7.341	1.00	20.00	O
ATOM	2530	O	HOH	D	30	12.205	9.020	−7.002	1.00	20.00	O
ATOM	2531	O	HOH	D	31	10.319	15.291	−12.878	1.00	20.00	O
ATOM	2532	O	HOH	D	32	13.474	26.530	21.387	1.00	20.00	O
ATOM	2533	O	HOH	D	33	−5.385	36.132	3.825	1.00	20.00	O
ATOM	2534	O	HOH	D	34	−12.238	40.692	−6.393	1.00	20.00	O
ATOM	2535	O	HOH	D	35	−7.910	35.441	3.507	1.00	20.00	O
ATOM	2536	O	HOH	D	36	16.595	21.733	4.395	1.00	20.00	O
ATOM	2537	O	HOH	D	37	6.286	16.055	−2.458	1.00	20.00	O
ATOM	2538	O	HOH	D	38	5.079	15.735	−7.772	1.00	20.00	O
ATOM	2539	O	HOH	D	39	0.584	7.759	−10.414	1.00	20.00	O
ATOM	2540	O	HOH	D	40	11.416	24.606	13.912	1.00	20.00	O
ATOM	2541	O	HOH	D	43	9.303	12.604	−3.017	1.00	20.00	O
ATOM	2542	O	HOH	D	45	28.991	19.384	1.268	1.00	20.00	O
ATOM	2543	O	HOH	D	46	21.356	43.725	10.404	1.00	20.00	O
ATOM	2544	O	HOH	D	49	−12.300	34.162	−0.864	1.00	20.00	O
END

TABLE 2
Crystallographic Statistics for the EphB4-ephrinB2 Complex
Resolution (Å)1          20-2.0 (2.1-2.0)
Wavelength (Å)           0.98
Space Group              P41
Unit Cell Dimensions (Å) a = b = 81.09 81.09 c = 50.95
Completeness (%)         99.6 (99.9)
Rsym (%)2                3.9 (20.8)
l/σ                      4.8
Mean Redundancy          4.7
No. Reflections          19,785
Rcryst (%)3              22.6 (26.5)
Rfree (%)4               29.5 (30.0)
R.m.s. deviations
Bond length (Å)          0.02
Bond angle (°)           1.7
Average B factor (Å2)    56.6
Number of atoms
Protein                  4,992
1Number in parentheses is for the highest shell.
2Rsym = Σ|I − <I>|/ΣI, where I is the observed intensity and <I> is the average intensity of multiple symmetry-related observations of that reflection.
3Rcryst = Σ||Fobs| − |Fcalc||/Σ|Fobs|, where Fobs and Fcalc are the observed and calculated structure factors. Rsym = Σ|I − <I>|/ΣI, where I is the observed intensity and <I> is the average intensity of multiple symmetry-related observations of that reflection.
4Rfree = Σ||Fobs| − |Fcalc||/Σ|Fobs| for 10% of the data not used at any stage of structural refinement.

TABLE 3
Effects of EphB4 mutation on binding to Alexa-532-TNYL-RAW
EphB4 mutant  Kd, nM
WT            5 ± 0.9
L95R          ND*
T147F         25 ± 5.6
R148S         4.5 ± 0.7
K149Q         23 ± 8
R150V         6.1 ± 0.8
RKR148-150SQV 21 ± 6
A186S         16 ± 4
*FP window is not significant to accurately determine Kd

TABLE 4
Binding of peptide (TNYL-RAW) and human ephrinB2 to the human EphB4
ephrin-binding domain and EphB4 mutants. Experiments were performed at
25° C. in 50 mM Tris pH 7.8, 150 mM NaCl, 1 mM CaCl2.
All values represent the average of at least two experiments.
		Kd	ΔG	ΔH	TΔS
Receptor	Ligand	(nM)	(kcal mol−1)	(kcal mol−1)	(kcal mol−1)
EphB4 (wt)	ephrinB2	40 ± 20	−10.2 ± 0.3	3.3 ± 0.1	13.4 ± 0.4
EphB4	ephrinB2	20 ± 10	−10.6 ± 0.4	3.7 ± 0.2	14.4 ± 0.3
(K149Q)
EphB4	ephrinB2	1900 ± 1100	−7.8 ± 0.3	5.2 ± 0.7	13.0 ± 0.8
(L95R)
EphB4 (wt)	TNYL-RAW	71 ± 14	−9.8 ± 0.1	−14.7 ± 0.2	−4.9 ± 0.2
EphB4	TNYL-RAW	160 ± 120	−9.4 ± 0.5	−12.5 ± 1.2	−3.2 ± 1.3
(K149Q)
EphB4	TNYL-RAW	35900 ± 5000	−6.1 ± 0.1	−12.0 ± 0.3	−5.8 ± 0.4
(L95R)

EXAMPLES

Aspects of the present teachings may be further understood in light of the following examples, which should not be construed as limiting the scope of the present teachings in any way.

Example 1

Construct Design, Expression and Purification of EphB4

Twelve sequential 4 amino acid truncations in human EphB4 were designed based on EphB4-EphB2 sequence alignment in the region C-terminal to the last β-strand in the EphB2 structure. The resulting fragments were cloned into the insect cell expression vector pBAC6 (Novagen, Wis.) under control of the heterologous GP64 signal peptide and containing a N-terminal six histidine tag. Constructs were sequence verified, and baculovirus was generated using homologous recombination into Sapphire Baculovirus DNA (Orbigen, Calif.) using the manufacturers protocol. After 3 rounds of viral amplification, a small scale expression screen was conducted for all constructs in both Sf9 and Hi5 insect cells. Briefly, 5×10⁶ cells were infected with baculovirus at an MOI of 2 in 38 mm tissue culture dishes; cells were harvested at 48 hours post infection and supernatant containing secreted EphB4 was concentrated 10-fold and buffer exchanged into 50 mM Tris pH 7.8, 400 mM NaCl, and 5 mM imidazole using an Amicon Ultra 5K concentrator (Millipore, MS). The secreted protein was bound to Ni-NTA magnetic beads (Qiagen, CA), washed with 50 mM Tris pH 7.8, 400 mM NaCl, 20 mM Imidazole buffer and eluted with 50 mM Tris pH 7.8, 400 mM NaCl, 250 mM Imidazole. Based on analysis of immobilized metal affinity chromatography (IMAC) elutes, the EphB4 (17-196) construct was identified as the highest expressor at ˜6 mg/L in Hi5 insect cells. Large scale expression was conducted using Wave Bioreactors (Wave Biotech LLC, NJ) at a MOI of 2 for 48 hours in Hi5 insect cells. Media containing secreted EphB4 was concentrated and buffer exchanged using a Hydrosart Crossflow filter (Sartorius, NY). Following IMAC purification on ProBond resin (Invitrogen, CA) as described above, EphB4 was concentrated to 5 mg/ml and loaded on a Superdex 75 16/60 column (GE HealthCare, N.Y.). A small amount of aggregated material was removed by preparative size exclusion chromatography, while most of the sample eluted in a single peak corresponding to an EphB4 (17-196) monomer. The complete removal of the GP64 secretion sequence and protein identity were confirmed by MALDI analysis.

The wtEphB4 construct was used as a template for the generation of site specific mutants. The human ephrinB2 (extracellular domain; residues 25-187) was designed based on the previously published EphB2-ephrinB2 structure and cloned into a modified pFastBac1 vector containing a GP67 leader peptide. Recombinant baculovirus was generated using the Bac-to-Bac system (Invitrogen, CA). Briefly, large scale expression of ephrinB2 was carried out using Wave Bioreactors on a 5 L scale at an MOI of 5 for 48 hr. resulting in 10 mg of ephrinB2 per liter of Hi-5 insect cells (Invitrogen, CA). Media containing secreted ephrinB2 protein was concentrated and buffer exchanged using a Hydrostart Crossflow Filter (Sartorius Edgewood, N.Y.). The ligand was purified by immobilized metal affinity chromatography (IMAC), and cleaved overnight with TEV protease. Material was further re-purified by IMAC chromatography to remove the protease and an N-terminal fragment containing the histidine tag. The EphB4-ephrinB2 complex was formed with a 1.5-fold molar excess of ephrinB2 overnight at 4° C. in buffer containing 50 mM Tris, pH 7.8, 100 mM NaCl, and 10 mM Imidazole. The complex was purified by IMAC chromatography, followed by size exclusion chromatography to remove trace aggregates (Phenomenex S2000).

Example 2

Crystallization, Data Collection, and Structure Solution

The EphB4-ephrinB2 complex was concentrated to 20 mg/mL and crystallized by sitting drop vapor diffusion at 20° C. against a precipitant of 2.2 M ammonium sulfate and 100 mM tris, pH 7.8. Crystals formed in the P4₁ spacegroup and contained one monomer of receptor and one monomer of ligand in the asymmetric unit. Data were collected at the Advance Photon Source (Argonne, IL) on beamline GM/CA-CAT. Images were processed and reduced using HKL2000 (31). The structure was solved by molecular replacement with MolRep (CCP4i), using the EphB2-ephrinB2 structure (PDB: 1 KGY) as a search model (10,32). The structure was refined by a rigid body refinement, followed by model building in 0 and iterative refinements with refmac (32,33). The structure exhibits good geometry with no Ramachandran outliers.

Example 3

Isothermal Titration Calorimetry

All mutants and ligands were dialyzed into buffer containing 50 mM Tris-Cl (pH 7.8), 150 mM NaCl, and 1 mM CaCl₂ prior to use in isothermal titration calorimetry (ITC) experiments. All experiments were performed with a Microcal MCS ITC at 25° C. Titrations were completed as described in Example 4. EphB4 (wild-type or mutant) was present in the sample cell at a concentration of 12 to 15 μM and the injection syringe contained either 127 μM ephrinB2 or 200 μM TNYL-RAW. Titrations of TNYL-RAW with the L95R mutant of EphB4 were performed with 2 mM TNYL-RAW in the injection syringe and 15 μM EphB4 (L95R) in the sample cell. Data for these titrations were fit assuming a stoichiometry of 1 and at least 60% saturation at the final peptide concentration as described (19,34).

Example 4

Isothermal titration calorimetry and ELISA experiments: EphB4 and ephrin-B2 were either dialyzed or buffer exchanged into 50 mM Tris-Cl (pH 7.8 at 25° C.), 150 mM NaCl, 1 mM CaCl₂, prior to use in calorimetry experiments. Peptides were dissolved into the same buffer used for the dialysis of EphB4. The concentration of EphB4, ephrin-B2 and the peptides was determined by measuring the A₂₈₀ and using the theoretical extinction coefficient (Gill and von Hippel, 1989). ITC experiments were performed with a Microcal MCS ITC at 25° C. Following an initial injection of 2 μl, titrations were performed by making 20 13 μl injections of peptide into EphB4 in the sample cell to produce an approximate final 2:1 ratio of injectant to sample in the cell. For most titrations the sample cell contained 15 μM EphB4 and the injection syringe contained a 200 μM solution of the peptide. Titrations with ephrin-B2 contained 13 μM EphB4 in the sample cell and 290 μM ephrin-B2 in the syringe. Prior to loading the sample cell, EphB4 was centrifuged at 18,000 g for 5 min at 4° C. to remove aggregates and degassed for 5 minutes at room temperature. Corrections for heats of dilution for the peptides and ephrin-B2 were determined by performing titrations of peptide or ephrin-B2 solutions into buffer. Dilution data were fit to a line and subtracted from the corresponding titration data. Titration data were analyzed using Origin ITC software (Version 5.0, Microcal Software Inc.) and curves were fit to a single binding site model (Wiseman et al., 1989). The low affinity of the TNYL peptide and the limited availability of EphB4 (17-196) precluded accurate determination of the K_d for this interaction by ITC. A lower limit for the binding constant was determined by performing a titration in which the sample cell contained 30 μM EphB4 and the injection syringe contained a 1.45 mM solution of the peptide, producing a final ratio of peptide to EphB4 of 10:1. The data was fit assuming a stoichiometry of 1 and at least 60% saturation of binding at the final peptide concentration (Turnbull and Daranas, 2003).

The ability of peptides to compete the binding of mouse ephrin-B2 alkaline phosphatase to immobilized mouse EphB4-Fc-His (R&D Systems) was measured by ELISA as previously described (Koolpe et al., 2005).

Example 5

This Example illustrates fluorescence polarization (FP) assays using a fluorescently-labeled reporter peptide to measure binding of various ligands to the EphB4-LBD.

We have evaluated TMR and Alexa-532 labeled peptides, and experimentally confirmed the preference of Alexa-532-TNYL-RAW peptide for the assay because of the better dynamic range. We have also evaluated mutants predicted to have altered binding affinity to the TNYL-RAW peptide based on structural observations. The dose-response curve in FIG. 6A shows the wild-type EphB4 and EphB4 K149Q mutant signal upon binding to labeled TNYL-RAW peptide. AK149Q mutant has a greater dynamic range and slightly lower affinity for the labeled peptide than wtEphB4. In competition experiments, the affinity for the TNYL-RAW peptide is 170 nM, which is slightly lower than for wtEphB4 (100 nM) (FIG. 7). Without being bound by a particular theory, a better dynamic range is likely a result of the interaction of this specific mutant with the Alexa-532 fluorophore of the reporter peptide. These characteristics make it an attractive tool for high throughput screening. The assay windows are approximately 6-fold for wtEphB4 and 12-fold for the EphB4 (K149Q) mutant. In addition we have validated the assay by studying binding of an L95R mutant, which was shown to have Kdephrin-B2=2 uM by ITC analysis. We have not detected a significant signal in FP analysis to accurately calculate KdAlexa-TNYL-RAW (FIG. 6B). This analysis also further validates the use of labeled TNYL-RAW peptide as a surrogate ligand for studies of ephrin-B2-EphB4 binding.

In this and other examples involving Alexa-532-TNYL-RAW peptide, A serial dilution of EphB4 was prepared in Assay Buffer (50 mM Tris pH 7.8, 150 mM NaCl, 1 mM CalCl2, 0.1% Pluronic 124). TNYL-RAW-Alexa-532 labeled peptide was prepared as a 100 μM stock solution in the Assay Buffer and a 300 nM working solution was made fresh prior to the measurements by dilution in the assay buffer. 5 μL of serially diluted EphB4 (9 nM-2362 nM concentration range) was combined with 5 μL of labeled peptide (final concentration 75 nM) in the final volume of 20 μL (Assay plate, 384 well flat bottom, black polystyrene, non-binding surface, Corning, cat #3654) in the absence and presence of 200 μM TNYL-RAW as a control for non-specific binding. The mixture was allowed to equilibrate for 30 min at room temperature, and measurements were performed with a Tecan Genios Pro (Tecan Instruments) using 535 nm excitation and 580 nm emission wavelength. All experimental data were analyzed using Prism 4.0 software (GraphPad Software Inc., San Diego, Calif.) and Kd values were generated by fitting the experimental data using a one-site binding hyperbola nonlinear regression model or equation 8.10 (.www.invitrogen.com/downloads/FP8.pdf).

In these experiments, the human EphB4 (17-196) ligand binding domain was cloned into the insect cell expression vector pBAC6 (Novagen, San Diego, Calif.) under control of the heterologous GP64 signal peptide and containing an N-terminal six histidine tag. The construct was sequence verified, and baculovirus was generated with homologous recombination into Sapphire Baculovirus DNA (Orbigen, San Diego, Calif.) following the manufacturer's protocol (10). The wtEphB4 construct was used as a template for generation of site specific mutants.

Large-scale expression was conducted with Wave Bioreactors (Wave Biotech LLC, Somerset, N.J.) at an MOI of 2 for 48 hr in Hi5 insect cells. Media containing secreted EphB4 (17-196) was concentrated and buffer exchanged with a Hydrosart Crossflow filter (Sartorius, Edgewood, N.Y.). Following immobilized metal affinity chromatography (IMAC) purification on ProBond resin (Invitrogen, Carlsbad, Calif.), EphB4 was concentrated to 5 mg/ml and loaded on a Superdex 75 16/60 column (GE HealthCare, Chicago, Ill.). A small amount of aggregated material was removed by preparative size exclusion chromatography, while most of the sample eluted in a single peak corresponding to an EphB4 (17-196) monomer. The complete removal of the GP64 secretion sequence and protein identity were confirmed by MALDI analysis.

The TNYL-RAW peptide was labeled with Alexa-532 (Biopeptides Inc., San Diego, Calif.). All peptides are purified to >95% purity, and supplied with rigorous analytical specifications, including HPLC and MS analysis.

Example 6

This Example illustrates that the fluorescence polarization assay (Example 5) is tolerant of organic solvents.

In these experiments, dimethylsulfoxide (DMSO) was added in various concentrations to a solution comprising Eph4 and Alexa-532-TNYL-RAW peptide, and FP was measured. As shown in FIG. 8, the FP assay is tolerant to 5% DMSO (filled diamonds in FIG. 8) as indicated by analysis of EphB4 binding in the presence of various concentrations of DMSO. We have also been successful in the crystallization of EphB4 with the TNYL-RAW peptide in the presence of 5% DMSO, which is indicative of excellent tolerance of this specific interaction to DMSO.

Example 7

This Example illustrates determination of Z-factor at protein concentrations representing upper and lower plateaus of the dose response curve for the EphB4 K149Q mutant (FIG. 6A). The calculated Z-factor for 108 samples, each at 2 different protein concentrations, is 0.715 (FIG. 9). The range of Z-factor between 0.5 and 1 is considered to be representative of a high quality assay.

Example 8

This Example illustrates thermodynamic characterization of TNYL-RAW peptide binding to EphB4-ligand binding domain (EphB4-LBD).

In these experiments, we monitored the binding of EphB4-LBD to ephrin-B2 and peptide ligands using isothermal titration calorimetry (ITC). The interaction between EphB4 (17-196) and ephrin-B2 yielded a Kd of 40 nM and a ΔHo of +3.3 kcal mol-1. This is slightly lower than the affinity reported for the interaction between the entire mouse EphB4 extracellular domain and mouse or human ephrin-B2. Without being limited by theory, we hypothesize that the difference may be explained by the existence of a third low affinity Eph-ephrin interface located outside the ephrin-binding domain (Smith, F. M., et al., J. Biol. Chem. 279: 9522-9531, 2004. In addition, N- and C-terminal truncations of the peptide, as well as targeted mutations in the center of the peptide, were synthesized in order to biophysically validate individual effects of the peptide upon EphB4 binding. Table 5 presents data of a thermodynamic analysis of wtEphB4 and mutant EphB4 binding to ephrin-B2 and TNYL-RAW and related peptides. The table shows the results of isothermal titration calorimetry (ITC) analysis. The Kd values reported from this method compare well with the Kd values determined from the FP assays (FIGS. 6 and 7). Three regions of interactions proved critical for receptor binding: The N-terminal Tyr, the Phe/IIe amino acids in the center of the peptide, and the high-affinity C-terminal RAW sequence. The N- and C-terminal truncations appear detrimental due to the loss of stability at the D-E (N-terminal) and J-K (C-terminal) loops, while the Phe/IIe mutations resulted in a loss of stability at an imperative disulfide bridge critical to EphB4 LBD stability.

TABLE 5
			ΔG (kcal		TΔS (kcal
Receptor	Ligand	Kd (nM)	mol−1)	ΔH (koal mol−1)	mol−1)
EphB4 (wt)	ephrin-B2	40 ± 20	−10.2 ± 0.3	3.3 ± 0.1	13.4 ± 0.4
EphB4	ephrin-B2	20 ± 10	−10.5 ± 0.4	3.6 ± 0.1	14.1 ± 0.4
(K149Q)
EphB4	ephrin-B2	1900 ± 1100	−7.8 ± 0.3	5.2 ± 0.7	13.0 ± 0.8
(L95R)
EphB4 (wt)	TNYL-RAW	71 ± 14	−9.8 ± 0.1	−14.7 ± 0.2	−4.9 ± 0.2
EphB4	TNYL-RAW	250 ± 50	−9.0 ± 0.1	−11.7 ± 0.2	−2.7 ± 0.2
(K149Q)
EphB4 (wt)	NYLF-RAW	65 ± 7	−9.8 ± 0.1	−15.5 ± 0.1	−5.7 ± 0.1
EphB4 (wt)	YLFS-RAW	80 ± 36	−9.7 ± 0.2	−13.8 ± 0.5	−4.1 ± 0.4
EphB4 (wt)	LFSP-RAW	3,500 ± 680	−7.4 ± 0.1	−5.3 ± 0.5	2.1 ± 0.4
EphB4 (wt)	TNYL	≧140,000	ND	−9.6 ± 0.3	ND
EphB4 (wt)	LFSP-RAW(F to	≧500,000	ND	−7.9 ± 0.9	ND
	A)
EphB4 (wt)	LFSP-RAW(I to	60,000 ± 20,000	−5.7 ± 0.1	−2.7 ± 0.3	3.0 ± 0.4,
	A)

Results

Anti-EphB4-ephrinB2 therapeutic development can be accomplished by providing the three dimensional crystal structure of the EphB4-ephrinB2 complex at a high resolution. EphB4 specificity can also be probed using the three dimensional crystal structure. In addition, site-directed mutagenesis and biophysical analyses were conducted to investigate the role of several residues within the ligand binding cavity of EphB4 in contributing to the binding of both ephrinB2 and the antagonistic TNYL-RAW peptide. These results allow the development of predictive models for structure-based drug design of small molecule compounds for use as therapeutics and to probe the biology of EphB4-ephrinB2 bi-directional signaling.

Overall Structure

EphB4 and ephrinB2 were co-concentrated to 20 mg/mL and crystallized by sitting drop vapor diffusion against a precipitant of 2.2 M ammonium sulfate and 100 mM Tris, pH 7.8 at 20° C. The co-crystal structure was refined to 2.0 Å resolution with an R-factor of 22.6% and a free R factor of 29.5% (Table 1). Unlike crystals of the of the EphB2-ephrinB2 complex, which consisted of a heterotetramer, crystals of the EphB4-ephrinB2 complex consist of a heterodimer. Previously, formation of ephrinB2-EphB2 tetramers was observed for a concentration range around 1 mM using size exclusion chromatography analysis (SEC), while analytical ultracentrifugation demonstrated that the EphB2-ephrinB2 complex was a heterodimer at concentrations in the low micromolar range (10). The SEC analysis of the of the present invention provides the EphB4-ephrinB2 complex in a concentration range up to 500 μM indicating that the EphB4-ephrinB2 complex exsists as a heterodimer (data not shown). The overall structure of the EphB4-ephrinB2 complex is similar to that of the EphB2-ephrinB2 complex, with an r.m.s. deviation of 5.0 Å over 316 equivalent Cα positions. Significant deviation is evident, however, throughout the structure of the loop regions compared with the EphB4-TNYL-RAW and EphB2-ephrinB2 structures, with r.m.s. deviations of 1.8 and 5.3 Å, respectively in the J-K loop. The ephrinB2 ligand deviates minimally between previously described apo and receptor-bound structures, shifting only 0.91 and 0.90 Å respectively (10, 17).

EphB4-EphrinB2 Interface

Although the overall shape of the EphB4-ephrinB2 interaction interface is in good agreement with that previously described in the EphB2-ephrinB2 structure, marked differences exist within the receptor loops that frame the ligand binding channel. The EphB4 J-K loop assumes a distinct position compared to previously described crystal structures, and is situated directly above the ligand G-H loop and 15 Å from the D-E loop (FIG. 2). The corresponding J-K loop from the EphB2-ephrinB2 structure, on the other hand, is shifted 6.4 Å from the D-E loop, and therefore maintains a more compact binding cavity. In fact, the J-K loops differ in position by up to 10 Å from furthest positions between the two ephrinB2-bound complex structures. Not surprisingly, the J-K loop shows remarkable flexibility in each structure described, also shifting in position by up to 20 Å from furthest positions between the EphB4-TNYL-RAW structure and the EphB4-ephrinB2 structure. Furthermore, crystallization trials with the apo form of EphB4 failed to produce diffracting crystals, likely because of the inherent flexibility of the J-K and D-E loops. A feature unique to EphB4 is a three residue insert in the J-K loop, which is absent in all other Eph receptors. It has been speculated that this insert contributes to the ligand binding specificity inherent to the EphB4 receptor (35). Indeed, two of the three residues (Pro-151, Gly-152, Ala-153) form the tip of the J-K loop, and make contacts with the ligand: Pro-151 R(R. receptor; L, ligand) forms a hydrophobic contact with Phe-120L, while Gly-152R makes a main-chain to side-chain polar contact with Glu-152L. In addition, the G-H and D-E loops, which form two walls of the ligand binding cleft, also shift in order to accommodate the ligand. The G-H loop is shifted by over 4.5 Å between the EphB4 and EphB2-bound ephrinB2 structures, while the D-E loop only deviates by 1.5 Å between the two structures.

The high affinity EphB4-ephrinB2 heterodimer is formed by insertion of the solvent exposed ligand G-H loop into the upper convex and hydrophobic surface of the EphB4 receptor, positioned above receptor strands E and M. Hydrophobic contacts drive receptor-ligand binding in this region. Ligand residues Phe-120, Pro-122, Trp-125 and Leu-127 participate in van der Waals interactions with receptor residues lining the receptor binding cavity in the D-E, G-H and J-K loops (FIG. 4). Phe-120L forms hydrophobic interactions with Leu-95R (see below), Leu-100R, and Pro-101R, while Leu-124L interacts with Thr-147R from the receptor J-K loop. Meanwhile, Trp-125L extends to the surface of the receptor, in-between the J-K and G-H loops, participating in hydrophobic interactions with residues Leu-48R, Glu-50R, Val-159R, Leu-188R, and Ala-186R. In addition, Pro-122L, similar to all previous crystal structures, maintains its position by participating in a direct interaction with the receptor Cys61-Cys-184 disulfide bridge. Few polar contacts are formed at the receptor-ligand dimer interface. Ser-121 L forms a side-chain side-chain hydrogen bond with Glu-59R as well as a main-chain side-chain hydrogen bond with Lys-149R, while Asn-123L forms a hydrogen bond with the main-chain oxygen of Leu-48R. Additionally, Lys-149R extends to the body of the ephrinB2 G-H loop, forming side-chain side-chain hydrogen bonds with Glu-128L, and side-chain main-chain hydrogen bonds with Ser-121L and Asn-123L, wich are both part of the high affinity ligand FSPN sequence (FIG. 3). The introduction of this new interaction at the EphB4-ephrinB2 interface is certain to contribute to the high affinity of this receptor-ligand complex.

Similar to the EphB2-ephrinB2 structure, a second portion of the high affinity heterodimerization interface exists immediately adjacent to the ligand binding cavity, formed by ligand strands C, G. and F. and receptor strands B-C, E, and D. This region of the complex deviates minimally from the corresponding structure of in the EphB2-ephrinB2 complex, with a maximum of 2.1 Å from furthest atoms, and is predominantly characterized by backbone-backbone, backbone-sidechain, and sidechain sidechain hydrogen bonds. In particular, sidechain-sidechain interactions between Glu-59R (Glu-68 in EphB2)-Gln-118L and Ser-121 L, Asp-29R (Glu-40 in EphB2)-Lys-112L, and Glu-43 (Glu-52, EphB2)-Lys 116L provide the binding potential characteristic of this low nanomolar interaction. Sidechain-mainchain interactions between Ser-55 and Lys-116L, and Glu-44R and Lys-60R complete the binding network in this region.

EphB4 Specificity

Sequence comparison and structural analysis of the EphB4 and EphB2 receptors suggested that one residue in EphB4 is particularly important in determining the specificity of the EphB4-ephrinB2 interaction: Leu-95. The corresponding residue in EphB2, Arg-103, is strictly conserved across both A and B subclasses, and deviates only in the EphB4 receptor. Arg-103R participates in hydrogen bonds with residues from the high affinity ephrin G-H loop, including Ser-121L and Glu-128L, and is situated in proximity to Phe-120L, a residue critical for receptor binding. However, superposition of Arg to Leu-95 in the EphB4-ephrinB2 structure suggests that a steric clash would result between an arginine at position 95R and Phe-120L. The corresponding Leu-95R, on the other hand, is able to form a 3.2 Å van der Waals interaction with Phe-120L due to its position within the ligand binding cavity. Thus, Arg-95R would also sterically clash with the phenylalanine from the TNYL-RAW peptide in the EphB4-TNYL-RAW structure (19), while the smaller Leu-95R forms favorable contacts with the peptide. Interestingly, the highly conserved Phe-120L is shifted in position by ˜90° as compared to previous complex structures (8, 10, 19) (FIG. 5) and is buried within the hydrophobic cleft of the receptor, unlike its position in the EphB2-ephrinB2 complex structure, where it is directed towards the surface. In addition, the position of Arg-103R requires the J-K loop of the EphB2 receptor to extend away from the ligand G-H loop and towards the receptor D-E loop to avoid steric interference with residues lining the ephrin-B2 G-H loop. The smaller Leu-95R, together with the Phe-120L, allows the J-K loop of EphB4 to adopt a novel position directly above the ligand G-H loop.

Biophysical Characterization of EphB4 Specificity: Enthalpic vs. Entropic Contributions

A series of site-specific mutations was generated by changing residues lining the EphB4 G-H and J-K loops to the corresponding residues found in EphB2 (Table 3). The EphB4 mutants were rank-ordered based on their binding to fluorescently labeled Alexa-532-TNYL-RAW peptide. Fluorescence Polarization (FP) analysis corroborated the prediction that Leu-95 is a critical determinant for binding of the TNYL-RAW peptide because the Leu95Arg mutant did not exhibit significant binding of the peptide in our assay. EphB4 mutants Thr147Phe, Ala186Ser and Lys149Gln showed approximately 4-5 fold reduction in binding affinity of the fluorescently labeled peptide. The reduction in affinity due to mutation of these residues is consistent with what would be expected based on the structural information. A Thr-147-Phe mutation would impose steric constraints between the receptor J-K loop and the ephrinB2 G-H loop, as well as with Leu-95R due to the position of the receptor J-K loop. Interestingly, EphB4 possesses an alanine at position 186, which is conserved across the A-subclass while other B-subclass receptors have a conserved Ser. Ala-186R forms a van der Waals interaction with the main chain carbon of Asn-123 of the high affinity ligand G-H loop. A Ser at position 186 of EphB4 would cause a polar redistribution at the heterodimerization interface with ephrinB2 and result in the displacement of the receptor G-H loop due to a steric clash with Thr-93L and potential displacement of the ephrinB2 G-H loop. Finally, Lys-149R forms interactions at the dimer interface with ephrinB2 residues Ser-121L, Asn-123L and Gln-128L. Mutation to Gln should not result in steric interference with the ligand G-H loop, but could result in a slight readjustment of the J-K loop in order to accommodate the bulkier Gln side chain.

Based on the structural information and preliminary binding characterization, two EphB4 mutants, Leu95Arg and Lys149Gln, were chosen for detailed thermodynamic analysis of their binding to both ephrinB2 and the TNYL-RAW peptide ligand using isothermal titration calorimetry (ITC). As reported previously, EphB4 binds to ephrinB2 with an affinity of 40 nM and a ΔH_obs of 3.3 kcal mol⁻¹ (19). Mutation of EphB4 Lys-149 to Gln has no effect on the binding affinity or enthalpy of ephrinB2 binding (Table 4). In contrast, mutation of EphB4 Leu-95 to Arg reduces the binding affinity of ephrinB2 by nearly two orders of magnitude. Binding of ephrinB2 to all forms of EphB4 is endothermic, and the binding of ephrinB2 is more endothermic with the L95R mutation in EphB4 (5.2 kcal mol⁻¹ versus 3.3 kcal mol⁻¹ for wild-type EphB4). Preliminary experiments carried out in a buffer with different enthalpy of ionization showed a similar enthalpy change to that reported here. For example, binding of ephrinB2 to EphB4 (K149Q) results in a ΔH_obs of 3.9 (±0.1) kcal mol⁻¹ in phosphate (ΔH_ion=0.8 kcal mol⁻¹) compared to the ΔH_obs of 3.7 (+0.2) kcal mol⁻¹ value obtained in Tris (ΔH_ion=11.34 kcal mol⁻¹) (Table 4). Thus, the protonation/deprotonation is not coupled to ephrinB2 binding under the conditions of the ITC experiments.

Binding of the TNYL-RAW peptide to the wild-type, Lys149Gln, and Leu95Arg forms of EphB4 was also monitored by ITC. TNYL-RAW binds to EphB4 with an affinity of 70 nM and a ΔH_obs of −14.7 kcal mol⁻¹ (19). In contrast to the different effects of mutations in EphB4 on the interaction of EphB4 with ephrinB2, mutation of EphB4 of either Lys-149 to Gln or Leu-95 to Arg reduces the affinity of the EphB4-TNYL-RAW interaction (three-fold and 500-fold, respectively; Table 4). Binding of the TNYL-RAW peptide to all three forms of EphB4 is characterized by an exothermic enthalpy.

Thus, thermodynamic analysis reveals that TNYL-RAW binding to the EphB4 ligand binding domain is an enthalpically driven process, while ephrinB2 binding to EphB4 is an entropically driven process. The differences in the binding thermodynamics are consistent with the available structural information. Burial of the hydrophobic ligand G-H loop within the hydrophobic receptor binding cleft could entropically drive the interaction through the release of water, increasing the solvent entropy. In addition, the ephrinB2 ligand G-H loop is quite rigid, both in apo and receptor-bound structures, minimizing massive conformational entropy losses. The small loss of conformational entropy counteracts the heterodimerization process by ordering the otherwise flexible receptor J-K, D-E, and G-H loops. Unlike ephrinB2, however, the free peptide ligand loses significant conformational degrees of freedom upon EphB4 binding, resulting in an entropy loss. This is compensated by an enthalpic gain due to the formation of favorable interactions, both polar and nonpolar, at the receptor-peptide interface.

It should be noted that we produced the ephrinB2 extracellular domain in insect cells in a glycosylated form, while the ephrins used for previous crystal structure determinations were produced in E. coli and therefore not glycosylated. A conserved glycosylation site exists in ephrinB2 at residue Asn-39, in proximity of the low affinity tetramerization interface. Consistent with its possible glycosylation, Asn-39 is located near the surface of the protein and its side chain extends toward the surface of the complex. Although the carbohydrate was not observed in our electron density map, most likely because it was disordered, there is a theoretical possibility that a sugar at this location could interfere with the formation of receptor-ligand tetramers in the crystal lattice. However, previous reports have suggested that carbohydrate moieties would play more a favorable than an unfavorable role in tetramerization (36).

OTHER EMBODIMENTS

The detailed description set-forth above is provided to aid those skilled in the art in practicing the present invention. However, the invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.

REFERENCES CITED

Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention. Specifically intended to be within the scope of the present invention, and incorporated herein by reference in its entirety, is the following publication: Chrencik, J. E., Brooun, A., Kraus, M. L., Recht, M. I., Kolatkar, A. R., Han, G. W., Seifert, J. M., Widmer, H., Auer, M., Kuhn, P. Structural and Biophysical Characterization of the EphB4-EphrinB2 Protein-Protein Interaction and Receptor Specificity. (2006) J. Biol. Chem. 281:28185-28192.

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Claims

1. A method for selecting a candidate drug which interferes with an activity of an EphB4 receptor, the method comprising: (a) providing a three-dimensional crystal structure of the EphB4 receptor in complex with an ephrinB2; and (b) designing a compound predicted to bind the EphB4 receptor configured in the EphB4 receptor and ephrinB2 complex.

2. A method for designing a compound which interferes with an activity of an EphB4 receptor, the method comprising: (a) providing on a digital computer a three-dimensional structure of a receptor-ligand complex comprising the EphB4 receptor and an ephrinB2; and (b) using software comprised by the digital computer to design a compound which is predicted to bind to the EphB4 receptor.

3. A method according to claim 2, further comprising: (c) synthesizing the compound; and (d) evaluating the compound for an ability to interfere with an activity of the EphB4 receptor.

4. A method according to claim 2, wherein the compound is designed by computational interaction with reference to a three-dimensional site of the structure of the receptor-ligand complex, wherein the three-dimensional site is selected from the group consisting of EphB4 D-E and J-K loops.

5. A method according to claim 4, wherein the three-dimensional site comprises Leu-95 of SEQ ID NO: 4.

6. A method according to claim 2, wherein the EphB4 receptor is a human EphB4 receptor.

7. A method for generating a model of a three-dimensional structure of an EphB-ligand complex, the method comprising: (a) providing an amino acid sequence of a reference EphB4 protein, atomic coordinates of the reference EphB4 protein, and an amino acid sequence of a target EphB, wherein the reference EphB4 is comprised by an EphB4-ephrinB2 complex; (b) identifying one or more structurally conserved regions shared between the reference EphB4 amino acid sequence and the target EphB amino acid sequence; and (c) assigning atomic coordinates from the one or more structurally conserved regions to a complex comprising the target EphB and an EphB ligand.

8. A method in accordance with claim 7, wherein the EphB4 protein comprises an amino acid sequence as set forth in SEQ ID NOs: 2 or 3.

9. A method in accordance with claim 7, wherein the EphB4 protein consists essentially of an amino acid sequence as set forth in SEQ ID NOs: 2 or 3.

10. A method in accordance with claim 7, wherein the reference EphB4-ephrinB2 complex comprises a three-dimensional structure described by atomic coordinates that substantially conform to atomic coordinates set forth in Table 1.

11. A method according to claim 7, wherein the EphB4 polypeptide is a human EphB4 polypeptide.

12. A method for generating a model of a three-dimensional structure of an EphB receptor-ligand complex, the method comprising: (a) providing an amino acid sequence of a known EphB4 receptor in complex with ephrinB2; (b) providing an amino acid sequence of a target EphB receptor; (c) identifying structurally conserved regions shared between the known receptor-ligand complex amino acid sequence and the target receptor-ligand complex amino acid sequence; and (d) assigning atomic coordinates of the conserved regions to the target receptor-ligand complex.

13. A method in accordance with claim 12, wherein the known EphB4 receptor comprises an amino acid sequence as set forth in SEQ ID NOs: 2 or 3.

14. A method in accordance with claim 12, wherein the known EphB4 receptor consists essentially of an amino acid sequence as set forth in SEQ ID NOs: 2 or 3.

15. A method according to claim 12, wherein the known EphB4 receptor is a human EphB4 receptor.

16. A method according to claim 12, wherein the known receptor-ligand complex comprises a three-dimensional structure described by atomic coordinates that substantially conform to atomic coordinates set forth in Table 1.

17. A crystal comprising an EphB4 ligand binding domain and ephrinB2.

18. A crystal according to claim 17, wherein the EphB4 ligand binding domain is a polypeptide having a sequence of SEQ ID NOs: 2 or 3.

19. A crystal according to claim 17, wherein the EphB4 ligand binding domain consists essentially of EphB4 D-E and J-K loops.

20. A crystal according to claim 17, wherein the EphB4 ligand binding domain consists essentially of Leu-48, Cys-61, Leu-95, Ser-99 Leu-100, Pro-101, Thr-147, Lys-149, Ala-155, and Cys-184 of SEQ ID NO: 4.

21. A crystal according to claim 17, wherein the EphB4 ligand binding domain is a human EphB4 ligand binding domain.

22. A crystal according to claim 17, wherein the ephrinB2 comprises Phe-120, Pro-122, Leu-124, Trp-125, and Leu-127 of SEQ ID NO: 6.

23. A crystal in accordance with claim 17, wherein the crystal comprises space group P41 so as to form a unit cell of dimensions a=81.09 Å, b=81.09 Å, and c=50.95 Å.

24. A crystal comprising a polypeptide having SEQ ID NOs: 2 or 3 complexed with an ephrinB2, wherein the crystal is sufficiently pure to determine atomic coordinates of the complex by X-ray diffraction to a resolution of about 1.65 Å.

25. A crystal according to claim 24, wherein the ephrinB2 comprises Phe-120, Pro-122, Leu-124, Trp-125, and Leu-127 of ephrinB2.

26. A polypeptide having SEQ ID NOs: 2 or 3 in complex with ephrinB2.

27. A complex according to claim 26, wherein the ephrin-B2 comprises Phe-120, Pro-122, Leu-124, Trp-125, and Leu-127.

28. A therapeutic compound that inhibits an activity of an EphB4 receptor, wherein the compound is selected by a) performing a structure based drug design using a three-dimensional structure determined for a crystal comprising an EphB4 receptor and ephrinB2; b) contacting a sample comprising the EphB4 receptor with the compound, and c) detecting inhibition of at least one activity of the EphB4 receptor.

29. A compound according to claim 28, wherein the EphB4 is a polypeptide having SEQ ID NOs: 2 or 3.

30. A compound according to claim 28, wherein the EphB4 receptor is a human EphB4 receptor.

31. A three-dimensional computer image of the three-dimensional structure of an EphB4-ephrinB2 complex, wherein the structure substantially conforms to the three-dimensional coordinates listed in Table 1.

32. A computer-readable medium encoded with a set of three-dimensional coordinates set forth in Table 1, wherein, using a graphical display software program, the three-dimensional coordinates of Table 1 create an electronic file that can be visualized on a computer capable of representing said electronic file as a three-dimensional image.

33. A computer-readable medium encoded with a set of three-dimensional coordinates of a three-dimensional structure which substantially conforms to the three-dimensional coordinates represented in Table 1, wherein, using a graphical display software program, the set of three-dimensional coordinates create an electronic file that can be visualized on a computer capable of representing said electronic file as a three-dimensional image.

34. A method for crystallizing an EphB4 receptor, the method comprising: a) providing an EphB4 receptor in contact with an ephrinB2; and b) contacting the EphB4 receptor in contact with the polypeptide with a compound of claim 27, wherein the EphB4 receptor in contact with the ephrinB2 and the compound forms an EphB4 receptor crystal.

35. A composition comprising EphB4 receptor, an ephrinB2, and a compound of claim 54.

36. A composition according to claim 28, wherein the EphB4 receptor is a polypeptide having SEQ ID NOs: 2 or 3.

37. A composition according to claim 36, wherein the EphB4 receptor consists essentially of EphB4 D-E and J-K loops.

38. A composition according to claim 36, wherein the EphB4 receptor consists essentially of Leu-48, Cys-61, Leu-95, Ser-99 Leu-100, Pro-101, Thr-147, Lys-149, Ala-155, and Cys-184 of SEQ ID NO: 4.

39. A composition according to claim 36, wherein the EphB4 receptor is a human EphB4 receptor.

40. A composition according to claim 36, wherein the ephrinB2 is a polypeptide having SEQ ID NO: 6.

41. A mutant EphB4 which binds ephrinB2, wherein the affinity for ephrinB2 is less than the affinity of wild type EphB4 for ephrinB2.

42. A mutant EphB4 in accordance with claim 41, comprising at least one mutation selected from the group consisting of T147F, K149Q and A186S.

43. A mutant EphB4 in accordance with claim 41, wherein the mutant EphB4 binds an EphB4 ligand, and wherein the dynamic range of binding of the ligand is greater than that of the ligand binding to wild type EphB4.

44. A mutant EphB4 in accordance with claim 43, wherein the dynamic range of ligand binding is about 2-fold.

45. A method of assaying a candidate compound for mutant EphB4 binding activity, the method comprising: contacting a complex comprising a mutant EphB4 and a labeled EphB4 ligand; and detecting release of the labeled EphB4 ligand from the complex.

46. A method of assaying a candidate compound for EphB4 binding activity, the method comprising: contacting a complex comprising an EphB4 and an EphB4 ligand which comprises a fluorescent label with the candidate compound; and determining fluorescence polarization, wherein a shift in fluorescence polarization indicates EphB4 binding activity.

47. A high throughput assay method for screening candidate compounds for EphB4 binding activity, comprising testing a plurality of candidate compounds for EphB4 binding activity, wherein each compound is tested by the method of claim 45.