CRYSTALLINE FRAP COMPLEX

Abstract: The invention relates to the human protein FRAP, and in particular to the FKBP12-rapamycin binding domain thereof and to the ternary complex formed by the FRB domain, rapamycin and FKBP12. A new crystalline composition comprising the ternary complex, coordinates defining its three dimensional structure in atomic detail, and uses thereof are disclosed.

Description: Crystalline FRAP Complex Copyright Notice A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever. Field of the Invention The invention relates to a complex, in crystalline form, of two proteins, FKBP12 and the FRB domain of FRAP, in association with rapamycin, a small organic molecule to which the proteins bind. The crystalline form of this ternary complex is particularly useful for the determination of the three-dimensional structure of the complex at the atomic level. The three dimensional structure provides information useful for the design of pharmaceutical compositions which inhibit the biological function of proteins such as FRAP which contain an FRB domain, particularly those biological functions mediated by molecular interactions involving rapamycin or other compounds capable of binding to an FRB domain. Background Rapamycin (sometimes called sirolimus) was first described in 1975 as an antifungal agent isolated from Streptomyces hygroscopicus (Vezina, 1975; Sehgal, 1975). In 1987, the structurally related compound FK506 (sometimes called tacrolimus) was characterized as a potent immunosuppressive agent (Tanaka, 1987), and shortly thereafter, rapamycin was also shown to have potent immunosuppressive activity. In spite of rapamycin's immunosuppressive activity and structural similarity to FK506, the two compounds suppress the immune response in completely different ways (Schreiber, 1992). FK506 inhibits the T cell receptor (TCR) signal and prevents activation of a resting helper T cell. Rapamycin inhibits the autocrine signaling pathway involving inter leukin-2 (I -2) and the IL-2 receptor (IL-2R). These latter signals commit the cell to a program of cell division by communicating with the components of the cell cycle machinery necessary for DNA replication. Both FK506 and rapamycin are potentially useful in the treatment of human disease. FK506 has been approved by the FDA for use in treating the rejection of transplanted organs. A similar use has been envisioned for rapamycin, and its demonstrated activity in organ transplantation and autoimmune animal models indicate a high clinical potential. Rapamycin has been shown to have antitumor activity against B16 melanocarcinoma, colon 26 tumor, EM ependymoblastoma, CD8F1 mammary and colon 38 murine tumors (Sehgal, 1993). Rapamycin has also shown immunosuppressive activity in assays to measure prevention of development of autoimmune adjuvant arthritis, experimental allergic encephalomyelitis and autoimmune uveoretinitis in the rat (Sehgal, 1993). The biological activity and structural novelty of both rapamycin and FK506 led to a search for their cellular target(s), and the target of both compounds was identified as the plentiful cytoplasmic protein FKBP12 (for FK506 binding protein) of 12 kDa molecular mass. Since FK506 and rapamycin bound to the same target (Kd of 0.4 and 0.2 nM, respectively) and affected different pathways, a new function was attributed to the FKBP12-ligand complex. This new function arises from the ability of FKBP12-FK506 and FKBP12-rapamycin complexes, but not the individual components, to bind to and inhibit still other protein targets. The FKBP12-FK506 complex inhibits the phosphatase activity of calcineurin, a crucial component of the TCR pathway. Calcineurin is a serine/threonine phosphatase also called PP2B. The FKBP12-rapamycin complex inhibits the IL-2R signal by binding to a large (289kDa) protein named FRAP in humans (Brown et al, 1994) or RAFT in rats (Sabatini et al, 1994; Chiu et al, 1994). The structural basis for the tight binding of FK506 and rapamycin by FKBP12 has been investigated by both X-ray diffraction and NMR techniques (Clardy, 1995). In particular, high resolution X-ray structures are available for FKBP12-FK506 (1.4 A resolution) and FKBP12- rapamycin (1.7 A resolution) (Van Duyne et al, 1991; Van Duyne et al, 1991a; Van Duyne et al, 1993). These structures reveal, among other things, the fold of FKBP12, the atomic details of the hydrophobic binding pocket, and the details of how FK506 and rapamycin interact with the binding pocket. A structural analysis of the complex formed between FKBP12-FK506- calcineurin is also available (Griffith et al, 1995). That structure reveals how the portion of FK506 not involved in binding FKBP12 interacts with calcineurin and inhibits its phosphatase activity. The biochemical characterization of FRAP, the target of the FKBP12-rapamycin complex, remains incomplete. The C-terminal domain resembles a phosphatidylinositol (PI) kinase, but to date no PI or protein kinase activity has been convincingly demonstrated. FRAP (RAFT, TOR) are members of a rapidly growing and important family of proteins that have been identified only recently (Zakian, 1995). ATM, TEL1, DNA-PK and MEC1 are some of the recently characterized members of this family of PIK-related kinases. (See e.g., Keith, 1995). ATM (for ataxia telngiectasia mutant) is responsible for a human autosomal hereditary disease characterized by cerebellar degeneration, progressive mental retardation, uneven gait, dilation of blood vessels, immune deficiencies, premature aging and a hundredfold increase in cancer susceptibility (Zakian, 1995). Persons who are heterozygous in ATM are believed to be at elevated risk for cancer. Mutations to TEL1 lead to abnormally short telomeres, and in conjunction with other mutations can lead to sensitivity to X-rays, UV radiation and hydroxyurea. DNA-PK is, as the name suggests, a DNA-dependent protein kinase that recognizes damaged DNA, and human cells without DNA-PK activity are radiation sensitive and repair deficient. MEC1 is required for both S-M and G2-M checkpoint progression as well as for meiotic recombination in yeast. Thus MEC1 is arguably the master checkpoint gene in yeast. FRAP is a large protein (2549 amino acid residues), and only a small fraction can be involved in recognizing the FKBP12-rapamycin complex. Fortunately all of these residues are in one domain, and this domain, which is called the FKBP12-rapamycin binding (FRB) domain, is the protein used in this invention. It was identified through tryptic digests of FRAP and independently produced as an 11 kDa soluble protein (Chen et al, 1995) Unfortunately, until now, three-dimensional structural details of the association of FKBP12-rapamycin with the FRB domain of FRAP have remained completely unknown. In the absence of such three-dimensional structural details, it has been impossible to design compounds based on that structure which would be capable of mimicking rapamycin's binding to the FRB domain. We have now obtained crystals of that ternary complex and have determined its three dimensional structure. With this information, it is now possible for the first time to rationally design compounds capable of binding to an FRB domain and mimicking the pharmacological activity of rapamycin. Such mimics may be used in place of rapamycin as immunosuppressive agents or in other pharmacological applications. Summary of the Invention This invention centers on the FRB domain of human FRAP and begins with obtaining crystals of human FKBP12-rapamycin-FRB of sufficient quality to determine the three dimensional (tertiary) structure of the complex by X-ray diffraction methods. In considering our work, it should be appreciated that obtaining protein crystals in any case is a somewhat unpredictable art, especially in cases in which the practitioner lacks the guidance of prior successes in preparing and/or crystalizing any closely related proteins. Obtaining our first crystals of the ternary complex was therefore itself an unexpected result. In addition, our data represents the first detailed information available on the three dimensional structure of FRAP or of any of the PIK-related kinases and revealed an unpredicted array of surface features. Our results are useful in a number of applications. As previously mentioned, the atomic details of how the FKBP12-rapamycin complex interacts with the FRB domain is essential for the structure-based design of rapamycin analogs. As noted above, rapamycin has several promising clinical indications, and improved rapamycin analogs would be useful therapeutic agents. This structure can be used as an essential starting point in predicting, via homology modeling, the structures of related proteins which contain homologous FRB domains, including other members of the PIK-related kinase family. Furthermore, the structure shows — in atomic detail — how a small organic molecule, rapamycin, can be used to hold two proteins, FKBP12 and FRB, in close proximity. As such, this structure contains important lessons for the design of heterodimerizing agents. Thus, the knowledge obtained concerning the FRB of FRAP can be used to model the tertiary structure of related proteins. By way of example, the structure of renin has been modeled using the tertiary structure of endothiapepsin as a starting point for the derivation. Model building of cercarial elastase and tophozoite cysteine protease were each built from known serine and cysteine proteases that have less than 35% sequence identity. The resultant models were used to design inhibitors in the low micromolar range. (Proc. Natl. Acad. Sci. 1993, 90, 3583). Furthermore, alternative methods of tertiary structure determination that do not rely on X-ray diffraction techniques and thus do not require crystallization of the protein, such as NMR techniques, are simplified if a model of the structure is available for refinement using the additional data gathered by the alternative technique. Thus, knowledge of the tertiary structure of the FRB region of FRAP provides a significant window to the structure of other proteins containing a homologous FRB domain, including the other PIK-related kinases. Accordingly, one object of this invention is to provide a composition, in crystalline form, comprising a protein containing an FRB domain. The protein may have a bound ligand or may be part of a complex with a second protein molecule and a shared ligand. For instance, the crystalline composition may contain a complex containing a first protein having a peptide sequence derived or selected from that of an FKBP12 protein, e.g., human FKBP12; a second protein having a peptide sequence derived or selected from that of an FRB domain of a PIK- related kinase family member, e.g. the FRB domain of human FRAP; and a ligand such as rapamycin which is capable of binding to both proteins to form a ternary complex. Such a crystalline composition may contain one or more heavy atoms, e.g., one or more lead, mercury, gold and /or selenium atoms. Such a heavy atom derivative may be obtained, for example, by expressing a gene encoding the protein of interest under conditions permitting the incorporation of one or more heavy atom labels (e.g. as in the incorporation of selenomethionine), reacting the protein with a reagent capable of linking a heavy atom to the protein (e.g. trimethyl lead acetate) or soaking a substance containing a heavy atom into the crystals. Preferred crystalline compositions of this invention are capable of diffracting x-rays to a resolution of better than about 3.5 A, and more preferably to a resolution of 2.7 A or better, and are useful for determining the three-dimensional structure of the material. (The smaller the number of angstroms, the better the resolution.) Crystalline compositions of this invention specifically include those in which the crystals are characterized by the structural coordinates of the FRB protein set forth in the accompanying Appendix I or characterized by coordinates having a root mean square deviation therefrom, with respect to backbone atoms of amino acids listed in Appendix I, of 1.5 A or less. Furthermore, our crystalline compositions include crystals characterized by the structural coordinates of both the FRB and FKBP12 proteins set forth in Appendix I, optionally including a molecule of rapamycin as defined structurally by the accompanying coordinates therefor. Structural coordinates of a crystalline composition of this invention may be stored in a machine-readable form on a machine-readable storage medium, e.g. a computer hard drive, diskette, DAT tape, etc., for display as a three-dimensional shape or for other uses involving computer-assisted manipulation of, or computation based on, the structural coordinates or the three-dimensional structures they define. For example, data defining the three dimensional structure of a composition of this invention or a portion thereof containing an FRB domain- containing protein of the PIK-related kinase family, or portions or structurally similar homologues of such proteins, may be stored in a machine-readable storage medium, and may be displayed as a graphical three-dimensional representation of the protein structure, typically using a computer capable of reading the data from said storage medium and programmed with instructions for creating the representation from such data. This invention thus encompasses a machine, such as a computer, having a memory which contains data representing the structural coordinates of a crystalline composition of this invention, e.g. the coordinates set forth in Appendix I, together with additional optional data and instructions for manipulating such data. Such data may be used for a variety of purposes, such as the elucidation of other related structures and drug discovery. A first set of such machine readable data may be combined with a second set of machine- readable data using a machine programmed with instructions for using the first data set and the second data set to determine at least a portion of the coordinates corresponding to the second set of machine-readable data. For instance, the first set of data may comprise a Fourier transform of at least a portion of the coordinates for the complex set forth in Appendix I, while the second data set may comprise X-ray diffraction data of a molecule or molecular complex. More specifically, one of the objects of this invention is to provide three-dimensional structural information on the FRB domain of FRAP, of other members of the PIK-related kinase family which containg homologous FRB domains, and of homologs or variants thereof, preferably in association with a bound ligand or bound ligandrprotein complex (such as FKBP12-rapamycin). To that end, we provide for the use of the structural coordinates of a crystalline composition of this invention, or portions thereof, to solve, e.g. by molecular replacement, the three dimensional structure of a crystalline form of another such protein, protein:ligand complex, or protein:ligand:protein complex. Doing so involves obtaining x-ray diffraction data for crystals of the protein or complex for which one wishes to determine the three dimensional structure. Then, one determines the three-dimensional structure of that protein or complex by analyzing the x-ray diffraction data using molecular replacement techniques with reference to the previous structural coordinates. As described in US Patent No. 5,353,236, for instance, molecular replacement uses a molecule having a known structure as a starting point to model the structure of an unknown crystalline sample. This technique is based on the principle that two molecules which have similar structures, orientations and positions in the unit cell diffract similarly. Molecular replacement involves positioning the known structure in the unit cell in the same location and orientation as the unknown structure. Once positioned, the atoms of the known structure in the unit cell are used to calculate the structure factors that would result from a hypothetical diffraction experiment. This involves rotating the known structure in the six dimensions (three angular and three spatial dimensions) until alignment of the known structure with the experimental data is achieved. This approximate structure can be fine-tuned to yield a more accurate and often higher resolution structure using various refinement techniques. For instance, the resultant model for the structure defined by the experimental data may be subjected to rigid body refinement in which the model is subjected to limited additional rotation in the six dimensions yielding positioning shifts of under about 5%. The refined model may then be further refined using other known refinement methods. For example, one may use molecular replacement to exploit a set of coordinates such as set forth in Appendix I to determine the structure of a crystalline co-complex of the FRB domain, FKBP12 and a ligand other than rapamycin. Likewise one may use that same approach to determine the three dimensional structure of a complex of FKBP12, rapamycin and a protein containing a modified FRAP FRB domain or an FRB domain from a homolog of FRAP. Another object of the invention is to provide a method for determining the three- dimensional structure of a protein containing an FRB domain, or a complex of the protein with a ligand therefor, using homology modeling techniques and structural coordinates for a composition of this invention. Homology modeling involves constructing a model of an unknown structure using structural coordinates of one or more related proteins, protein domains and/or subdomains. Homology modeling may be conducted by fitting common or homologous portions of the protein or peptide whose three dimensional structure is to be solved to the three dimensional structure of homologous structural elements. Homology modeling can include rebuilding part or all of a three dimensional structure with replacement of amino acids (or other components) by those of the related structure to be solved. The structural coordinates obtained for the related protein or complex may be stored, displayed, manipulated and otherwise used in like fashion as those for the ternary complex of FKBP12-rapamycin-FRB set forth in Appendix I. Crystalline compositions of this invention thus provide a starting material, and their three dimensional structure coordinates a point of reference, for use in solving the three-dimensional structure of other proteins containing an FRB domain homologous to that of FRAP, as well as complexes containing such a protein. Sequence similarity may be determined using any conventional similarity matrix. (See e.g. Dayhoff,1979; Greer, 1981; and Gonnet, 1992). Proteins containing at least one FRB domain having at least 15% peptide sequence identity or similarity with respect to our FRB, as determined by any of the approaches described above, are considered FRAP homologs for the purpose of this disclosure. By way of further example, the three dimensional structure defined by the machine readable data for the FRB domain (with or without the FKBP12 component) may be computationally evaluated for its ability to associate with various chemical entities. The term "chemical entity", as used herein, refers to chemical compounds, complexes of at least two chemical compounds, and fragments of such compounds or complexes. For instance, a first set of machine-readable data defining the 3-D structure of FRAP or a FRAP homolog, or a portion or complex thereof, is combined with a second set of machine- readable data defining the structure of a chemical entity or moiety of interest using a machine programmed with instructions for evaluating the ability of the chemical entity or moiety to associate with the FRAP or FRAP homolog protein or portion or complex thereof and /or the location and/or orientation of such association. Such methods provide insight into the location, orientation and energetics of association of protein surfaces with such chemical entities. Chemical entities that are capable of mimicking rapamycin's ability to associate with FRAP or a FRAP homolog should share part or all of rapamycin's pharmacologic activities, e.g. immunosuppressive activity, but may be designed for more convenient or economical preparation, improved pharmacokinetics, reduced side effects, etc. Such chemical entities therefore include potential drug candidates. The three dimensional structure defined by the data may be displayed in a graphical format permitting visual inspection of the structure, as well as visual inspection of the association of the protein component(s) with rapamycin or other chemical entities. Alternatively, more quantitative or computational methods may be used. For example, one method of this invention for evaluating the ability of a chemical entity to associate with any of the molecules or molecular complexes set forth herein comprises the steps of: (a) employing computational means to perform a fitting operation between the chemical entity and a binding pocket or other surface feature of the molecule or molecular complex; and (b) analyzing the results of said fitting operation to quantify the association between the chemical entity and the binding pocket. This invention further provides for the use of the structural coordinates of a crystalline composition of this invention, or portions thereof, to identify reactive amino acids, such as cysteine residues, within the three-dimensional structure, preferably within or adjacent to a ligand binding site; to generate and visualize a molecular surface, such as a water-accessible surface or a surface comprising the space-filling van der Waals surface of all atoms; to calculate and visualize the size and shape of surface features of the protein or complex, e.g., ligand binding pockets; to locate potential H-bond donors and acceptors within the three-dimensional structure, preferably within or adjacent to a ligand binding site; to calculate regions of hydrophobicity and hydrophilicity within the three-dimensional structure, preferably within or adjacent to a ligand binding site; and to calculate and visualize regions on or adjacent to the protein surface of favorable interaction energies with respect to selected functional groups of interest (e.g. amino, hydroxyl, carboxyl, methylene, alkyl, alkenyl, aromatic carbon, aromatic rings, heteroaromatic rings, etc.). One may use the foregoing approaches for characterizing the FRB domain-containing protein and its interactions with moieties of potential ligands to design or select compounds capable of specific covalent attachment to reactive amino acids (e.g., cysteine) and to design or select compounds of complementary characteristics (e.g., size, shape, charge, hydrophobicity /hydrophilicity, ability to participate in hydrogen bonding, etc.) to surface features of the protein, a set of which may be preselected. Using the structural coordinates, one may also predict or calculate the orientation, binding constant or relative affinity of a given ligand to the protein in the complexed state, and use that information to design or select compounds of improved affinity. In such cases, the structural coordinates of the FRAP or FRAP homolog protein, or portion or complex thereof, are entered in machine readable form into a machine programmed with instructions for carrying out the desired operation and containing any necessary additional data, e.g. data defining structural and /or functional characteristics of a potential ligand or moiety thereof, defining molecular characteristics of the various amino acids, etc. One method of this invention provides for selecting from a database of chemical structures a compound capable of binding to FRAP or a FRAP homolog. The method starts with structural coordinates of a crystalline composition of the invention, e.g., coordinates defining the three dimensional structure of FRAP or a FRAP homolog or a portion thereof or a complex thereof. Points associated with that three dimensional structure are characterized with respect to the favorability of interactions with one or more functional groups. A database of chemical structures is then searched for candidate compounds containing one or more functional groups disposed for favorable interaction with the protein based on the prior characterization. Compounds having structures which best fit the points of favorable interaction with the three dimensional structure are thus identified. It is often preferred, although not required, that such searching be conducted with the aid of a computer. In that case a first set of machine-readable data defining the 3D structure of a FRAP or FRAP homolog protein, or a portion or protein-ligand complex thereof, is combined with a second set of machine readable data defining one or more moieties or functional groups of interest, using a machine programmed with instructions for identifying preferred locations for favorable interaction between the functional group(s) and atoms of the protein. A third set of data, i.e. data defining the location(s) of favorable interaction between protein and functional group(s) is so generated. That third set of data is then combined with a fourth set of data defining the 3D structures of one or more chemical entities using a machine programmed with instructions for identifying chemical entities containing functional groups so disposed as to best fit the locations of their respective favorable interaction with the protein. Compounds having the structures selected or designed by any of the foregoing means may be tested for their ability to bind to FRAP or a FRAP homolog, inhibit the binding of FRAP or a FRAP homolog to a natural or non-natural ligand therefor (e.g. FKBP12-rapamycin, in the case of FRAP), and/or inhibit a biological function mediated by FRAP or the FRAP homolog. This invention also permits methods for designing a compound capable of binding to a FRAP or FRAP homolog based on the three dimensional structure of bound rapamycin. One such method involves graphically displaying a three-dimensional representation based on coordinates defining the three-dimensional structure of a FRAP or FRAP homolog protein or a portion thereof complexed with a ligand such as the FKBP12:rapamycin complex. Interactions between portions of ligand and protein are characterized in order to identify candidate moieties of the ligand for replacement. One or more portions of the ligand which interact with the protein may be replaced with substitute moieties selected from a knowledge base of one or more candidate substitute moieties, and /or moieties may be added to the ligand to permit additional interactions with the protein. Compounds first identified by any of the methods described herein are also encompassed by this invention. Brief Description of the Drawings FIG. 1 depicts a computer system. FIG. 2 depicts storage media of this invention. FIG. 3 depicts a ribbon diagram of the three dimensional structure of the FKBP12:rapamycin:FRB domain complex, as defined by the coordinates of Appendix I. Detailed Description of the Invention Despite the key role played by the FKBP12:rapamycin:FRAP complex in the IL-2/IL-2R signaling pathway, and despite the growing appreciation of the biological importance of the PIK-related kinase family, nothing was known of the three-dimensional architecture by which the FRB domain of FRAP (or of any FRAP homolog) engages the FKBP12:rapamycin complex required for its biological activity. X-ray crystallographic techniques could in principle address such issues. However, notwithstanding the key biological functions mediated by FRAP, there have been no reports disclosing that suitable crystals had been or could be obtained, let alone reports disclosing any x-ray crystallographic data or other information concerning the three- dimensional structure of any FRB domain. Even in the event that crystals had been obtained, then-available three-dimensional structural data relating to the FKBP12:rapamycin complex would not have been been sufficient for solving the ternary complex structure, at least in part, because the initial electron density maps wouldn't have permitted the chain of FRB to be traced. Even if parts of the chain could have been traced, they would not have refined under least- squares minimization techniques. Nonetheless, we have succeeded in producing FKBP12 and FRAP FRB proteins, and have obtained crystals of their ternary complex with rapamycin. We have solved the three- dimensional structure of the crystalline complex using x-ray diffraction techniques. In view of our successes as disclosed herein, it can now be said that proteins comprising FRB domains can be produced in stable form, purified, and crystallized, and that their three-dimensional structures can be determined, all using materials and methods such as disclosed herein. As mentioned elsewhere, FRAP is one of a number of PIK-related kinase family members that contain an FRB domain. PIK-related kinase family members share regions of homology including lipid kinase homologous regions, kinase domains and, in at least a number of cases, FRB domains. The presence and boundaries of homologous regions in a protein sequence can be identified by using a computer alignment program that identifies amino acid sequence homology to a known sequence or domain. For example, the FRB domain (amino acids 2015 - 2114) of FRAP may be used for such analysis, but FRB domains from other proteins such as RAPT or TORI or TOR2 can be used as well. The alignment method typically used by such programs is the Needleman-Wunch alignment. See e.g., "A General Method Applicable to the Search for Similarities in the Amino Acid Sequence of Two Proteins." Needlman, S.B.; Wunch, CD. /. Mol. Biol. 1970, 48 , 443-453. We expressed the FRAP FRB domain as a glutathione-S-transferase (GST) fusion protein. The cDNA encoding residues 2015 - 2114 from human FRAP (Chen et al, 1995) was cloned into a pGEX vector and expressed in E coli, the resulting fusion protein was recovered and cleaved to yield the FRB protein which was then purified, all as described in detail below. FKBP12 protein was similarly obtained using a cDNA encoding residues 1 - 107 from human FKBP12 (Standaert et al, 1990, Nature 246.: 671-674.. Other proteins containing an FRB domain may also be used, including larger FRAP fragments containing the FRB and flanking peptide sequence, including up to the entire FRAP protein. Additionally, FRB proteins can be prepared by analogous means containing homologous FRB regions from other proteins, including RAFT, TORI, TOR2 or other members of the PIK-related kinase family. It should further be appreciated that other expression systems may be readily employed., including , e.g., materials and methods for expression in E. coli using T7, maltose-binding protein fusion (MBP), with epitope tags (His6, HA, myc, Flag) included or cleaved off. Baculoviral expression may be used, e.g. using pVL1393 or derivatives, for tFRB domain, fused (or not) to epitope tag or fusion partner such as GST. Conventional materials and methods for expression in mammalian, yeast or other cells may also be used. Rapamycin may be prepared by known methods or may be obtained from commercial sources. Rapamycin analogs such as disclosed, e.g., in Luengo et al, 1995, Chemistry & Biology 2(7):471-481, may be used in place of rapamycin, in forming complexes of this invention. Complex formation, crystallization, X ray diffraction experiments and interpretation of the diffraction data were conducted as described in detail in the Experimental Examples below. The resulting structural coordinates for a crystalline composition comprising FKBP12:rapamycin:FRB of FRAP (one molecule of complex per asymmetric unit) are set forth in Protein Database format in Appendix I. Solving the X-ray crystal structure of the ternary complex allowed us to conduct the first three dimensional characterization of an FRBrligand complex (viewing FKBP12:rapamycin as the "ligand"). The complex, depicted in schematic form in FIG. 3, involves an elaborate array of contacts between the two protein domains and their mutual small molecule ligand. This work reveals the first structural insights into an FRB dornain-containing protein. Structure of the Ternary Complex The ternary complex of FKBP12-rapamycin-FRB has overall dimensions of 60 A x 45 A x 35 A with the rapamycin sandwiched between FKBP12 and FRB. The FKBP12 structure is basically the same as in previously reported binary structures, with a five stranded anti parallel β-sheet and a short α-helix. This binary structure was originally determined in the FKBP12-FK506 complex and later in the FKBP12-rapamycin complex (Van Duyne et al, 1993). The four helix bundle of FRB does not wrap around the effector site of FKBP12-rapamycin; it just touches the effector (i.e., FRB-binding) interface of the binary complex with few protein- protein interactions. All of the interactions between rapamycin and FRB are hydrophobic interactions, and protein-protein interactions between FKBP12 and FRB are limited to the 80s loop and one side chain of the 40s loop of FKBP12 (Table 2). The solvent accessible surface ° 2 - 2 areas of FKBP12 and FRB are 5348 A and 5711 A , respectively. Since the solvent accessible • 2 surface area of the FKBP12-FRB complex (protein only) is 10342 A , binding results in a very modest 6% reduction of solvent accessible surface area. Two long side chains in the 40s loop (Lys44 and Lys47) and three residues in the 80s loop (Thr85, Gly86 and His87) of FKBP12 appear to make crucial contact in the ternary complex. In the FRB site, two residues at the end of αl and the αl-α2 loop (Arg2042 and Tyr2038) contact the 80s loop of FKBP12, and two residues in helix α4 (Tyr2105 and Asp2102) form direct or water-mediated hydrogen bonds to the 40s loop of FKBP12. The loop-loop interaction between 80s loop (FKBP12) and the αl-α2 loop (FRB) and the loop-helix interaction between 40s loop (FKBP12) and helix α4 are the main protein-protein interactions in this ternary complex and thus contribute all of the protein- protein binding force forming the ternary complex. Structure of FRB domain of FRAP The FRB domain of the FRAP forms a typical four helix bundle, which is one of the most common structural motifs in globular proteins. The overall dimensions of this domain are 45 A x 30 A x 30 A. All four helices (termed αl-α4) are connected with short underhand loops. The longest helix cc3 (residues 2065-2091) has a bend at residue 2074 of 59°. Except for a small bent part of α3 (residues 1065-2073), all four helices have similar lengths (16-19 residues, about 30 A in length). The α2 helix also has a small bend around residues Glu2049, Val2050 and Leu2051 to form a 3ιo-helical turn rather than a normal α-helix. The angle between αl and ct2 is 22° and the angle between α3 and α4 is 20°. The angles between these pairs are in the range of 40-60°, which indicates that this four helix bundle is close to the 'X' type interhelical Table 2 Intra-molecular hydrogen bonds and close contacts in the ternary complex Inter-helical interactions in the FRB domain of FRAP Distance (A) Close contacts of rapamycin and FRB domain of FRAP Rapamycin FRB domain of FRAP Dis tance (A ) C50 Thr 2098 O 3 . 13 C27 Ser 2035 θγ 3 . 39 C51 Ser 2035 θγ 3 . 38 pattern which is the alternating pattern of parallel and perpendicular helix-helix interactions (Harris et αl, 1994). As usual, most of the hydrophobic and aromatic residues are located in the inter-helical interface and most of the hydrophilic residues are in the outside of the bundle, which is exposed to the solvent. Only two strong hydrogen bonds were found for the inter- helical interactions (Table 2) and could be key interactions maintaining the overall conformation of the four helix bundle. Helices αl and α4 , which have an interhelical angle of 44°, form a deep cleft on the molecular surface of this domain. This cleft is surrounded by six aromatic side chains forming the 'aromatic pocket' which has exquisite steric complementary for the rapamycin effector domain binding. Structure of FKBP12-rapamycin The structure of FKBP12 in the ternary complex is basically the same as that in the binary complex of FKBP12-rapamycin or FKBP12-FK506. The protein fold and the architecture of the secondary structure are exactly the same as in the binary complex, and the interaction with rapamycin is also the same as that of the binary complex. The overall r.m.s. deviation between the FKBP12 in the ternary complex and that in the FKBP12-rapamycin complex is 1.14 A (0.49 A for the main chain), and the deviation between FKBP12 in the ternary complex and that in the FKBP12-FK506 complex is 1.11 A (0.48 A for the main chain), which implies that binding of FKBP12:rapamycin to the FRAP FRB domain is not accompanied by significant changes in the conformation of the FRB binding site on FKBP12 or of the effector domain of rapamycin. Even the 40s loop and 80s loop regions in the FKBP12, that have direct interaction to the FRB domain, are not significantly different in 3D structure from that seen in the binary complexes. These r.m.s. values were calculated by the rigid-body fitting on the main chain atoms in the FKBP12 using QUANTA. The overlay of FKBP12-FK506 to the ternary complex clearly confirmed the fact that FKBP12-FK506 complex can't bind FRAP as FK506's effector region does not extend enough. The protein-protein interactions by themselves between FKBP12 and FRB are not enough for the formation of a binary complex; rapamycin is essential to mediate the interaction of the two proteins. FKBP12-rapamycin binding to FRAP While the interactions of rapamycin with FRB are all hydrophobic, rapamycin-FKBP12 interactions employ five hydrogen bonds which are the same found in the binary complex of FKBP12-rapamycin, to govern this interaction. Rapamycin is surrounded by five conserved aromatic residues in FKBP12, which makes the binding pocket for the rapamycin a complete aromatic pocket' along with six aromatic residues in FRB domain. Comparing the sequence of these aromatic residues of FRB domain with other FKBP-rapamycin target proteins, these six aromatic residues are all conserved in RAFT (Sabatini et al, 1994), TORI, and TOR2 (Stan, et al, 1994) — suggesting that these structural results will be applicable to other members of the PIK- related kinase family. It is expected that binding domains of these other proteins have a similar structure with FRB domain. For the interaction between rapamycin and FRB domain, two major sites on FRB are considered crucial for rapamycin binding. Ser2035, which is also conserved in other FKBP12-rapamycin target proteins, has close contact with C27 and C51 of rapamycin (Table 2). The other site is Thr2098 which has a close contact with C50 of rapamycin. C50 of the rapamycin is at the end of C16 methoxy group, which has been a key target for substituted analogs. All of the hydrophobic interactions between rapamycin and FRB including Ser2035 and Thr2098 can be considered as the main force contributing to complete ternary complex. Mutational studies Ser2035 in FRB has been the major site for the site-directed mutation studies of FRAP (Chen et al, 1995). Those studies revealed that the substitution of this residue to other residues larger than alanine abolish binding affinity toward FKBP12-rapamycin . The crystal structure of the ternary complex shows the direct effect of steric hindrance when this position is substituted by longer side chains. It has been suggested that this conserved serine site is a phosphorylation site, and phosphorylation would abrogate binding. By the binding of FKBP12-rapamycin, this serine site, which is open to the solvent when unbound, is protected from phosphorylation and this probably causes the inhibition of the downstream of the signaling pathway. For rapamycin, C16 has been the main site for substitution in published structure-activity studies (Luengo et al, 1995). The studies of C16 analogs of rapamycin showed that the bulky group substitutions on this position have lower affinity for the FKBP12 binding and lower activity. However some analogs with different stereochemistry or different groups showed retained activity and affinity to FKBP12. Such C-16 substituted analogs could be of therapeutic use. Applications of the invention This invention encompasses crystalline compositions containing FRAP or a FRAP homolog protein or portion thereof having a region characterized by structural coordinates of the FRB domain set forth in Appendix I, or by coordinates having a root mean square deviation therefrom of less than about 1.5 A, preferably less than about 1 A, and even more preferably less than about 0.5 A, with respect to backbone atoms of amino acid residues listed there. As practitioners in this art will appreciate, various computational analyses may be used to determine the degree of similarity between the three dimensional structure of a given protein (or a portion or complex thereof) and FRAP or a FRAP homolog protein or portion (e.g. the FRB domain) or complex thereof such as are described herein. Such analyses may be carried out with commercially available software applications, such as the Molecular Similarity application of QUANTA (Molecular Simulations Inc., Waltham, MA) version 3.3, and as described in the accompanying User's Guide, Volume 3 pgs. 134 - 135. The Molecular Similarity application permits comparisons between different structures, different conformations of the same structure, and different parts of the same structure. The procedure used in Molecular Similarity to compare structures is divided into four steps: (1) load the structures to be compared; (2) define the atom equivalences in these structures; (3) perform a fitting operation; and (4) analyze the results. Each structure is identified by a name. One structure is identified as the target (i.e., the fixed structure); all remaining structures are working structures (i.e., moving structures). Since atom equivalency within QUANTA is defined by user input, for the purpose of this invention we define equivalent atoms as protein backbone atoms (N, Cα, C and O) for all conserved residues between the two structures being compared and consider only rigid fitting operations. When a rigid fitting method is used, the working structure is translated and rotated to obtain an optimum fit with the target structure. The fitting operation uses a least squares fitting algorithm that computes the optimum translation and rotation to be applied to the moving structure, such that the root mean square difference of the fit over the specified pairs of equivalent atom is an absolute minimum. This number, given in angstroms, is reported by QUANTA. For the purpose of this invention, any set of structural coordinates of a FRAP or FRAP homolog protein, portion of a FRAP or FRAP homolog protein or molecular complex thereof that has a root mean square deviation of conserved residue backbone atoms (N, Cα, C, O) of less than 1.5 A when superimposed — using backbone atoms — on the relevant structural coordinates of a protein or complex of this invention, e.g. the coordinates listed in Appendix I, are considered identical. More preferably, the root mean square deviation is less than l.oA. Most preferably, the root mean square deviation is less than 0.5A. The term "root mean square deviation" means the square root of the arithmetic mean of the squares of the deviations from the mean. It is a way to express the deviation or variation from a trend or object. For purposes of this invention, the "root mean square deviation" defines the variation in the backbone of a protein from the backbone of a protein of this invention, such as the FRB of FRAP, as defined by the structural coordinates of Appendix I and described herein. The term "least squares" refers to a method based on the principle that the best estimate of a value is that in which the sum of the squares of the deviations of observed values is a minimum. In order to use the structural coordinates generated for a crystalline substance of this invention, e.g. the structural coordinates of the FRB of FRAP set forth in Appendix I, it is often necessary or desirable to display them as, or convert them to, a three-dimensional shape, or to otherwise manipulate them. This is typically accomplished by the use of commercially available software such as a program which is capable of generating three-dimensional graphical representations of molecules or portions thereof from a set of structural coordinates. By way of illustration, a non-exclusive list of computer programs for viewing or otherwise manipulating protein structures include the following: Midas (Univ. of California, San Francisco) X-Plor MidasPlus (Univ. of Cal., San Francisco) (Molecular Simulations, Inc.; Yale Univ.) MOIL (Univeristy of Illinois) Spartan (Wavefunction, Inc.) Yummie (Yale University) Catalyst (Molecular Simulations, Inc.) Sybyl (Tripos, Inc.) Molcadd (Tripos, Inc.) Insight/Discover (Biosym Technologies) VMD (Univ.of Illinois /Beckman Institute) MacroModel (Columbia University) Sculpt (Interactive Simulations, Inc.) Quanta (Molecular Simulations, Inc.) Procheck (Brookhaven NatT Laboratory) Cerius (Molecular Simulations, Inc.) DGEOM (QCPE) Alchemy (Tripos, Inc.) RE_VIEW (Brunei University) Lab Vision (Tripos, Inc.) Modeller (Birbeck Col., Univ. of London) Rasmol (Glaxo Research and Development) Xmol (Minnesota Supercomputing Center) Ribbon (University of Alabama) Protein Expert (Cambridge Scientific) NAOMI (Oxford University) HyperChem (Hypercube) Explorer Eyechem (Silicon Graphics, Inc.) MD Display (University of Washington) Univision (Cray Research) PKB Molscript (Uppsala University) (Nat'l Center for Biotech. Info., NIH) Chem-3D (Cambridge Scientific) ChemX (Chemical Design, Ltd.) Chain (Baylor College of Medicine) Cameleon (Oxford Molecular, Inc.) O (Uppsala University) Iditis (Oxford Molecular, Inc.) GRASP (Columbia University) For storage, transfer and use with such programs of structural coordinates for a crystalline substance of this invention, a machine-readable storage medium is provided comprising a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data, e.g. a computer loaded with one or more programs of the sort identified above, is capable of displaying a graphical three- dimensional representation of any of the molecules or molecular complexes described herein. Machine-readable storage media comprising a data storage material include conventional computer hard drives, floppy disks, DAT tape, CD-ROM, and other magnetic, magneto- optical, optical, floptical and other media which may be adapted for use with a computer. Even more preferred is a machine-readable data storage medium that is capable of displaying a graphical three-dimensional representation of a molecule or molecular complex that is defined by the structural coordinates of a complex, FRB-containing protein component thereof, or portion thereof, comprising structural coordinates of an FRB domain such as the FRAP FRB coordinates set forth in our attached Appendix I ± a root mean square deviation from the conserved backbone atoms of the amino acids thereof of not more than 1.5 A. An illustrative embodiment of this aspect of the invention is a conventional 3.5" diskette, DAT tape or hard drive encoded with a data set, preferably in PDB format, comprising the coordinates of our Appendix I. FIG. 3 illustrates a print-out of a graphical three-dimensional representation of such a complex. In another embodiment, the machine-readable data storage medium comprises a data storage material encoded with a first set of machine readable data which comprises the Fourier transform of the structural coordinates set forth in Appendix I (or again, a derivative thereof), and which, when using a machine programmed with instructions for using said data, can be combined with a second set of machine readable data comprising the X-ray diffraction pattern of a molecule or molecular complex to determine at least a portion of the structural coordinates corresponding to the second set of machine readable data. FIG. 1 illustrates one version of these embodiments. The depicted system includes a computer A comprising a central processing unit ("CPU"), a working memory which may be, e.g., RAM (random-access memory) or "core" memory, mass storage memory (such as one or more disk drives or CD-ROM drives), one or more cathode-ray tube ("CRT") display terminals, one or more keyboards, one or more input lines (IP), and one or more output lines (OP), all of which are interconnected by a conventional bidirectional system bus. Input hardware B, coupled to computer A by input lines, may be implemented in a variety of ways. Machine-readable data of this invention may be inputted via the use of a modem or modems connected by a telephone line or dedicated data line L. Alternatively or additionally, the input hardware may comprise CD-ROM drives or disk drives D. In conjunction with the CRT display terminal, a keyboard may also be used as an input device. Output hardware, coupled to computer A by output lines, may similarly be implemented by conventional devices. By way of example, output hardware may include a CRT display terminal for displaying a graphical representation of a protein of this invention (or portion thereof) using a program such as QUANTA as described herein. Output hardware might also include a printer, so that hard copy output may be produced, or a disk drive, to store system output for later use. In operation, the CPU coordinates the use of the various input and output devices, coordinates data accesses from mass storage and accesses to and from working memory, and determines the sequence of data processing steps. A number of programs may be used to process the machine-readable data of this invention. Examples of such programs are discussed in reference to the computational methods of drug discovery as described herein. Specific references to components of the hardware system of FIG. 1 are included as appropriate throughout the following description of the data storage medium. FIG. 2A shows a cross section of a magnetic data storage medium 100 which can be encoded with a machine-readable data that can be carried out by a system such as a system of FIG. 1. Medium 100 can be a conventional floppy diskette or hard disk, having a suitable substrate 101, which may be conventional, and a suitable coating 102, which may be conventional, on one or both sides, containing magnetic domains (not visible) whose polarity or orientation can be altered magnetically. Medium 100 may also have an opening (not shown) for receiving the spindle of a disk drive or other data storage device 24. The magnetic domains of coating 102 of medium 100 are polarized or oriented so as to encode in a manner which may be conventional, machine readable data such as that described herein, for execution by a system such as a system of FIG. 1. FIG. 2B shows a cross section of an optically-readable data storage medium 110 which also can be encoded with such machine-readable data, or set of instructions, which can be carried out by a system such as a system of FIG. 1. Medium 110 can be a conventional compact disk read only memory (CD-ROM) or a rewritable medium such as a magneto-optical disk which is optically readable and magneto-optically writable. Medium 100 preferably has a suitable substrate 111, which may be conventional, and a suitable coating 112, which may be conventional, usually of one side of substrate 111. In the case of CD-ROM, coating 112 is reflective and is impressed with a plurality of pits 113 to encode the machine-readable data. The arrangement of pits is read by reflecting laser light off the surface of coating 112. A protective coating 114, which preferably is substantially transparent, is provided on top of coating 112. In the case of a magneto-optical disk, coating 112 has no pits 113, but has a plurality of magnetic domains whose polarity or orientation can be changed magnetically when heated above a certain temperature, as by a laser (not shown). The orientation of the domains can be read by measuring the polarization of laser light reflected from coating 112. The arrangement of the domains encodes the data as described above. Use of Structure in Drug Discovery The availability of the three-dimensional structure of the ternary complex of FKBP12:rapamycin:FRB of FRAP makes structure-based drug discovery approaches possible. Structure-based approaches include de Novo molecular design, computer-aided optimization of lead molecules, and computer-based selection of candidate drug structures based on structural criteria. Rapamycin mimetics may be developed from the bound conformation of rapamycin by design, by searching databases for replacements of one or more structural segments of rapamycin, or by enhancement of existing ligand-protein interactions (i.e., by replacing a component moiety of a ligand with a substitute moiety capable of greater interaction with the target protein, whether through accessible protein contact points or by extrusion of otherwise sequestered waters). Knowledge of the bound conformation of a ligand can suggest avenues for conformational restriction and replacement of atoms and/or bonds of rapamycin. A less biased approach involves computer algorithms for searching databases of three dimensional structures to identify replacements for one or more portions of the ligand. By this method, one can generate compounds for which the bioactive conformation is heavily populated, i.e., compounds which are based on particularly biologically relevant conformations of the ligand. Algorithms for this purpose are implemented in programs such as Cast-3D (Chemical Abstracts Service), 3DB Unity (Tripos, Inc.), Quest-3D (Cambridge Crystallographic Data Center), and MACCS/ISIS-3D (Molecular Design Limited). These geometric searches can be augmented by steric searching, in which the size and shape requirements of the binding site are used to weed out hits that have prohibitive dimensions. Programs that may be used to synchronize the geometric and steric requirements in a search applied to the FRB of FRAP include CAVEAT (P. Bartlett, University of California, Berkeley), HOOK (MSI), ALADDIN (Daylight Software) and DOCK (I.D. Kuntz, University of California, San Francisco; see e.g. http://www.cmpharrn.ucsf.edu/kuntz-/kuntz.html and references cited therein). All of these searching protocols may be used in conjunction with existing corporate databases, the Cambridge Structural Database, or available chemical databases from chemical suppliers. Characterization of Compounds Compounds designed, selected and /or optimized by methods described above may be evaluated for binding activity with respect to proteins containing one or more FRB domains using various approaches, a number of which are well known in the art. For instance, compounds may be evaluated for activity as competitive inhibitors of the binding of a natural ligand for the FRB, e.g. FKBP12:rapamycin in the case of the FRAP FRB. Competitive inhibition may be determined using any of the numerous available technologies known in the art. Such compounds may be further evaluated for activity in inhibiting cellular or other biological events mediated by a pathway involving the interaction of interest using a suitable cell-based assay or an animal model. Cell-based assays and animal models suitable for evaluating inhibitory actvity of a compound with respect to a wide variety of cellular and other biological events are known in the art. New assays and models are regularly developed and reported in the scientific literature. For example, compounds which mimic the binding of rapamycin or FKBP12:rapamycin with respect to FRAP may be evaluated for biological activity in the mouse spelocyte mitogenesis assay or the high-flux yeast-based assay of Luengo et al, supra. A battery of in vivo models may be used to profile the breadth of the compound's immunosuppressive (or other) activity and compare the profile to those of positive controls such as rapamycin itself. Comparisons may also be made to other currently accepted immunosuppressive compounds, e.g. cyclophosphamide, and leflunomide. Initial in vivo screening models include: Delayed type hypersensitivity testing, Allogeneic skin transplantation, and Popliteal lymph node hyperplasia. Compounds demonstrating optimal profiles in the above models are advanced into more sophisticated models designed to confirm immunosuppressive activity in specific therapeutic areas including: Rheumatoid arthritis, Transplantation, Graft vs. host disease, and Asthma. By way of further illustration, compounds may be evaluated in relevant conventional in vitro and in vivo assays for inhibition of the initiation, maintenance or spread of cancerous growth. See e.g., Ishii et al, J. Antibiot. XLI 1877-1878 (1989) (in vitro evaluation of cytotoxic /antitumor activity); Sun et al, US Patent 5,206,249 (issued 27 April 1993)(m vitro evaluation of growth inhibitory activity on cultured leukemia cells); and Sun et al, supra (xenograft models using various human tumor cell lines xenografted into mice, as well as various transgenic animal models). Single and multiple (e.g., 5 to 7 days) dose investigative toxicology studies are typically performed in the efficacy test species using the intended route of administration for the efficacy study. These investigative toxicology studies are performed to identify maximum tolerated dose, subjective bioavailability from the intraperitoneal or oral routes of administration , and estimation of an initial safety margin. Initial bioavailability and pharmacokinetics (blood clearance) of the compounds may be determined, with standard cold or radioactive assay methods, to assist in defining appropriate dosing regimens for the compounds in the animal models. Pharmaceutical Compositions and Uses of rapamycin mimetics and other FRAP-binding compounds Compounds which bind to an FRB domain may be used as biological reagents in binding assays as described herein for functional classification of members of the PIK-related kinase family, particularly newly discovered proteins, based on ligand specificity. Moreover, compounds identified as described above can be used for their immunosuppressive or other pharmacologic activity in place of rapamycin. A compound selected or identified in accordance with this invention can be formulated into a pharmaceutical composition containing a pharmaceutically acceptable carrier and /or other excipient(s) using conventional materials and means. Such a composition can be administered as an immunosuppresant, for example, to an animal, either human or non-human. Administration of such composition may be by any conventional route (parenteral, oral, inhalation, and the like) using appropriate formulations as are well known in this art. The compound can be employed in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral administration. Pharmaceutical applications By virtue of its capacity to mimic the interaction of rapamycin with FRAP, a compound identified as described herein may be used in pharmaceutical compositions and methods for treatment or prevention of various diseases and disorders in a mammal in need thereof. Mammals include rodents such as mice, rats and guinea pigs as well as dogs, cats, horses, cattle, sheep, non-human primates and humans. The preferred method of such treatment or prevention is by administering to a mammal an effective amount of the compound to prevent, alleviate or cure said disease or disorder. Such effective amounts can be readily determined by evaluating the compounds of this invention in conventional assays well-known in the art, including assays described herein. Therapeutic/Prophylactic Administration & Pharmaceutical Compositions The invention provides methods of treating, preventing and /or alleviating the symptoms and /or severity of an untoward immune response or other disease or disorder referred to above by administration to a subject of a in an amount effective therefor. The subject will be an animal, including but not limited to animals such as cows, pigs, chickens, etc., and is preferably a mammal, and most preferably human. Various delivery systems are known and can be used to administer the compound, e.g., encapsulation in liposomes, microparticles, microcapsules, etc. One mode of delivery of interest is via pulmonary administration, as detailed more fully infra. Other methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The compound may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. For treatment or prophylaxis of nasal, bronchial or pulmonary conditions, preferred routes of administration are oral, nasal or via a bronchial aerosol or nebulizer. In specific embodiments, it may thus be desirable to administer the compound locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, by injection, by means of a catheter, by means of a suppository, or by means of a skin patch or implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. This invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically (or prophylactically) effective amount of the compound, and a pharmaceutically acceptable carrier or excipient. Such a carrier includes but is not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The carrier and composition can be sterile. The formulation should suit the mode of administration. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous adrrtinistration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic to ease pain at the side of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. Administration to an individual of an effective amount of the compound can also be accomplished topically by administering the compound(s) directly to the affected area of the skin of the individual. For this purpose, the compound is administered or applied in a composition including a pharmacologically acceptable topical carrier, such as a gel, an ointment, a lotion, or a cream, which includes, without limitation, such carriers as water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils. Other topical carriers include liquid petroleum, isopropyl palmitate, polyethylene glycol, ethanol (95%), polyoxyethylene monolaurate (5%) in water, or sodium lauryl sulfate (5%) in water. Other materials such as anti-oxidants, humectants, viscosity stabilizers, and similar agents may be added as necessary. In addition, in certain instances, it is expected that the compound may be disposed within devices placed upon, in, or under the skin. Such devices include patches, implants, and injections which release the compound into the skin, by either passive or active release mechanisms. Materials and methods for producing the various formulations are well known in the art [see e.g. US Patent Nos. 5,182,293 and 4,837,311 (tablets, capsules and other oral formulations as well as intravenous formulations)]. The effective dose of the compound will typically be in the range of about 0.01 to about 50 mg/kgs, preferably about 0.1 to about 10 mg/kg of mammalian body weight, administered in single or multiple doses. Generally, the compound may be administered to patients in need of such treatment in a daily dose range of about 1 to about 2000 mg per patient. The amount of the compound which will be effective in the treatment or prevention of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. The precise dosage level of the compound, as the active component(s), should be determined as in the case of all pharmaceutical treatments, by the attending physician or other health care provider and will depend upon well known factors, including route of administration, and the age, body weight, sex and general health of the individual; the nature, severity and clinical stage of the disease; and the use (or not) of concomitant therapies. The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. Pulmonary Administration In one embodiment of this invention, the compound is administered by pulmonary administration, e.g. via aerosolization. This route of administration may be particularly useful for treatment or prophylaxis of bronchial or pulmonary infection or tumors. Pulmonary administration can be accomplished, for example, using any of various delivery devices known in the art (see e.g., Newman, S.P., 1984, in Aerosols and the Lung , Clarke and Davia (eds.), Butterworths, London, England, pp. 197-224; PCT Publication No. WO 92/16192 dated October 1, 1992; PCT Publication No. WO 91/08760 dated June 27, 1991; NTIS Patent Application 7-504-047 filed April 3, 1990 by Roosdorp and Crystal), including but not limited to nebulizers, metered dose inhalers, and powder inhalers. Various delivery devices are commercially available and can be employed, e.g., Ultra vent nebulizer (Mallinckrodt, Inc., St. Louis, Missouri); Acorn II nebulizer (Marquest Medical Products, Englewood, Colorado), Ventolin metered dose inhaler (Glaxo Inc., Research Triangle Park, North Carolina); Spinhaler powder inhaler (Fisons Corp., Bedford, Massachusetts) or Turbohaler (Astra). Such devices typically entail the use of formulations suitable for dispensing from such a device, in which a propellant material may be present. Ultrasonic nebulizers tend to be more efficient than jet nebulizers in producing an aerosol of respirable size from a liquid (Smith and Spino, "Pharmacokinetics of Drugs in Cystic Fibrosis," Consensus Conference, Clinical Outcomes for Evaluation of New CF Therapies, Rockville, Maryland, December 10-11, 1992, Cystic Fibrosis Foundation). A nebulizer may be used to produce aerosol particles, or any of various physiologically acceptable inert gases may be used as an aerosolizing agent. Other components such as physiologically acceptable surfactants (e.g., glycerides), excipients (e.g., lactose), carriers, and diluents may also be included. This invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the the scope of the appended claims. Various patents, patent applications and publications are cited herein, the disclosures of which are incorporated by reference in their entireties. Experimental Examples I. Protein Preparation cDNAs encoding human FKBP12 (Standaert et al, 1990) and the 12-kDa FRAP fragment containing the FRB domain (Chen et al, 1995) (FRAP12) were subcloned into pGEX-2T (Pharmacia) for the expression of GST-FKBP12 and GST-FRAP12 fusion proteins in E.coli strain BL21. Typically, a 2-liter culture was grown to OD600~0-6 at 30 °C and induced with 0.3 mM IPTG at room temperature for 6 hours. Purification and thrombin cleavage of the fusion proteins were performed according to standard procedures (manual from Pharmacia). After removal of free GST, the samples containing FKBP12 or FRAP12 were concentrated to -10 mL in a 50 mL stir-cell ultraconcentrator (Amicon) with a 3-kDa cutoff filter, and fractionated on a Sephacryl S-100 column (2.5 cm x 85 cm) equilibrated in 10 mM phosphate buffer (pH 7.4) containing 136 mM NaCl, 3 mM KC1, 1 mM DTT. Fractions containing pure FKBP12 or FRAP12 (>95% purity judged by SDS-PAGE) were combined and concentrated to -10 mg/mL using a stir-cell ultraconcentrator. The concentrated samples were stored in the same phosphate buffer at 4 °C. II. Crystallization & Structure Determination Crystallization Recombinant human FKBP12 purified from E. coli was used at 10 mg/mL in 10 mM tris- HC1 pH 8.0. Rapamycin was dissolved in methanol and mixed with FKBP12 in a 2:1 molar ratio. The mixture was lightly vortexed and stored overnight at 4°C to insure complete complex formation. Purified 12-kDa FRB domain of FRAP at 10 mg/mL in 50 mM tris-HCl pH 8.0 was added to this mixture in a 1:1 (FKBP12-rapamycin complex:FRB domain) molar ratio. This mixture was also lightly vortexed and let sit overnight at 4°C to insure complete complex formation. Crystallization conditions were screened using the hanging drop method, and rectangular rod-shaped crystals were obtained using: 20% PEG 8000, 10% MPD and 10 mM tris-HCl at pH 8.5. For the hanging drop method, drops of 4μL containing 2μL of complex solution and 2μL of reservoir solution were equilibrated against 0.5 mL of the reservoir solution. Micro-seeding techniques were used to prepare additional crystals. The initial crystals were crushed and diluted to prepare a seed solution that was added to newly prepared drops. After two weeks, a shower of tiny crystals was obtained. Macro-seeding techniques were then applied to get large crystals suitable for X-ray diffraction. A tiny but well-formed crystal was picked and used as a crystallization seed. After two to three weeks, rectangular rod-shaped crystals with a maximum size of 0.3 x 0.2 x 0.1 mm' were obtained, and these crystals were suitable for data collection. The Hg-derivative crystal was obtained by soaking the native crystal in 2 mM Hgθ2 solution overnight. All of the crystallization experiments were done at 4°C. Data Collection All data sets were collected at room temperature on a San Diego multiwire area detector system mounted on a Rigaku RU-200 rotating anode X-ray source operating at 50 kV and 150mA. The detector was positioned at a 20-value of -30° with a 544 mm detector-crystal distance for the high resolution data and 12° with a 506 mm detector-crystal distance for the low resolution data. The data collection was performed using an co-scan with an increment of 0.10° for each frame and 40 second exposure time per frame. Crystals belong to the orthorhombic space group P2ι2ι2ι with unit-cell dimension of a=44.63, b=52.14, c=102.53 A and one FKBP12-rapamycin-FRB complex in the asymmetric unit. Hg-derivative crystal data were collected under the same conditions. For the native data set, the measured intensity data were processed using SCALEPACK (Otwinski et al, 1992) giving 6920 unique reflections out of 43447 measured reflections to 2.7 A resolution (98.5% data coverage) with R S y m of 7.1%. For the Hg-derivative data set, the number of unique reflection was 6884 out of 42681 measured reflections to 2.7 A (98.0% data coverage), with R S y m of 7.1%. Structure determination The crystal structure of the ternary complex was solved using the molecular replacement (MR) method combined with the single isomorphous replacement with anomalous scattering (SIRAS) method. Initial phases were obtained from the molecular replacement search using the FKBP12-rapamycin complex structure as a search model. The cross rotation search revealed a clear peak at ©1=10.8°, ©2=70.0°, ©3=309.4° with height/r.m.s. ratio of 12.9 and the translation search also showed a clear peak at x=0.000, y=0.230, z=0.417 with height/r.m.s. ratio of 10.5. Rigid body refinement resulted in an R factor of 0.449 (10-2.7 A). All molecular replacement calculations used the X-PLOR program (Brunger, 1990). However, the resulting difference electron density map was noisy and hard to interpret. In order to improve the map quality, an Hg derivative crystal was obtained. These data were compared with the native data to give an Rdiff of 12.7%. Two heavy atom sites were found from the difference Patterson map and were refined using the program PHASES (Furey et α/,1990). One Hg is bound to Cys22 of FKBP12 with full occupancy - the same Hg site seen in the FKBP12-FK506 complex. The other heavy atom site is in the middle of FRB domain where it is bound to Cys2085 of FRAP with an occupancy factor of 0.6. Both Patterson-deduced heavy atom positions were validated in the Fo-Fc difference map using Fo of the heavy atom derivative and Fc from the molecular replacement solution. Anomalous dispersion measurements were included in this data set and 16 cycles of a solvent flattening procedure were applied, resulting in a phasing power of 2.76 and mean figure of merit of 0.840. All of these calculations were performed using the program PHASES. The electron density map was calculated using the combined phase from the SIRAS and the molecular replacement solution, which clearly showed four helix bundle architecture of FRB domain of FRAP. Model Building and refinement The FKBP12-rapamycin part was well defined in the initial electron density map; only minor changes in the backbone of 30s loop and some side chains were enough to fit the model of FKBP12-rapamycin structure to this electron density map. For the FRB domain part, most of a polyalanine chain could be traced for the helix regions in the initial map. After several cycles of the positional refinement using X-PLOR, loop regions could be traced and the amino acid sequence could be assigned. The program CHAIN (Sack, 1988) was used for the model fitting and building the ternary complex. A total of 95 residues were built for the FRB domain of FRAP; three residues in the N-terminal and two residues in the C-terminal of FRB domain had no electron density and were not included. Positional refinement was followed by simulated annealing (slow cooling from 3000K to 300K in 25 K steps, 0.0005 ps per step and 50 total steps were used in the simulation at each temperature) and restrained B-factor refinement. All refinements were done using the X-PLOR package. Solvent molecules were assigned during the iterative positional and B-factor refinement procedure, if they appeared at the 3.5 σ level of Fo- Fc map, showed good hydrogen bonding geometry and had a low B-factor (less than 50 A^). The current structure includes 202 amino acids (107 for FKBP12 and 95 for FRB domain), one rapamycin, and 23 water molecules. The final R factor is 19.3% with an Rfree of 29.9%. The free R-factor is calculated with 10% of the data that were selected at the beginning of the analysis. Crystallographic statistics are summarized in Table 1. Quality of the coordinates The final coordinates have good geometry and r.m.s. deviations from the ideality are 0.008 A for bond lengths and 1.5° for bond angles. Examined by the program PROCHECK (Laskowski, 1993), the current 2.7 A resolution structure shows that the main-chain and side- chain geometrical parameters are better than expected at this resolution with an overall G- factor of 0.0. Ramachandran plots of φ, ψ, angles showed that 86% of the nonglycine and nonproline residues are in energetically most favored regions. The average temperature factors for total atoms and main-chain atoms are 17.0 and 14.7 A^ respectively. The r.m.s. variation in the B-factor of bonded atoms is 2.5 A^. The Luzzati plot (Luzzati, 1952) indicates that the average coordinate error of this complex structure is between 0.25 and 0.30 A. Those structural coordinates are set forth in Protein Databank format in Appendix I , below. Such data may be transferred to any desired medium, and formatted as desired, for the practitioner's computer. This invention encompasses those coordinates as well as any translation or rotation or the like thereof which maintains the internal coordinates, i.e., which maintains their intrinsic, internal relationship. Those skilled in the art will appreciate that the coordinates may be subjected to other transformations including, e.g. molecular mechanics calculations such as dynamic simulation, minimization, etc. This invention further encompasses the use of coordinates of the FRB of FRAP, of the ternary complex, or of the corresponding region of FRAP homologs, and in particular, the coordinates set forth in Appendix I, in conducting such transformations (or more extensive transformations such as the generation of alternative conformations), as well as the products of such transformations (i.e., derivatives of the coordinates). Table 1 Crystallographic statistics of the ternary complex FKBP12-rapamycin-FRB domain of FRAP Molecular replacement results Rotation function Θι=10. 82 o Θ 2 =70 . 00° Θ 3 =309 . 35° Height/r .m. s . =12 .9σ Translation function x=0.000 y=0.230 2=0.417 Height/r .m. s . =10.5σ Heavy atom data statistics (SIRAS) Mean Sites Rdiff ( % ) 1 Phasing power figure-of-merit 2 12.7 2.76 0.840 Refinement statistics Resolution Reflections Number of R-factor R free R.M. S . deviation (A) (with | F | >3σ) atoms (% ) (%) Bond lengths Bond angles (A) (°) -2 .7 6206 1727 19.3 29.9 0.008 1.48 "phasing power=r.m.s. (F jj /ε) , where FJJ is heavy-atom structure factor amplitude and residual lack of closure error. DI. Assays Compounds which bind to the FRB of FRAP may be evaluated using materials and methods useful for testing the biological or pharmacological activity of rapamycin analogs. See e.g. Luengo et al, 1995. In addition, the following animal models may be used for further evaluation of such compounds: (a) DELAYED TYPE HYPERSENSITIVITY Mouse abdomens are painted with sensitizing chemicals (sensitization) such as dinitroflourobenzene or oxazalone. Seven days later the ears of sensitized mice are painted (challenge) with a lower concentration of the compound. Antigen processing and presentation, T lymphocyte activation, leukocyte infiltration, humoral mediator release, increased microvascular permeability, and plasma exudation all result from challenge of sensitized mice and lead to edema formation. Edema presents as a two- to three- fold increase in ear thickness within twenty-four hours. The test compounds or standards can be applied (topical or parenteral) at various times before or after the sensitization or challenge phases. Increased ear thickness is prevented by several compounds including immunosuppressive agents and steroids. This model is a primary model for contact dermatitis. (b) ALLOGENEIC SKIN TRANSPLANTATION An allogeneic skin transplant model is used to identify immunosuppressive activity of test compounds. In this model, donor mouse thoracic skin (Balb/c) is surgically grafted onto the thorax of recipient mice (C57bl/6). Host rejection of the graft is evidenced by erythema, drying out, and retraction of donor skin. The mean graft survival time is 10 to 11 days, with 80% of the grafts being rejected by 12 days. Active novel immunosuppressive compounds, like existing immunosuppressive compounds, will prolong graft survival. (c) POPLITEAL LYMPH NODE HYPERPLASIA This model directly assesses T lymphocyte proliferation in vivo. Spleen cells, obtained from Balb/c mice, are isolated and administered into the foot pads of C3H mice. Within four days, the popliteal lymph nodes can be removed from the recipient mice and weighed. Other hematological assessments including FACS scanning for T lymphocyte subpopulations may also be performed. Active compounds, like existing immimosuppressive compounds, will inhibit the increase in node mass. (d) RHEUMATOID ARTHRITIS Several models are available for assessment of anti-arthritic activity, including adjuvant- induced, carageenan-induced, and collagen-induced arthritis in rats and /or mice. Paw pads are injected with one of these agents. Paws increase in volume, and measurements are made between 20 and 30 days later. The ability of test compounds to prevent the induction of paw swelling is tested with daily treatment for 12 consecutive days following the injection of inducing agent. The ability for the test compounds to reverse the progression of the paw swelling is tested by administration of the compound for 12 consecutive days beginning on the twelfth day following the injection of inducing agent. Paw swelling measurements are made by water displacement plethysmography. Histology is also an appropriate endpoint for these studies. The MRL/lpr-mouse model, described above, is required for the rheumatoid arthritis indication. This model is a spontaneous autoimmune model that develops rheumatoid arthritis resembling the human condition, including the presence of circulating rheumatoid factor, pannus formation, and bone and cartilage erosion. e) SYSTEMIC LUPUS ERYTHEMATOSUS Systemic lupus erythematosus is another autoimmune disease with several animal models. Several murine strains develop spontaneous SLE. One such strain is MRL/lpr-mice. These mice, over time (20 to 30 weeks) develop auto-antibodies against dsDNA, nuclear antigens, and renal basement membrane. This leads to complement fixation and immune complex formation. Damage to the kidney becomes apparent with the onset of proteinuria. Many of the other physiologic, hematologic, and immunologic aberrations described below for the CGVHD model are present. Immunosuppressive compounds such as cyclosporin, cyclophosphamide, and leflunomide can prevent and reverse the course of disease in this model. Interestingly, these mice also develop pathologies akin to rheumatoid arthritis. The murine chronic graft versus host disease model (CGVHD, described below) is a model of SLE that contains many of the clinical features of SLE. Activity in this model has been shown to be predictive of activity in the more clinically relevant SLE models. (f) TRANSPLANTATION Allograft transplantation (skin graft) assay is often used as an initial test of immunosuppressive activity. While this model is useful as a screen, it may be supplemented with assays based on animal transplant models involving transplantation of internal organ (heart, liver, kidney, bone marrow) with use of "clinically acceptable" physiologic endpoints to assess graft survival. Efficacy of test compounds in only a very limited number of these rodent models is required. Following observation of activity in a rodent model, the test compounds are typically tested in further animal models (e.g., canine, porcine or non-human primate). Active compounds decrease acute and chronic rejection and prolong transplant survival. (g) GRAFT VS. HOST DISEASE Chronic GVHD (CGVHD) can be used to model CD4 + -dependent humoral immunity. It is induced in BDFi mice (which are progeny of DBA/2 male x C57BL/6 female matings) by administering to them isolated spleen:lymph node cells from DBA/2 mice. This results in: a) disregulation and stimulation of CD4 + T lymphocyte (Lyl + ; murine marker) activity due to incompatibilities at MHC II molecules, and b) abnormal T-B lymphocyte cooperation. The resulting pathological state, in many ways, mimics systemic lupus erythematosus (SLE). Several measurable endpoints develop within 14 days; including, circulating anti-host IgG and IgE antibodies, altered T and B lymphocyte proliferation activity measured in vitro, complement utilization, hemagglutination, slow progressive wasting, dermal aberrations, splenomegaly, lymphoid hyperplasia, and proteinuria. Only a few of these endpoints need to be measured. Active compounds are are those which limit T lymphocyte disregulation and abrogate changes in these variables. Many steroids (e.g., prednisolone), cyclosporine, FK-506, cyclophosphamide, and leflunomide are all active in this model and can be used as positive controls. The acute GVHD model (AGVHD) is also produced in BDFj mice. In this case, isolated spleen:lymph node cells from C57BL/6 mice are administered. This results in disregulation and stimulation of CD8 + T lymphocytes due to incompatibilities in the MHC I molecules. Elevated cytokine levels and donor clonal expansion occurs. Ultimately, donor cytotoxic T lymphocytes and NK cells rapidly reject host tissue and cause relatively rapid death of the recipient. The progression of AGVHD in this model is assessed by measurement of hematologic abnormalities (including T cell number and type), cytokine elevations (TNF, IL-1, IL-2, and/or IL-4), low body weight, hypoγglobulinemia, circulating hematologic characteristics indicative of aplastic anemia (granulocytopenia, thrombocytopenia), ex vivo NK or CTL activity, and host survival. Active compounds are those which abrogate changes in the variables, and prolong survival over 4 to 6 weeks. (h) ASTHMA Asthma offers another opportunity for safe immunosuppressive therapy. Atopic asthmatics have antibody mediated hypersensitivity and the often occurring late phase reaction is likened to a DTH response. Asthma has only recently been defined as an inflammatory disease (1992). Since then, several publications from prominent asthmatologists demonstrate the presence of activated CD4 + and CD8 + T lymphocytes in bronchoalveolar lavage fluid and blood of atopic asthmatics. The ratios of these cells changes in asthmatic conditions. Furthermore, several of the T cell associated cytokines (IL-1, IL-2, IL-4, IL-5, and TNF) are all implicated in clinical and experimental asthma. Inflammatory events in asthma are now considered to be T lymphocyte driven. Initial clinical trials with inhaled cyclosporin suggest that local immunosuppression can ameliorate airway hyperreactivity - the underlying defect in asthma. The guinea pig model of antigen-induced pulmonary aberrations is used as a model for asthma. These animals are actively sensitized to ovalbumin to generate high circulating titers of anti-ovalbumin antibody with seroconversion to the IgE class, as is the case with atopic asthmatics. Aerosol challenge of sensitized guinea pigs results in measurable eosinophil rich pulmonary infiltrates (approximately a 16-fold increase in eosinophils), pulmonary edema, and mucous plugging of the small airways; all culminating in the expression of the underlying defect in asthma- airway hyperreactivity (approximately a 3 to 4-fold increase in reactivity). Acute bronchoconstriction is obviously present and points the aforementioned presence of the pathophysiologic sequelae. Active compounds are those which lessen or abrogate such symptoms. The above description is meant to illustrate, rather than limit the scope of the invention. Given the foregoing description, numerous variations in the materials or methods employed in performing the invention will be obvious to one skilled in the art. Any such obvious variation is to be considered within the scope of the invention. Full references to literature cited above (by reference to author and year) are provided below: References Brown, E. J., Albers, M. W., Shin, T. B., Ichickawa, K., Keith, C. T., Lane, W. S. & Schreiber, S. L. Nature 369, 756-758 (1994). Brunger, A. T. X-PLOR Version 3.1 Manual (Yale Univ. Press, New Haven, CT, 1992) Chen, J., Zheng, X.-F., Brown, E. J. & Schreiber, S. L. Proc. Natl. Acad. Sci. USA 92, 4947- 4951 (1995). Chiu, M. I., Katz, H & Berlin, V. Proc. Natl. Acad. Sci. USA 91, 12574-12578 (1994). Clardy, J. . Proc. Natl. Acad. Sci. USA 92, 56-61 (1995). Dayhoff, M.O.; Schwartz, R.M.; Orcutt, B.C., Atlas of Protein Sequence and Structure, 5, Suppl. 3,345 (1979) Furey, W. and Swaminathan, S. American Crystallographic Association Mtg. Abstr. Ser. 2 18, 73 (1990) Gonnet, G.H., Cohen, M.A., Benner, S.A. Science , 256, 1443 (1992) Greer, J., J. Mol. Biol. , 153, 1027 (1981) Griffith, J. P., Kim, J. L., Kim, E. E., Sintchak, M. D., Thomson, J. A., Fitzgibbon, M. J., Fleming, M. A., Caron, P. R., Hsiao, K. & Navia, M. A. Cell 82, 507-522 (1995). Harris, N. L., Presnell, S. R., and Cohen, F. E. /. Mol. Biol. 236, 1356-1368 (1994) Keith & Schreiber, 1995, Science 270:50-51. Laskowski, R. A. /. Appl. Cryst. 26, 283-291 (1993) Luengo, J. I., Yamashita, D. S., Dunnington, D., Konialian Beck, A., Rozamus, L. W., Yen, H., Bossard, M. J., Levy, M. A., Hand, A., Newman-Tarr, T., Badger, A., Faucette, L., Johnson, R. K., D'Alessio, K., Porter, T., Shu, A. Y., Heys, R., Choi, J., Kongsaeree, P., Clardy, J., and Holt, D. A. Chemistry & Biology 2, 471-481 (1995). Luzzati, P. V. Ada Cryst. 5, 802-810 (1952) Otwinski, Z. The SCALEPACK Manual (Howard Hughes Medical Institute, Yale Univ., New Haven, CT, 1992). Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S. H. Cell 78, 35-43 (1994). Sack, J. S. /. Mol. Graphics 6, 224-225 (1988) Schreiber, S. L. Cell 70, 365-368 (1992). Sehgal, S. N., Baker, H. & Vezina, C. J. Antibiot. 6, 727-732 (1975). Sehgal, S. N. Ann. N.Y. Acad. Sci. 696, 1-8 (1993). Stan, R., McLaughlin, M. M., Cafferkey, R., Johnson, R. K., Rosenberg, M., and Livi, G. P. /. Biol. Chem. 269, 32027-32030 (1994) Standaert, R. F., Galat, A., Verdine, G. L. & Schreiber, S. L. Nature 346, 671-674 (1990) Tanaka, H., Kuroda, A., Marusawa, H., Hatanaka, H., Kino, T., Goto, T. & Hashimoto, M. J. Amer. Chem. Soc. 109, 5031-5033 (1987). VanDuyne, G. D., Standaert, R. F., Schreiber, S. L. & Clardy, J. Science 251, 839-842 (1991). VanDuyne, G. D., Standaert, R. F., Schreiber, S. L. & Clardy, J. J. Am. Chem. Soc. 113, 7433- 7434 (1991a). Van Duyne, G. D., Standaert, R. R, Kaφlus, A., Schreiber, S. L. & Clardy, J. J. Mol. Biol. 229, 105-124 (1993). Vezina, C, Kudelski, A. & Sehgal, S. N. J. Antibiot. 28, 721-726 (1975). Zakian, V. A. Cell 82, 685-687 (1995) Appendix I 4.588 25.968 49.843 1.00 12.34 FKBP 3 .587 26.690 49.931 1.00 3 .24 EKBP 5.460 28.281 50.881 0.00 0.00 FKBP 5.463 28.482 49.221 0.00 0.00 FKBP 5.987 28.058 50.014 1.00 24.95 FKBP 6.961 28.429 50.048 0.00 0.00 FKBP 5.986 26.568 49.849 1.00 14.30 FKBP 4.539 24.648 49.684 1.00 9.85 FKBP 5.366 24.143 49.539 0.00 0.00 FKBP 3 .311 23 .862 49.748 1.00 11.89 FKBP 2.889 23.360 48.318 1.00 9.17 FKBP 4.114 23 .006 47.492 1.00 14.93 FKBP 1.975 22.155 48.411 1.00 2 .00 FKBP 3 .549 22.668 50.692 1.00 15.67 FKBP 4.576 21.989 50.605 1.00 16.61 FKBP 2 .643 22.482 51.646 1.00 17.91 FKBP 1.852 23 .045 51.649 0.00 0.00 FKBP 2 .789 21.445 52.664 1.00 20.42 FKBP 2.600 22.065 54.056 1.00 26.51 FKBP 2 .416 21.064 55.181 1.00 34.77 FKBP 3 .718 20.451 55.660 1.00 41.28 FKBP 4.754 20.581 55.015 1.00 44.41 FKBP 3 .665 19.760 56.792 1.00 42.31 FKBP 2.812 19.651 57.241 0.00 0.00 FKBP 4.510 19.373 57.085 0.00 0.00 FKBP 1.817 20.280 52.454 1.00 17.06 FKBP 0.608 20.466 52 .367 1.00 17.79 FKBP 2.363 19.082 52.313 1.00 14.50 FKBP 3 .336 19.008 52.381 0.00 0.00 FKBP 1.540 17.890 52.127 1.00 13 .12 FKBP 2 .054 17.030 50.930 1.00 10.68 FKBP 0.924 16.172 50.364 1.00 7 .51 FKBP 2.630 17.930 49.842 1.00 9.85 FKBP 1.544 17.037 53 .401 1.00 12 .15 FKBP 2.600 16.705 53 .947 1.00 15.65 FKBP 0.363 16.733 53 .914 1.00 6.97 FKBP -0.430 17.182 53 .551 0.00 0.00 FKBP 0.275 15.856 55.071 1.00 5.19 FKBP -0.096 16.664 56.308 1.00 8.81 FKBP 0.621 17.998 56.389 1.00 13.30 FKBP 0.346 18.726 57.674 1.00 15.76 FKBP 1.188 18.629 58.586 1.0022.97 FKBP -0.710 19.385 57.778 1.0022.20 FKBP -0.743 14.752 54.848 1.00 3.46 FKBP -1.937 15.023 54.745 1.00 4.04 FKBP -0.271 13.511 54.805 1.00 2.00 FKBP 0.666 13.372 55.050 0.00 0.00 FKBP -1.125 12.365 54.508 1.00 5.26 FKBP -0.337 11.045 54.575 1.00 3.67 FKBP 0.881 11.178 53.836 1.0013.50 FKBP 1.493 10.508 54.158 0.00 0.00 FKBP -1.132 9.919 53.972 1.00 2.01 FKBP -2.355 12.240 55.415 1.00 9.57 FKBP -2.281 12.454 56.629 1.00 15.36 FKBP -3.509 12.099 54.772 1.00 8.03 FKBP -3.506 12.334 53.824 0.00 0.00 FKBP -4.755 11.709 55.423 1.00 7.62 FKBP -5.965 12.465 54.799 1.00 5.96 FKBP -7.275 11.841 55.244 1.00 2.71 FKBP -5.918 13.947 55.170 1.00 2.00 FKBP -7.008 14.764 54.527 1.00 2.01 FKBP -4.979 10.199 55.249 1.00 11.96 FKBP -5.686 9.576 56.034 1.00 17.57 FKBP -4.469 9.648 54.151 1.00 12.78 FKBP -4.039 10.240 53.499 0.00 0.00 FKBP -4.629 8.226 53.842 1.00 12.24 FKBP -6.079 7.930 53.450 1.00 6.63 FKBP -6.236 6.581 53.064 1.00 12.33 FKBP -7.179 6.384 53.022 0.00 0.00 FKBP -3.685 7.798 52.707 1.0019.11 FKBP -3.607 8.454 51.664 1.00 17.14 FKBP -2.830 6.798 52.965 1.0023.27 FKBP -2.665 6.076 54.238 1.0022.82 FKBP -1.706 6.548 52.055 1.0025.68 FKBP -0.709 5.793 52.932 1.0025.08 FKBP -1.572 5.093 53.920 1.0026.18 FKBP 5.766 50.778 1.0028.63 FKBP 5.014 50.737 1.0030.17 FKBP 5.988 49.728 1.00 28.78 FKBP 6.696 49.796 0.00 0.00 FKBP 5.168 48.531 1.0032.81 FKBP 4.154 48.412 1.0034.72 FKBP 3.916 49.386 1.00 37.49 FKBP 3.626 47.208 1.00 30.71 FKBP 3.846 46.504 0.00 0.00 FKBP 2.585 47.006 1.0028.23 FKBP 1.862 45.675 1.0023.26 FKBP 2.804 44.493 1.0021.83 FKBP 3.686 44.377 1.00 13.66 FKBP 2.635 43.659 1.00 23.38 FKBP 3.073 47.085 1.0029.86 FKBP 2.273 47.190 1.00 31.65 FKBP 4.372 46.898 1.0031.53 FKBP 4.932 46.696 0.00 0.00 FKBP 4.948 47.081 1.00 34.79 FKBP 4.585 46.015 1.00 37.89 FKBP 4.621 46.262 1.00 38.20 FKBP 4.222 44.833 1.0040.35 FKBP 3.918 44.840 0.00 0.00 FKBP 4.030 43.667 1.0043.98 FKBP 2.552 43.526 1.0048.12 FKBP 1.555 43.724 1.00 56.08 FKBP 0.296 44.418 1.00 64.50 FKBP 0.361 45.870 1.0070.55 FKBP 1.005 46.370 0.00 0.00 FKBP -0.435 46.567 1.0073.54 FKBP -0.266 47.877 1.0074.82 FKBP 0.450 48.341 0.00 0.00 FKBP -0.864 48.399 0.00 0.00 FKBP -1.415 45.961 1.0075.14 FKBP -1.557 44.977 0.00 0.00 FKBP -2.001 46.485 0.00 0.00 FKBP 4.537 42.369 1.00 40.88 FKBP 4.995 41.459 1.0041.05 FKBP 4.531 42.328 1.0036.51 FKBP 2.944 3.906 42.915 0.00 0.00 FKBP 2.654 5.085 41.199 1.00 31.82 FKBP 1.296 4.362 41.010 1.00 34.22 FKBP 1.477 2.945 41.172 1.00 31.38 FKBP 0.659 2.484 40.952 0.00 0.00 FKBP 0.722 4.651 39.621 1.00 29.70 FKBP 2.416 6.589 41.356 1.00 28.19 FKBP 1.373 7.023 41.846 1.00 25.30 FKBP 3.430 7.364 41.000 1.00 27.12 FKBP 4.257 6.922 40.707 0.00 0.00 FKBP 3.354 8.822 40.970 1.00 30.73 FKBP 4.725 9.405 41.330 1.00 30.56 FKBP 5.202 9.018 42.701 1.00 31.81 FKBP 5.046 9.885 43.775 1.00 31.26 FKBP 5.732 7.756 42.936 1.00 31.84 FKBP 5.400 9.499 45.062 1.00 28.40 FKBP 6.089 7.363 44.218 1.00 31.05 FKBP 5.919 8.237 45.283 1.00 31.16 FKBP 2.902 9.358 39.596 1.00 34.59 FKBP 3.176 8.739 38.557 1.00 32.29 FKBP 2.232 10.532 39.571 1.00 35.21 FKBP 2.068 11.493 40.671 1.00 32.43 FKBP 1.814 11.122 38.296 1.00 36.14 FKBP 0.852 12.243 38.710 1.00 33.90 FKBP 0.905 12.310 40.215 1.00 34.16 FKBP 2.998 11.672 37.512 1.00 38.59 FKBP 3.580 12.683 37.895 1.00 40.62 FKBP 3.408 10.958 36.467 1.00 44.97 FKBP 3.044 10.054 36.366 0.00 0.00 FKBP 4.463 11.441 35.572 1.00 49.95 FKBP 4.856 10.356 34.563 1.00 53.22 FKBP 5.973 9.427 35.030 1.00 61.47 FKBP 5.425 8.075 35.497 1.00 69.15 FKBP 6.545 7.050 35.721 1.00 73.13 FKBP 6.050 5.706 36.174 1.00 72.77 FKBP 5.395 5.316 35.466 0.00 0.00 FKBP 5.550 5.803 37.081 0.00 0.00 FKBP 6.857 5.061 36.292 0.00 0.00 FKBP 4.031 12.703 34.823 1.00 50.23 FKBP ATOM 155 O LYS 17 2.882 12.813 34.389 1.00 51.36 FKBP ATOM 156 N ARG 18 4.938 13.672 34.718 1.00 48.43 FKBP ATOM 157 H ARG 18 5.782 13.553 35.190 0.00 0.00 FKBP ATOM 158 CA ARG 18 4.666 14.908 33.986 1.00 46.13 FKBP ATOM 159 CB ARG 18 5.968 15.671 33.732 1.00 47.22 FKBP ATOM 160 CG ARG 18 5.755 17.034 33.092 1.00 53.52 FKBP ATOM 161 CD ARG 18 7.030 17.572 32.467 1.00 60.93 FKBP ATOM 162 NE ARG 18 8.005 18.008 33.466 1.00 68.56 FKBP ATOM 163 HE ARG 18 8.698 17.375 33.748 0.00 0.00 FKBP ATOM 164 CZ ARG 18 7.995 19.201 34.054 1.00 71.82 FKBP ATOM 165 NED. ARG 18 8.954 19.528 34.910 1.00 73.41 FKBP ATOM 166 HHL1 ARG 18 9.674 18.876 35.143 0.00 0.00 FKBP ATOM 167 HH12 ARG 18 8.923 20.425 35.358 0.00 0.00 FKBP ATOM 168 H2 ARG 18 7.000 20.052 33.826 1.00 74.07 FKBP ATOM 169 HH21 ARG 18 6.256 19.798 33.207 0.00 0.00 FKBP ATOM 170 HH22 ARG 18 6.994 20.950 34.267 0.00 0.00 FKBP ATOM 171 C ARG 18 3.965 14.637 32.652 1.00 44.43 FKBP ATOM 172 O ARG 18 4.440 13.832 31.844 1.00 44.85 FKBP ATOM 173 N GLY 19 2.775 15.209 32.491 1.00 41.63 FKBP ATOM 174 H GLY 19 2.437 15.781 33.210 0.00 0.00 FKBP ATOM 175 CA GLY 19 2.037 15.058 31.246 1.00 36.64 FKBP ATOM 176 C GLY 19 0.878 14.072 31.281 1.00 33.71 FKBP ATOM 177 0 GLY 19 0.242 13.821 30.256 1.00 31.30 FKBP ATOM 178 N GLN 20 0.603 13.509 32.454 1.00 31.51 FKBP ATOM 179 H GLN 20 1.278 13.579 33.162 0.00 0.00 FKBP ATOM 180 CA GLN 20 -0.571 12.655 32.647 1.00 27.89 FKBP ATOM 181 CB GLN 20 -0.290 11.586 33.702 1.00 27.47 FKBP ATOM 182 CG GLN 20 0.907 10.723 33.416 1.00 29.05 FKBP ATOM 183 CD GLN 20 0.945 9.516 34.305 1.00 28.73 FKBP ATOM 184 OE1 GLN 20 1.852 9.355 35.112 1.00 29.95 FKBP ATOM 185 E2 GLN 20 -0.064 8.672 34.191 1.00 29.76 FKBP ATOM 186 HE21 GLN 20 -0.781 8.854 33.542 0.00 0.00 FKBP ATOM 187 HE22 GLN 20 -0.025 7.895 34.776 0.00 0.00 FKBP ATOM 188 C GLN 20 -1.784 13.458 33.096 1.00 26.36 FKBP ATOM 189 0 GLN 20 -1.641 14.558 33.652 1.00 23.69 FKBP ATOM 190 Ν THR 21 -2.957 12.836 32.994 1.00 23.74 FKBP ATOM 191 H THR 21 -2.993 11.964 32.525 0.00 0.00 FKBP ATOM 192 CA THR 21 -4.185 13.406 33.551 1.00 19.78 FKBP ATOM 193 CB THR 21 -5.398 13.137 32.648 1.00 18.09 FKBP -5.103 13.576 31.319 1.0025.65 FKBP -4.667 12.831 30.862 0.00 0.00 FKBP -6.624 13.882 33.159 1.0015.30 FKBP -4.502 12.869 34.945 1.00 19.51 FKBP -4.895 11.707 35.112 1.0021.36 FKBP -4.390 13.744 35.939 1.00 15.33 FKBP -4.044 14.636 35.726 0.00 0.00 FKBP -4.794 13.421 37.302 1.00 7.92 FKBP -4.056 14.322 38.281 1.00 4.88 FKBP -2.300 14.464 37.959 1.00 9.58 FKBP -6.301 13.589 37.492 1.00 7.02 FKBP -6.840 14.676 37.284 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FKBP -10.813 23.538 49.128 1.00 8.04 FKBP -11.438 24.437 50.175 1.00 8.15 FKBP -12.646 24.729 50.131 1.00 9.73 FKBP -10.619 24.887 51.117 1.00 4.38 FKBP -9.683 24.601 51.122 0.00 0.00 FKBP -11.091 25.812 52.138 1.00 6.14 FKBP -11.512 25.047 53.404 1.00 11.72 FKBP -10.445 24.128 53.999 1.00 14.88 FKBP -11.065 22.500 54.510 1.00 7.90 FKBP -12.824 22.854 54.721 1.00 5.60 FKBP -10.033 26.845 52.477 1.00 6.50 FKBP -8.847 26.630 52.242 1.00 5.89 FKBP -10.477 28.013 52.923 1.00 11.28 FKBP -11.444 28.168 52.902 0.00 0.00 FKBP -9.561 29.028 53.443 1.00 14.74 FKBP -10.281 30.379 53.572 1.00 12.99 FKBP -10.887 30.967 52.292 1.00 10.36 FKBP -12.064 31.842 52.668 1.00 12.99 FKBP -9.848 31.761 51.510 1.00 3.34 FKBP -9.042 28.573 54.805 1.00 14.12 FKBP -9.664 27.732 55.453 1.00 16.16 FKBP -7.944 29.169 55.262 1.00 14.66 FKBP -7.506 29.828 54.682 0.00 0.00 FKBP -7.266 28.722 56.483 1.00 17.28 FKBP -6.294 29.799 56.962 1.00 14.61 FKBP -5.818 29.586 58.382 1.00 22.25 FKBP -4.510 30.284 58.698 1.0026.77 FKBP -4.245 31.362 58.107 1.00 21.74 FKBP -3.774 29.762 59.576 1.0023.08 FKBP -8.187 28.313 57.642 1.00 18.96 FKBP -8.008 27.258 58.262 1.00 18.93 FKBP -9.238 29.090 57.855 1.00 17.34 FKBP -9.405 29.814 57.223 0.00 0.00 FKBP -10.116 28.866 58.996 1.00 19.84 FKBP -10.894 30.142 59.308 1.0027.98 FKBP -11.601 30.704 58.090 1.00 34.72 FKBP -12.727 30.254 57.801 1.0032.49 FKBP -11.023 31.588 57.415 1.00 43.34 FKBP -11.096 27.713 58.816 1.00 18.08 FKBP -11.986 27.541 59.638 1.00 17.85 FKBP -10.994 26.998 57.697 1.00 18.90 FKBP -10.204 27.111 57.137 0.00 0.00 FKBP -11.909 25.896 57.417 1.00 14.65 FKBP -13.146 26.270 56.616 1.00 10.95 FKBP -14.020 25.437 56.370 1.00 11.28 FKBP -13.235 27.536 56.230 1.00 5.53 FKBP -12.565 28.159 56.564 0.00 0.00 FKBP -14.320 27.999 55.379 1.00 7.65 FKBP -14.270 29.521 55.255 1.00 15.91 FKBP -15.468 30.131 54.554 1.0023.47 FKBP -15.360 31.646 54.513 1.00 34.71 FKBP -15.213 32.245 55.918 1.00 38.38 FKBP -13.805 32.635 56.227 1.0041.83 FKBP -13.475 33.324 55.520 0.00 0.00 FKBP -13.196 31.792 56.185 0.00 0.00 FKBP -13.749 33.055 57.176 0.00 0.00 FKBP -14.222 27.369 53.991 1.00 7.56 FKBP -13.290 27.653 53.232 1.00 3.26 FKBP -15.067 26.371 53.757 1.00 8.73 FKBP -15.554 26.012 54.530 0.00 0.00 FKBP -15.178 25.719 52.459 1.00 8.15 FKBP -16.269 24.657 52.511 1.00 2.40 FKBP -16.379 23.854 51.249 1.00 7.41 FKBP -17.142 22.573 51.484 1.00 11.33 FKBP -18.637 22.803 51.464 1.00 15.67 FKBP -19.352 21.501 51.304 1.00 20.77 FKBP -19.180 20.892 52.129 0.00 0.00 FKBP -19.004 21.025 50.450 0.00 0.00 FKBP -20.373 21.681 51.212 0.00 0.00 FKBP -15.520 26.736 51.378 1.00 13.32 FKBP -16.387 27.596 51.587 1.00 16.59 FKBP -14.796 26.690 50.257 1.00 12.19 FKBP -13.981 26.149 50.278 0.00 0.00 FKBP -15.167 27.504 49.098 1.00 8.93 FKBP -14.077 28.541 48.753 1.00 4.86 FKBP -12.728 27.959 48.415 1.00 3.36 FKBP -11.660 28.108 49.295 1.00 4.33 FKBP -12.470 27.442 47.151 1.00 7.57 FKBP -10.350 27.758 48.916 1.00 5.11 FKBP -11.167 27.092 46.766 1.00 5.95 FKBP -10.110 27.250 47.648 1.00 2.00 FKBP -15.553 26.696 47.861 1.00 11.24 FKBP -16.499 27.050 47.152 1.00 9.15 FKBP -14.972 25.507 47.738 1.00 11.21 FKBP -14.365 25.202 48.445 0.00 0.00 FKBP -15.201 24.672 46.568 1.00 8.81 FKBP -14.340 25.220 45.416 1.00 12.70 FKBP -14.583 24.518 44.091 1.00 11.57 FKBP -15.679 23.968 43.855 1.00 7.88 FKBP -13.665 24.565 43.254 1.00 15.66 FKBP -14.874 23.199 46.864 1.00 2.00 FKBP -13.905 22.904 47.545 1.00 2.01 FKBP -15.751 22.291 46.450 1.00 2.52 FKBP -16.607 22.613 46.095 0.00 0.00 FKBP -15.461 20.850 46.493 1.00 2.33 FKBP -15.954 20.223 47.800 1.00 12.19 FKBP -15.979 18.804 47.722 1.00 9.54 FKBP -15.613 18.490 48.571 0.00 0.00 FKBP -16.108 20.110 45.349 1.00 2.00 FKBP -17.313 20.210 45.168 1.00 2.31 FKBP -15.339 19.252 44.684 1.00 2.00 FKBP -14.397 19.223 44.967 0.00 0.00 FKBP -15.840 18.414 43.584 1.00 3.72 FKBP -14.682 17.758 42.825 1.00 3.50 FKBP -13.861 16.976 43.683 1.00 3.28 FKBP -14.195 17.054 44.589 0.00 0.00 FKBP -16.762 17.317 44.088 1.00 9.63 FKBP -17.547 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31.10 FKBP 1.283 21.482 32.739 1.00 31.85 FKBP 0.651 20.805 33.051 0.00 0.00 FKBP 0.883 22.452 31.724 1.00 30.54 FKBP -0.281 21.887 30.899 1.00 33.91 FKBP -0.110 20.427 30.479 1.00 38.74 FKBP 1.015 20.263 29.458 1.00 44.12 FKBP 1.708 18.913 29.584 1.0044.68 FKBP 2.954 18.849 28.767 1.0046.84 FKBP 3.632 19.546 29.134 0.00 0.00 FKBP 2.732 19.066 27.773 0.00 0.00 FKBP 3.361 17.895 28.831 0.00 0.00 FKBP 0.475 23.795 32.323 1.0027.06 FKBP -0.349 24.498 31.741 1.00 30.79 FKBP 1.025 24.130 33.490 1.0021.58 FKBP 1.847 23.671 33.747 0.00 0.00 FKBP 0.572 25.282 34.279 1.00 18.83 FKBP 1.219 26.571 33.768 1.00 25.35 FKBP 2.599 26.848 34.333 1.00 34.50 FKBP 3.585 25.737 34.025 1.0042.12 FKBP 3.854 25.432 32.865 1.00 46.61 FKBP 4.096 25.098 35.067 1.00 46.53 FKBP 3.837 25.352 35.970 0.00 0.00 FKBP 4.723 24.391 34.821 0.00 0.00 FKBP -0.950 25.457 34.313 1.00 15.57 FKBP -1.456 26.570 34.380 1.00 17.17 FKBP -1.672 24.344 34.338 1.0012.00 FKBP -1.188 23.505 34.304 0.00 0.00 FKBP -3.126 24.378 34.306 1.00 6.49 FKBP -3.666 23.022 33.878 1.00 6.66 FKBP -4.296 23.020 32.516 1.00 4.63 FKBP -4.414 21.628 31.960 1.00 11.57 FKBP -3.543 21.242 31.157 1.00 18.19 FKBP -5.339 20.896 32.368 1.00 10.83 FKBP -3.741 24.762 35.642 1.00 5.69 FKBP -4.873 25.238 35.696 1.00 4.44 FKBP -3.035 24.444 36.722 1.00 4.70 FKBP -2.142 24.084 36.580 0.00 0.00 FKBP -3.513 24.731 38.071 1.00 6.95 FKBP -3.774 23.446 38.849 1.00 3.43 FKBP -4.995 22.759 38.309 1.00 9.22 FKBP -2.573 22.538 38.761 1.00 2.21 FKBP -2.500 25.559 38.849 1.00 9.75 FKBP -1.369 25.737 38.408 1.00 9.34 FKBP -2.887 26.026 40.031 1.00 12.04 FKBP -3.799 25.844 40.322 0.00 0.00 FKBP -1.964 26.785 40.869 1.00 10.94 FKBP -2.674 27.365 42.123 1.00 9.38 FKBP -3.665 28.449 41.701 1.00 9.44 FKBP -3.377 26.263 42.920 1.00 4.02 FKBP -4.003 26.756 44.206 1.00 2.00 FKBP -0.734 25.962 41.286 1.0012.55 FKBP -0.759 24.729 41.270 1.00 15.13 FKBP 0.353 26.651 41.615 1.00 10.58 FKBP 0.284 27.627 41.637 0.00 0.00 FKBP 1.648 26.013 41.850 1.00 12.39 FKBP 2.707 27.091 42.058 1.00 13.28 FKBP 4.115 26.573 42.013 1.00 16.07 FKBP 5.090 27.708 42.068 1.00 18.63 FKBP 6.447 27.196 42.189 1.0029.56 FKBP 6.567 26.228 42.278 0.00 0.00 FKBP 7.535 27.957 42.208 1.0029.74 FKBP 8.728 27.390 42.332 1.0034.84 FKBP 8.794 26.398 42.443 0.00 0.00 FKBP 9.551 27.954 42.380 0.00 0.00 FKBP 7.430 29.277 42.124 1.00 24.22 FKBP 6.534 29.712 42.038 0.00 0.00 FKBP 8.258 29.836 42.149 0.00 0.00 FKBP 1.700 25.006 43.014 1.00 15.27 FKBP 2.321 23.946 42.901 1.00 16.77 FKBP 1.084 25.349 44.142 1.00 13.48 FKBP 0.719 26.253 44.227 0.00 0.00 FKBP 0.973 24.402 45.240 1.00 12.25 FKBP 0.326 23.080 44.849 1.00 9.23 FKBP 0.633 22.043 45.438 1.00 8.04 FKBP -0.567 23.124 43.856 1.00 6.52 FKBP -0.838 24.004 43.525 0.00 0.00 FKBP -1.177 21.927 43.269 1.00 2.00 FKBP -2.399 22.294 42.443 1.00 2.00 FKBP -3.672 22.138 43.172 1.00 2.87 FKBP -4.707 21.189 42.889 1.00 4.49 FKBP -5.725 21.386 43.843 1.00 5.98 FKBP -4.874 20.193 41.921 1.00 2.00 FKBP -4.093 22.857 44.252 1.00 2.00 FKBP -5.327 22.413 44.659 1.00 4.48 FKBP -5.830 22.768 45.422 0.00 0.00 FKBP -6.897 20.615 43.859 1.00 7.28 FKBP -6.043 19.433 41.939 1.00 4.10 FKBP -7.033 19.648 42.900 1.00 2.01 FKBP -0.215 21.196 42.365 1.00 3.20 FKBP -0.186 19.969 42.345 1.00 9.79 FKBP 0.507 21.955 41.550 1.00 3.19 FKBP 0.323 22.919 41.539 0.00 0.00 FKBP 1.484 21.388 40.636 1.00 5.73 FKBP 2.142 22.502 39.819 1.00 10.18 FKBP 2.585 22.086 38.415 1.00 13.55 FKBP 1.463 22.147 37.398 1.00 16.71 FKBP 1.649 22.793 36.348 1.00 22.45 FKBP 0.393 21.551 37.640 1.00 19.83 FKBP 2.538 20.587 41.395 1.00 8.89 FKBP 2.703 19.395 41.150 1.00 14.67 FKBP 3.116 21.189 42.428 1.00 11.93 FKBP 2.859 22.117 42.606 0.00 0.00 FKBP 4.123 20.510 43.249 1.00 15.22 FKBP 5.053 21.533 43.916 1.00 18.18 FKBP 5.177 22.868 43.171 1.00 28.20 FKBP 6.615 23.314 42.926 1.00 31.43 FKBP 7.478 23.101 43.807 1.00 35.07 FKBP 6.865 23.933 41.867 1.00 34.62 FKBP 3.519 19.581 44.315 1.00 14.96 FKBP 4.101 18.558 44.663 1.00 21.59 FKBP 2.355 19.938 44.840 1.00 16.29 FKBP 1.970 20.809 44.617 0.00 0.00 FKBP 1.687 19.077 45.801 1.00 12.82 FKBP 1.281 17.734 45.219 1.00 12.55 FKBP 1.782 16.697 45.639 1.00 12.58 FKBP 0.438 17.764 44.190 1.00 12.60 FKBP 0.172 18.639 43.830 0.00 0.00 FKBP -0.092 16.550 43.570 1.00 12.62 FKBP -1.164 16.899 42.511 1.00 7.73 FKBP -1.788 15.628 41.954 1.00 7.25 FKBP -2.234 17.780 43.122 1.00 3.26 FKBP 0.996 15.674 42.921 1.00 15.97 FKBP 0.927 14.446 42.958 1.00 18.69 FKBP 2.048 16.305 42.416 1.00 15.67 FKBP 2.009 17.279 42.315 0.00 0.00 FKBP 3.196 15.570 41.905 1.00 14.59 FKBP 4.201 16.542 41.338 1.00 13.86 FKBP 3.856 14.687 42.976 1.00 16.87 FKBP 4.548 13.726 42.656 1.00 19.52 FKBP 3.657 15.026 44.245 1.00 16.81 FKBP 3.161 15.844 44.449 0.00 0.00 FKBP 4.202 14.233 45.353 1.00 14.57 FKBP 4.359 15.097 46.606 1.00 15.78 FKBP 5.473 16.118 46.542 1.00 27.03 FKBP 5.524 16.996 47.782 1.00 35.69 FKBP 5.543 16.500 48.910 1.00 39.86 FKBP 5.516 18.307 47.580 1.00 36.82 FKBP 5.428 18.638 46.667 0.00 0.00 FKBP 5.596 18.845 48.387 0.00 0.00 FKBP 3.325 13.037 45.706 1.00 11.92 FKBP 3.694 12.226 46.553 1.00 12.99 FKBP 2.094 13.034 45.210 1.00 8.83 FKBP 1.872 13.655 44.491 0.00 0.00 FKBP 1.119 12.044 45.646 1.00 9.40 FKBP -0.286 12.651 45.616 1.00 5.56 FKBP -0.487 13.766 46.628 1.00 3.07 FKBP -2.084 14.610 46.495 1.00 12.38 FKBP 3.186 13.301 46.911 1.00 12.15 FKBP 1.186 10.788 44.774 1.00 13.38 FKBP 1.705 10.831 43.660 1.00 16.22 FKBP 0.832 9.643 45.346 1.00 13.44 FKBP 0.710 9.638 46.319 0.00 0.00 FKBP 0.727 8.409 44.565 1.00 11.42 FKBP 1.649 7.317 45.134 1.00 7.60 FKBP 1.250 6.897 46.427 1.00 7.91 FKBP 1.986 7.045 47.038 0.00 0.00 FKBP -0.721 7.926 44.518 1.00 12.45 FKBP -1.556 8.364 45.309 1.00 14.85 FKBP -1.055 7.115 43.523 1.00 12.38 FKBP -0.361 6.855 42.883 0.00 0.00 FKBP -4.006 11.764 52.060 1.00 4.39 FKBP -4.628 13.489 50.774 1.00 2.46 FKBP -5.218 13.805 50.054 0.00 0.00 FKBP -3.725 14.428 51.425 1.00 2.00 FKBP -2.456 14.557 50.636 1.00 2.00 FKBP -4.326 15.803 51.654 1.00 4.21 FKBP -5.376 16.145 51.119 1.00 10.57 FKBP -3.766 16.490 52.632 1.00 8.68 FKBP -3.101 16.042 53.199 0.00 0.00 FKBP -4.121 17.861 52.917 1.00 4.13 FKBP -4.387 18.018 54.410 1.00 6.40 FKBP -4.104 19.408 54.956 1.00 13.82 FKBP -4.807 19.628 56.287 1.00 15.85 FKBP -4.136 20.729 57.086 1.00 18.32 FKBP -5.033 21.240 58.148 1.00 22.33 FKBP -5.238 20.469 58.817 0.00 0.00 FKBP -5.920 21.583 57.728 0.00 0.00 FKBP -4.569 22.019 58.657 0.00 0.00 FKBP -2.943 18.713 52.488 1.00 4.72 FKBP -1.794 18.396 52.814 1.00 6.20 FKBP -3.212 19.628 51.566 1.00 6.47 FKBP -4.064 19.565 51.121 0.00 0.00 FKBP -2.218 20.582 51.082 1.00 8.06 FKBP -2.303 20.706 49.560 1.00 12.85 FKBP -1.440 19.791 48.695 1.00 11.86 FKBP -1.789 18.330 48.947 1.00 11.50 FKBP -1.663 20.157 47.241 1.00 12.57 FKBP -2.403 21.962 51.695 1.00 8.90 FKBP -3.449 22.600 51.515 1.00 14.56 FKBP -1.385 22.431 52.405 1.00 7.32 FKBP -0.717 21.784 52.717 0.00 0.00 FKBP -1.383 23.796 52.913 1.00 6.76 FKBP -0.905 23.830 54.397 1.00 6.87 FKBP -1.957 23.327 55.227 1.00 2.01 FKBP -2.720 23.901 55.117 0.00 0.00 FKBP -0.556 25.238 54.861 1.00 3.73 FKBP -0.513 24.654 52.000 1.00 6.27 FKBP 0.683 24.416 51.846 1.00 5.48 FKBP -1.180 25.508 51.234 1.00 10.43 FKBP -2.141 25.633 51.388 0.00 0.00 FKBP -0.542 26.284 50.167 1.00 11.16 FKBP -1.326 26.090 48.830 1.00 6.31 FKBP -0.653 26.827 47.719 1.00 9.44 FKBP -1.388 24.601 48.459 1.00 5.62 FKBP -2.630 24.205 47.691 1.00 2.00 FKBP -0.454 27.788 50.522 1.00 12.21 FKBP -1.476 28.460 50.752 1.00 13.89 FKBP 0.768 28.287 50.692 1.0010.50 FKBP 1.535 27.692 50.566 0.00 0.00 FKBP 0.947 29.700 51.009 1.00 11.73 FKBP 2.354 29.978 51.571 1.00 11.33 FKBP 3.405 29.669 50.667 1.0018.57 FKBP 4.140 30.103 51.109 0.00 0.00 FKBP 0.681 30.566 49.790 1.00 12.45 FKBP 0.922 30.149 48.662 1.00 15.48 FKBP 0.151 31.778 49.998 1.00 14.32 FKBP 0.192 32.544 51.251 1.0018.10 FKBP -0.362 32.607 48.906 1.00 14.95 FKBP -0.594 33.957 49.573 1.00 15.74 FKBP 0.309 33.944 50.759 1.00 15.85 FKBP 0.574 32.728 47.710 1.00 15.21 FKBP 0.109 32.790 46.576 1.0020.63 FKBP 1.882 32.698 47.956 1.00 13.60 FKBP 2.162 32.697 48.889 0.00 0.00 FKBP 2.877 32.679 46.874 1.00 19.42 FKBP 4.305 32.510 47.424 1.0028.97 FKBP 4.599 33.401 48.629 1.00 37.43 FKBP 5.657 33.195 49.270 1.00 39.71 FKBP 3.792 34.306 48.939 1.00 45.91 FKBP 2.616 31.548 45.877 1.00 17.87 FKBP 2.547 31.777 44.676 1.0020.31 FKBP 2.442 30.335 46.392 1.00 15.45 FKBP 2.347 30.254 47.356 0.00 0.00 FKBP 2.142 29.178 45.557 1.00 12.31 FKBP 2.611 27.897 46.234 1.0010.17 FKBP 4.082 27.626 46.070 1.00 9.13 FKBP 5.022 28.600 46.373 1.00 5.08 FKBP 6.373 28.303 46.419 1.00 6.16 FKBP 4.536 26.347 45.781 1.00 12.62 FKBP 5.889 26.037 45.827 1.00 15.72 FKBP 6.801 27.021 46.159 1.00 13.97 FKBP 8.124 26.683 46.343 1.00 19.55 FKBP 8.729 27.408 46.126 0.00 0.00 FKBP 0.657 29.033 45.227 1.00 9.68 FKBP 0.194 27.936 44.907 1.00 9.28 FKBP -0.104 30.115 45.344 1.00 9.06 FKBP 0.347 31.010 45.423 0.00 0.00 FKBP -1.536 30.071 45.028 1.00 8.94 FKBP -2.362 29.899 46.312 1.00 10.95 FKBP -1.973 31.342 44.290 1.00 11.59 FKBP -1.507 31.630 43.192 1.00 14.63 FKBP -2.886 32.106 44.874 1.00 13.59 FKBP -3.142 32.049 45.838 0.00 0.00 FKBP -3.462 33.239 44.147 1.00 15.87 FKBP -4.982 33.249 44.324 1.00 15.49 FKBP -5.676 32.084 43.658 1.00 19.64 FKBP -6.283 31.091 44.415 1.00 18.02 FKBP -6.918 30.013 43.804 1.00 16.50 FKBP -5.724 31.975 42.262 1.00 19.36 FKBP -6.357 30.904 41.648 1.00 12.44 FKBP -6.946 29.930 42.425 1.00 12.60 FKBP -7.546 28.871 41.800 1.00 12.06 FKBP -7.818 28.255 42.478 0.00 0.00 FKBP -2.869 34.591 44.552 1.00 15.70 FKBP -3.388 35.646 44.183 1.00 15.54 FKBP -1.763 34.539 45.288 1.00 17.13 FKBP -1.475 33.662 45.571 0.00 0.00 FKBP -0.972 35.719 45.566 1.00 15.64 FKBP -1.681 36.878 46.233 1.00 20.32 FKBP -2.708 36.728 46.910 1.00 23.74 FKBP -1.099 38.055 46.055 1.00 19.06 FKBP -0.306 38.078 45.480 0.00 0.00 FKBP -1.639 39.270 46.628 1.00 15.70 FKBP -0.640 40.394 46.455 1.00 19.93 FKBP -2.965 39.637 45.982 1.00 13.85 FKBP -3.823 40.230 46.618 1.00 14.46 FKBP -3.131 39.247 44.726 1.00 17.88 FKBP -2.470 38.659 44.303 0.00 0.00 FKBP -4.308 39.623 43.934 1.00 24.03 FKBP -4.036 39.482 42.419 1.00 21.29 FKBP -3.482 38.185 42.150 1.0028.80 FKBP -4.132 37.483 42.316 0.00 0.00 FKBP -3.054 40.541 41.956 1.00 16.23 FKBP -5.537 38.787 44.254 1.0024.35 FKBP -6.660 39.189 43.954 1.00 27.70 FKBP -5.304 37.579 44.761 1.00 25.09 FKBP -4.382 37.292 44.914 0.00 0.00 FKBP -6.388 36.655 45.020 1.00 19.79 FKBP -7.151 36.310 43.759 1.0021.57 FKBP -6.589 36.200 42.659 1.00 18.32 FKBP -8.454 36.149 43.930 1.0021.72 FKBP -8.780 36.318 44.827 0.00 0.00 FKBP -9.355 35.858 42.828 1.0024.25 FKBP -9.432 34.350 42.568 1.00 25.61 FKBP -10.134 33.994 41.292 1.00 29.60 FKBP -11.360 33.466 41.064 1.0027.65 FKBP -9.564 34.185 40.050 1.00 31.39 FKBP -8.690 34.592 39.843 0.00 0.00 FKBP -10.405 33.783 39.115 1.00 32.76 FKBP -11.503 33.347 39.703 1.0030.12 FKBP -12.329 33.167 39.202 0.00 0.00 FKBP -10.727 36.387 43 .212 1.00 22.13 FKBP -11.356 35.891 44.152 1.00 27.18 FKBP -11.105 37.531 42.639 1.00 19.63 FKBP -10.357 38.290 41.620 1.00 20.36 FKBP -11.989 38.403 43.410 1.00 18.79 FKBP -11.946 39.707 42.626 1.00 18.51 FKBP -10.550 39.713 42.059 1.00 16.30 FKBP -13.399 37.848 43.580 1.00 18.22 FKBP -13.974 37.286 42.650 1.00 21.77 FKBP -13.851 37.819 44.828 1.00 15.16 FKBP -13.303 38.201 45.539 0.00 0.00 FKBP -15.160 37.271 45.120 1.00 12.28 FKBP -15.116 35.891 45.749 1.00 13.88 FKBP -16.142 35.385 46.211 1.00 13.05 FKBP -13.932 35.289 45.812 1.00 12.11 FKBP -13.164 35.742 45.410 0.00 0.00 FKBP -13.831 33.928 46.328 1.00 17.75 FKBP -13.950 32.875 45.177 1.00 23.54 FKBP -13.063 33.252 44.007 1.0024.28 FKBP -13.590 31.478 45.688 1.0028.28 FKBP -14.036 30.361 44.764 1.0034.25 FKBP -12.577 33.670 47.150 1.00 14.47 FKBP -12.663 33.134 48.247 1.00 15.69 FKBP -11.416 34.013 46.600 1.00 12.99 FKBP -11.413 34.380 45.696 0.00 0.00 FKBP -10.150 33.915 47.328 1.00 9.92 FKBP -9.091 33.085 46.559 1.00 6.38 FKBP -7.873 32.881 47.428 1.00 2.00 FKBP -9.681 31.762 46.041 1.00 4.55 FKBP -10.163 30.821 47.084 1.00 3.68 FKBP -9.584 35.324 47.520 1.00 15.34 FKBP -9.285 36.025 46.539 1.00 13.98 FKBP -9.520 35.797 48.781 1.00 17.29 FKBP -9.964 35.110 50.011 1.00 14.17 FKBP -9.007 37.143 49.062 1.00 12.40 FKBP -9.421 37.381 50.514 1.00 10.67 FKBP -9.477 36.019 51.107 1.0011.96 FKBP -7.492 37.264 48.855 1.00 14.30 FKBP -6.815 36.290 48.516 1.00 17.48 FKBP -6.966 38.493 48.923 1.00 15.65 FKBP -7.700 39.762 48.785 1.00 18.15 FKBP -5.518 38.704 48.833 1.00 16.50 FKBP -5.380 40.217 48.941 1.00 17.10 FKBP -6.629 40.717 48.308 1.0022.16 FKBP -4.743 37.999 49.933 1.0016.97 FKBP -5.160 37.971 51.090 1.00 20.11 FKBP -3.609 37.424 49.563 1.00 15.46 FKBP -3.476 37.286 48.598 0.00 0.00 FKBP -2.701 36.830 50.538 1.00 14.40 FKBP -2.366 37.855 51.608 1.00 12.10 FKBP -1.762 39.103 51.061 1.00 15.95 FKBP -2.313 40.308 50.781 1.00 16.10 FKBP -0.455 39.165 50.621 1.00 16.58 FKBP 0.241 38.484 50.761 0.00 0.00 FKBP -0.230 40.351 50.086 1.00 20.16 FKBP -1.342 41.063 50.171 1.00 21.63 FKBP -1.470 41.979 49.833 0.00 0.00 FKBP -3 .176 35.531 51.202 1.00 13.30 FKBP -2.380 34.843 51.836 1.00 16.61 FKBP -4.403 35.112 50.915 1.00 6.56 FKBP -4.911 35.568 50.215 0.00 0.00 FKBP -4.982 33.954 51.576 1.00 7.81 FKBP -6.365 33.676 51.026 1.00 2.72 FKBP -4.132 32.683 51.516 1.00 10.01 FKBP -3.691 32.260 50.456 1.00 10.42 FKBP -3.801 32.165 52.691 1.00 12.98 FKBP -3.847 32.758 53.468 0.00 0.00 FKBP -3.319 30.797 52.831 1.0012.92 FKBP -2.740 30.568 54.254 1.00 9.93 FKBP -1.655 31.480 54.472 1.00 11.98 FKBP -1.236 31.644 53.620 0.00 0.00 FKBP -2.240 29.139 54.430 1.00 3.68 FKBP -4.501 29.852 52.600 1.00 14.35 FKBP -5.569 30.025 53.212 1.00 14.86 FKBP -4.349 28.937 51.642 1.00 8.43 FKBP -3.495 28.902 51.157 0.00 0.00 FKBP -5.406 27.976 51.332 1.00 3.80 FKBP -5.672 27.930 49.826 1.00 3.61 FKBP -5.948 29.193 49.011 1.00 6.56 FKBP -5.831 28.841 47.534 1.00 2.62 FKBP -7.326 29.758 49.318 1.00 6.52 FKBP -5.083 26.557 51.814 1.00 5.71 FKBP -3.926 26.123 51.815 1.00 7.74 FKBP -6.121 25.814 52.167 1.00 2.33 FKBP -7.012 26.221 52.183 0.00 0.00 FKBP -5.968 24.407 52.476 1.00 3.09 FKBP -6.461 24.079 53.900 1.00 4.96 FKBP -6.144 22.638 54.230 1.00 2.00 FKBP -5.824 25.011 54.917 1.00 2.00 FKBP -6.801 23.602 51.491 1.00 7.78 FKBP -8.012 23.836 51.346 1.00 8.13 FKBP -6.166 22.622 50.853 1.00 7.58 FKBP -5.202 22.540 50.970 0.00 0.00 FKBP ATOM 935 CA EHE 99 -6.877 21.677 49.996 1.00 6.62 FKBP ATOM 936 CB PHE 99 -6.303 21.728 48.578 1.00 2.00 FKBP ATOM 937 CG PHE 99 -6.824 22.873 47.763 1.00 4.66 FKBP ATOM 938 CDl PHE 99 -6.115 24.070 47.687 1.00 4.09 FKBP ATOM 939 CD2 PHE 99 -8.069 22.787 47.138 1.00 2.68 FKBP ATOM 940 CEl PHE 99 -6.638 25.166 47.008 1.00 2.00 FKBP ATOM 941 CE2 PHE 99 -8.598 23.874 46.462 1.00 2.00 FKBP ATOM 942 CZ PHE 99 -7.879 25.068 46.399 1.00 2.00 FKBP ATOM 943 C PHE 99 -6.849 20.239 50.519 1.00 5.20 FKBP ATOM 944 0 PHE 99 -5.796 19.718 50.860 1.00 5.24 FKBP ATOM 945 N ASP 100 -8.014 19.613 50.627 1.00 3.90 FKBP ATOM 946 H ASP 100 -8.834 20.147 50.593 0.00 0.00 FKBP ATOM 947 CA ASP 100 -8.070 18.167 50.830 1.00 7.59 FKBP ATOM 948 CB ASP 100 -9.205 17.817 51.804 1.00 6.95 FKBP ATOM 949 CG ASP 100 -9.424 16.310 51.966 1.00 7.89 FKBP ATOM 950 ODl ASP 100 -8.564 15.494 51.568 1.00 14.35 FKBP ATOM 951 OD2 ASP 100 -10.480 15.937 52.511 1.00 12.55 FKBP ATOM 952 C ASP 100 -8.280 17.463 49.482 1.00 9.31 FKBP ATOM 953 0 ASP 100 -9.379 17.490 48.934 1.00 10.21 FKBP ATOM 954 N VAL 101 -7.232 16.832 48.954 1.00 9.09 FKBP ATOM 955 H VAL 101 -6.416 16.741 49.499 0.00 0.00 FKBP ATOM 956 CA VAL 101 -7.306 16.202 47.633 1.00 11.24 FKBP ATOM 957 CB VAL 101 -6.417 16.956 46.557 1.00 7.24 FKBP ATOM 958 CGI VAL 101 -6.122 18.380 47.014 1.00 5.62 FKBP ATOM 959 CG2 VAL 101 -5.118 16.208 46.278 1.00 3.42 FKBP ATOM 960 C VAL 101 -6.957 14.711 47.652 1.00 12.17 FKBP ATOM 961 0 VAL 101 -5.962 14.296 48.251 1.00 12.83 FKBP ATOM 962 N GLU 102 -7.796 13.913 47.001 1.00 11.69 FKBP ATOM 963 H GLU 102 -8.591 14.307 46.611 0.00 0.00 FKBP ATOM 964 CA GLU 102 -7.527 12.490 46.813 1.00 14.51 FKBP ATOM 965 CB GLU 102 -8.697 11.660 47.356 1.0012.86 FKBP ATOM 966 CG GLU 102 -8.562 10.171 47.074 1.00 18.32 FKBP ATOM 967 CD GLU 102 -9.681 9.340 47.666 1.0020.79 FKBP ATOM 968 OE1 GLU 102 -10.840 9.811 47.715 1.0026.66 FKBP ATOM 969 OE2 GLU 102 -9.402 8.187 48.052 1.00 23.60 FKBP ATOM 970 C GLU 102 -7.266 12.132 45.336 1.00 13.17 FKBP ATOM 971 O GLU 102 -8.100 12.392 44.465 1.00 15.41 FKBP ATOM 972 N LEU 103 -6.147 11.465 45.079 1.00 9.34 FKBP ATOM 973 H LEU 103 -5.600 11.178 45.846 0.00 0.00 FKBP -4.585 9.896 34.325 0.00 0.00 FKBP -4.910 8.585 32.718 1.0028.85 FKBP -6.410 8.650 32.415 1.0024.83 FKBP -7.125 9.812 33.068 1.0028.14 FKBP -8.428 10.140 32.379 1.00 33.36 FKBP -9.439 9.461 32.672 1.0026.99 FKBP -8.433 11.070 31.534 1.0036.01 FKBP -4.122 9.520 31.789 1.0032.85 FKBP -2.875 9.520 31.888 1.00 37.58 FKBP -4.739 10.301 31.034 1.0039.52 FKBP -7.715 26.739 39.504 1.00 6.16 RAPX -6.816 26.014 40.365 1.00 5.94 RAPX -5.659 25.863 39.953 1.00 4.69 RAPX -7.234 25.472 41.742 1.00 2.10 RAPX -6.748 24.038 41.963 1.00 2.00 RAPX -7.531 22.968 41.204 1.00 2.86 RAPX -9.027 23.085 41.430 1.00 2.00 RAPX -9.492 24.485 41.139 1.00 2.08 RAPX -8.685 25.389 41.985 1.00 3.45 RAPX -9.287 26.223 42.852 1.00 2.80 RAPX -8.653 27.066 43.484 1.00 4.16 RAPX -10.645 26.309 43.120 1.00 3.33 RAPX -11.026 25.607 44.055 1.00 2.89 RAPX -11.647 27.189 42.361 1.00 7.35 RAPX -11.102 28.623 42.177 1.00 5.50 RAPX -12.102 29.453 41.362 1.00 2.25 RAPX -12.661 28.755 40.117 1.00 3.81 RAPX -12.744 27.225 40.197 1.00 5.55 RAPX -11.749 26.675 41.029 1.00 5.80 RAPX -12.815 27.195 43.206 1.00 7.04 RAPX -10.856 29.287 43.527 1.0010.83 RAPX -12.476 26.558 38.844 1.00 6.36 RAPX -13.491 26.688 37.700 1.00 7.22 RAPX -14.764 26.288 38.070 1.00 6.77 RAPX -15.819 26.946 37.457 1.00 2.69 RAPX -13.020 25.794 36.553 1.00 7.17 RAPX -12.882 24.304 36.817 1.00 5.39 RAPX -12.702 26.344 35.400 1.00 12.19 RAPX -12.183 25.694 34.165 1.00 14.38 RAPX Lo LO Ul O ui NJ O fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe 99 X 2 O O Θ NJ ΘH 4 8 Θ 9 td 2 o o 9 m 2 o n o g Q g 8899 X 2 O O Θ NJ 88 g K; gπς gμς gKJ gι- 8O C 8O 8O 8CO 8CO 8CO 8O 8O 8O 8CO NJ NJ NJ O O O NJ NJ NJ 00 00 00 ATOM 1247 CG GLU 2032 -6.692 27.831 25.861 1.0023.62 FRAP ATOM 1248 CD GLU 2032 -5.792 26.772 25.235 1.0030.03 FRAP ATOM 1249 0E1 GLU 2032 -4.617 27.092 24.948 1.0031.98 FRAP ATOM 1250 OE2 GLU 2032 -6.241 25.611 25.078 1.0032.01 FRAP ATOM 1251 C GLU 2032 -8.629 30.210 26.154 1.00 12.81 FRAP ATOM 1252 0 GLU 2032 -8.263 30.588 27.261 1.00 21.81 FRAP ATOM 1253 N GLU 2033 -8.837 31.053 25.147 1.00 11.47 FRAP ATOM 1254 H GLU 2033 -9.243 30.710 24.323 0.00 0.00 FRAP ATOM 1255 CA GLU 2033 -8.462 32.473 25.225 1.00 12.69 FRAP ATOM 1256 CB GLU 2033 -8.631 33.140 23.854 1.00 19.44 FRAP ATOM 1257 CG GLU 2033 -7.834 34.437 23.650 1.0030.82 FRAP ATOM 1258 CD GLU 2033 -8.155 35.152 22.319 1.00 42.12 FRAP ATOM 1259 OE1 GLU 2033 -7.793 36.346 22.186 1.00 44.44 FRAP ATOM 1260 OE2 GLU 2033 -8.759 34.530 21.408 1.00 39.63 FRAP ATOM 1261 C GLU 2033 -9.308 33.226 26.254 1.00 10.31 FRAP ATOM 1262 0 GLU 2033 -8.808 34.068 26.994 1.00 6.92 FRAP ATOM 1263 N ALA 2034 -10.600 32.933 26.275 1.00 6.18 FRAP ATOM 1264 H ALA 2034 -10.945 32.334 25.587 0.00 0.00 FRAP ATOM 1265 CA ALA 2034 -11.509 33.572 27.205 1.00 2.76 FRAP ATOM 1266 CB ALA 2034 -12.920 33.101 26.943 1.00 2.50 FRAP ATOM 1267 C ALA 2034 -11.101 33.257 28.641 1.00 6.07 FRAP ATOM 1268 0 ALA 2034 -10.907 34.157 29.453 1.00 11.33 FRAP ATOM 1269 N SER 2035 -10.811 31.988 28.903 1.00 8.47 FRAP ATOM 1270 H SER 2035 -10.871 31.330 28.175 0.00 0.00 FRAP ATOM 1271 CA SER 2035 -10.482 31.543 30.250 1.00 4.56 FRAP ATOM 1272 CB SER 2035 -10.357 30.016 30.294 1.00 2.00 FRAP ATOM 1273 CG SER 2035 -9.012 29.595 30.200 1.00 7.26 FRAP ATOM 1274 HG SER 2035 -8.700 29.696 29.288 0.00 0.00 FRAP ATOM 1275 C SER 2035 -9.201 32.193 30.749 1.00 5.40 FRAP ATOM 1276 0 SER 2035 -9.171 32.734 31.846 1.00 11.51 FRAP ATOM 1277 N ARG 2036 -8.195 32.265 29.886 1.00 3.96 FRAP ATOM 1278 H ARG 2036 -8.314 31.862 28.998 0.00 0.00 FRAP ATOM 1279 CA ARG 2036 -6.934 32.909 30.233 1.00 6.68 FRAP ATOM 1280 CB ARG 2036 -5.959 32.792 29.065 1.00 7.24 FRAP ATOM 1281 CG ARG 2036 -4.695 33.631 29.210 1.00 17.54 FRAP ATOM 1282 CD ARG 2036 -4.229 34.185 27.860 1.00 17.93 FRAP ATOM 1283 NE ARG 2036 -3.637 35.515 27.997 1.00 18.57 FRAP ATOM 1284 HE ARG 2036 -2.897 35.626 28.628 0.00 0.00 FRAP ATOM 1285 CZ ARG 2036 -4.055 36.595 27.344 1.0020.32 FRAP to o Ul O fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe rf* NJ 88 ffi 2 0 Ω g B Θ 9 W 2 O Ω § g θ 889 X 2 O tsi 8 I— 4 ΘNJ 8I— 4 8 8 9 K Z O Ω 8 I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I- 4 - 4 H 4 h- 4 h- 4 h- 4 h- 4 I- 4 h 4 I- 4 h 4 H 4 H 4 h- 4 H 4 H 4 H 4 h- 4 I- 4 I- 4 H 4 I- 4 H 4 - 4 H 4 h- 4 H 4 I- 4 -o -o cn cn Ul it* rf* NJ NJ LO LO rf* Ul NJ LO LO rf* rf* Ul Ul Ul ON VD VO vo CO 00 00 cn LΠ Ui ui rf * 85 CO LO Ul O H 4 cn VD O O ON O O 00 o NJ VD cn i* O VO ui rf* ON 00 H 4 O co cn CO D LO NJ it* 00 NJ O oo 00 if* LO NJ - 4 VO 00 o o cn io VO 00 ON -o if* o V ■ o -J cn σs rf* rf* cn rf* o o o o - 4 rf* vo o -25.781 23.568 7.181 1.00 22.10 FRAP -23.685 23.880 7.897 1.00 16.77 FRAP -23.114 24.477 8.406 0.00 0.00 FRAP -23.220 22.593 7.423 1.00 17.61 FRAP -21.689 22.551 7.414 1.00 18.02 FRAP -21.213 22.465 8.763 1.00 16.37 FRAP -21.145 21.529 8.956 0.00 0.00 FRAP -21.128 23.812 6.763 1.00 19.18 FRAP -23.743 21.471 8.322 1.00 17 .50 FRAP -24.272 21.725 9.402 1.00 19.82 FRAP -23.481 20.231 7.922 1.00 17.20 FRAP -23.146 20.079 7.018 0.00 0.00 FRAP -23.813 19.063 8.731 1.00 13 .79 FRAP -23.667 17.808 7.879 1.00 17.73 FRAP -24.909 16.954 7 .614 1.00 18.83 FRAP -26.158 17.819 7 .466 1.00 19.10 FRAP -24.658 16.129 6.365 1.00 14.71 FRAP -22.940 18.949 9.988 1.00 13 .22 FRAP -23.445 18.670 11.070 1.00 12 .57 FRAP -21.649 19.264 9.848 1.00 9.29 FRAP -21.297 19.271 8.935 0.00 0.00 FRAP -20.707 19.308 10.976 1.00 8.13 FRAP -19.297 19.636 10.475 1.00 2.00 FRAP -18.442 18.438 10.157 1.00 2 .00 FRAP -17.028 18.870 9.846 1.00 2 .00 FRAP -16.122 17.672 9.553 1.00 9.62 FRAP -16.549 16.861 8.378 1.00 5.28 FRAP -16.491 17.449 7.520 0.00 0.00 FRAP -17.527 16.533 8.514 0.00 0.00 FRAP -15.912 16.043 8.283 0.00 0.00 FRAP -21.072 20.317 12.070 1.00 11.53 FRAP -20.704 20.148 13.226 1.00 16.33 FRAP -21.548 21.479 11.646 1.00 14.92 FRAP -21.556 21.672 10.692 0.00 0.00 FRAP -21.998 22.508 12.569 1.00 15.78 FRAP -22.143 23.842 11.835 1.00 22.50 FRAP -20.877 24.292 11.105 1.00 25.09 FRAP -21.032 25.619 10.365 1.00 25.97 FRAP -22.161 26.174 10.309 1.00 16.81 FRAP Note: FKBP sequence is SEQ ID NO: 1 FRAP sequence is SEQ ID NO: 2 SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: CORNELL RESEARCH FOUNDATION, INC. (ii) TITLE OF INVENTION: CRYSTALLINE FRAP COMPLEX (iii) NUMBER OF SEQUENCES: 2 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: ARIAD Pharmaceuticals, Inc. (B) STREET: 26 Landsdo ne Street (C) CITY: Cambridge (D) STATE: MA (E) COUNTRY: USA (F) ZIP: 02139-4234 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.30 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: HEREWITH (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: US 60/005,808 (B) FILING DATE: 23-OCT-1995 (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: US 60/006,069 (B) FILING DATE: 24-OCT-1995 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: BERSTEIN, David L. (B) REGISTRATION NUMBER: 31,235 (C) REFERENCE/DOCKET NUMBER: ARIAD 350A-PCT (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 617-494-0400 (B) TELEFAX: 617-494-0208 (2) INFORMATION FOR SEQ ID NO: 1 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 107 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: Gly Val Gin Val Glu Thr lie Ser Pro Gly Asp Gly Arg Thr Phe Pro 1 5 10 15 Lys Arg Gly Gin Thr Cys Val Val His Tyr Thr Gly Met Leu Glu Asp 20 25 30 Gly Lys Lys Phe Asp Ser Ser Arg Asp Arg Asn Lys Pro Phe Lys Phe 35 40 45 Met Leu Gly Lys Gin Glu Val lie Arg Gly Trp Glu Glu Gly Val Ala 50 55 60 Gin Met Ser Val Gly Gin Arg Ala Lys Leu Thr lie Ser Pro Asp Tyr 65 70 75 80 Ala Tyr Gly Ala Thr Gly His Pro Gly lie lie Pro Pro His Ala Thr 85 90 95 Leu Val Phe Asp Val Glu Leu Leu Lys Leu Glu 100 105 (2) INFORMATION FOR SEQ ID NO:2 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 100 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Glu Leu lie Arg Val Ala lie Leu Trp His Glu Met Trp His Glu Gly 1 5 10 15 Leu Glu Glu Ala Ser Arg Leu Tyr Phe Gly Glu Arg Asn Val Lys Gly 20 25 30 Met Phe Glu Val Leu Glu Pro Leu His Ala Met Met Glu Arg Gly Pro 35 40 45 Gin Thr Leu Lys Glu Thr Ser Phe Asn Gin Ala Tyr Gly Arg Asp Leu 50 55 60 Met Glu Ala Gin Glu Trp Cys Arg Lys Tyr Met Lys Ser Gly Asn Val 65 70 75 80 Lys Asp Leu Thr Gin Ala Trp Asp Leu Tyr Tyr His Val Phe Arg Arg 85 90 95 lie Ser Lys Gin 100

Claims: Claims 1. A crystalline composition comprising a complex formed by a first protein containing an FRB domain, a second protein containing an FKBP domain and a ligand capable of forming a ternary complex with the first and second proteins. 2. A composition of claim 1 in which the complex is characterized by the coordinates of Appendix I, or by coordinates having a root mean square deviation therefrom, with respect to conserved backbone atoms of the listed amino acids, of not more than 1.5 A. 3. A machine-readable data storage medium, comprising a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data, is capable of displaying a graphical three-dimensional representation of a molecule or molecular complex comprising a protein containing an FRB domain. 4. A machine-readable data storage medium of claim 3 in which the machine readable data includes data corresponding to the coordinates for the FRB domain set forth in Appendix I, or coordinates having a root mean square deviation therefrom, with respect to conserved protein backbone atoms, of not more than 1.5 A. 5. A machine-readable data storage medium comprising a data storage material encoded with a first set of machine readable data which, when combined with a second set of machine- readable data, using a machine programmed with instructions for using said first set of data and said second set of data, can determine at least a portion of the coordinates corresponding to the second set of machine-readable data, wherein: said first set of data comprises a Fourier transform of at least a portion of the coordinates of the FRB domain set forth in Appendix I and said second set of data comprises an X-ray diffraction pattern of a molecule or molecular complex. 6. A method for displaying a three dimensional representation of a composition of claims 1 or 2 which comprises: (a) providing a machine capable of reading data stored on a machine-readable storage medium of any of claims 3-5, programmed with instructions for using said data to display a graphical three-dimensional representation of a protein or protein:ligand complex or portion thereof defined by said data, and loaded with a machine-readable storage medium of any of claims 3-5; and, (b) permitting the machine to read said data and display the three-dimensional representation. 7. A method for detern iriing the three-dimensional structure of a protein containing an FRB domain, or a complex of such protein with a ligand therefor, which comprises (a) obtaining x-ray diffraction data for crystals of the protein or complex, (b) providing three-dimensional structural coordinates for a composition of claims 1 or 2, and (c) deteriTiining the three-dimensional structure of the protein or complex by analyzing the x-ray diffraction data with reference to the previous structural coordinates using molecular replacement techniques. 8. A method for deteπnining the three dimensional structure of a protein containing an an FRB domain or co-complex of said protein with a ligand therefor, which method comprises: (a) providing structural coordinates for a composition of claims 1 or 2, and (b) deteπriining the three-dimensional structure of the FRB domam-containing protein or complex by homology modeling with reference to the previous structural coordinates. 9. A method for selecting a compound capable of binding to an FRB domain which comprises: (a) providing coordinates defining the three dimensional structure of the FRB domain; (b) characterizing points associated with that three dimensional structure with respect to the favorability of interactions with one or more selected functional groups; (c) providing a database of one or more candidate compounds; and (d) identifying from the database those compounds having structures which best fit the points of favorable interaction with the three dimensional structure. 10. A method of claim 9 which further comprises testing a compound so identified for its ability to: (a) bind to FRAP, with or without FKBP12, (b) inhibit the binding of rapamycin or FKBP12:rapamycin to FRAP, and/or (c) trigger a biological function mediated by rapamycin.

Inventors: CHOI JUNGWON, CLARDY JON C, CHOI, JUNGWON, CLARDY, JON, C.
Applicants: CORNELL RES FOUNDATION INC, CORNELL RESEARCH FOUNDATION, INC.
Application year: 1996
Main classification: C12N9
IPC codes: B82B1, C07K14, C12N9