CRYSTALLIZATION AND STRUCTURE DETERMINATION OF <i>STAPHYLOCOCCUS AUREUS</i> ELONGATION FACTOR P

Abstract: <i>Staphylococcus aureus</i> elongation factor P <i>S. aureus</i>EF-P has been crystallized, and the three dimensional x-ray crystal structure has been solved to 1.9 ANGSTROM resolution. The x-ray crystal structure is useful for solving the structure of other molecules or molecular complexes, and designing inhibitors of <i>S. aureus</i>EF-P.

Description: CRYSTALLIZATION AND STRUCTURE DETERMINATION OF STAPHYLOCOCCUS AUREUS ELONGATION FACTOR P This application claims the benefit of U.S. Provisional Application Serial- No. 60/147,851 filed 6 August 1999, which is incoφorated herein by reference in its entirety. FIELD OF THE INVENTION This invention relates to the crystallization and structure determination of Staphylococcus aureus elongation factor P (S aureus EF-P). BACKGROUND OF THE INVENTION Translation is fundamental to the biochemical and cellular process of all cells; therefore, it is not surprising that many antibacterial agents target this process. Preparation for translation begins with the binding of the mRNA to the ribosome placing the first codon, AUG, in position for interaction with the fMet-tRNA. Translation is initiated with the binding of the fMet-tRNA to the 30S subunit in the P site. Subsequently, the second tRNA is transported to the ribosome via the GTP dependent elongation factor-TU which situates the tRNA in the A site enabling the first peptide bond to be synthesized. After synthesis, the newly free tRNA localizes to the E site while the tRNA containing the growing amino acid chain moves to the P site vacating the A site for the next aminoacyl-tRNA. This translocation step is catalyzed by the GTP dependent elongation factor G. Several decades ago it was observed by Ganoza that another purified factor, EF-P, could increase the rate of formation of the first peptide bond as demonstrated in a model system by its stimulation of the synthesis of N- formylmethionyl-puromycin from fMet-tRΝA and puromycin which serves as a mimic of an aminoacyl tRΝA (M.C. Ganoza et al., Eur. J. Biochem; 146:287-94 (1985); B.R. Glick & M.C. Ganoza, Proc. Natl. Acad. Sci. U.S.A.; 72:4257-60 (1975)). The precise mechanism for stimulation by elongation factor P has not yet been determined, although experiments have shown a selectivity of EF-P for the stimulation of peptide bond synthesis with small to medium amino acids such as Gly and Leu rather than larger amino acids such as Phe, Met, and Lys (B.R. Glick et al., Eur. J. Biochem; 97:23-28 (1979)). The gene for EF-P from Escherichia coli has been cloned (H. Aoki et al., Nucl. Acid Res; 19:6215-20 (1991)) and it has been shown to be essential (H. Aoki et al., J. Biol. Chem. 272:32254-59 (1997)). The quantities of EF-P within E. coli are about one EF- P molecule per ten ribosomes suggesting that it plays a catalytic role in translation (G. An, Can. J. Biochem; 58:1312-14 (1980)). This 193 amino acid protein has homologs throughout bacteria and eukaryotes, although the sequence identity with higher organisms is quite low. SUMMARY OF THE INVENTION In one aspect, the present invention provides a method of crystallizing an S. aureus EF-P molecule or molecular complex that includes preparing purified S. aureus EF-P at a concentration of about 1 mg/ml to about 50 mg/ml; and crystallizing S aureus EF-P from a solution including about 0 wt. % to about 50 wt. % polyethylene glycol and 0 to about 20 wt. % DMSO, and buffered to a pH of about 3.5 to about 5.5. In another aspect, the present invention provides crystalline forms of S. aureus EF-P. In one embodiment, a crystal of S. aureus EF-P is provided having the orthorhombic space group symmetry P2,2 1 2 1 . In another aspect, the present invention provides a scalable three dimensional configuration of points wherein at least a portion of the points are derived from structure coordinates of a least a portion of an S. aureus EF-P molecule or molecular complex listed in Figure 4, preferably comprising amino acids Val 29, Lys30, Pro31, Gly32, Lys 33, Gly 34, Ser 35, and Ala 36. In one embodiment, at least a portion of the points are derived from S. aureus EF-P stmcture coordinates representing the locations of at least the backbone atoms of amino acids defining an S. aureus EF-P or EF-P-like binding surface, the binding surface comprising amino acids selected from the surface residues listed in Table 1. In another embodiment, at least a portion of points are derived from S. aureus EF-P stmcture coordinates representing the backbone atoms of amino acids within 4 A, preferably within 7 A, more preferably within 10 A, and most preferably within 15 A of Lys 33, as shown in Table 2. In another aspect, the present invention provides a scalable three dimensional configuration of points with at least a portion of the points derived from stmcture coordinates of at least a portion of a molecule or a molecular complex that is stmcturally homologous to an S. aureus EF-P molecule or molecular complex, On a molecular scale, with points derived from a molecule or molecular complex preferably have a root mean square deviation of less than about 1.9 A from the stmcture coordinates. In another aspect, the present invention provides a molecule or molecular complex that includes at least a portion of an S. aureus EF-P binding surface. In one embodiment the binding surface comprises amino acids selected from the surface residues listed in Table 1. In one embodiment, the binding surface is further defined by a set of points having a root mean square deviation of less than about 1.9 A from points representing the backbone atoms of amino acids Val 29, Lys30, Pro31, Gly32, Lys 33, Gly 34, Ser 35, and Ala 36 as represented by the stmcture coordinates listed in Figure 4. In another embodiment, the binding surface is further defined by a set of points having a root mean square deviation of less than about 1.9 A from points representing the backbone atoms of the amino acids that are within 4 A of Lys33, preferably within 7 A of Lys33, more preferably within 10 A of Lys33, and most preferably within 15 A of Lys33, as shown in Table 2 and represented by the structure coordinates listed in Figure 4. TABLE 1 Identified Surface Residues for S. aureus EF-P ALA 57 ASN 104 GLY 158 Table 2. Residues that are near Lys33 in S. aureus EF-P Atoms with in 4 A of Lys 33 PRO 31 GLY 32 GLY 34 Atoms within 7 A of Lys 33 LYS 30 PRO 31 GLY 32 GLY 34 SER 35 PHE 37 ARG 56 Atoms within 10 A of Lys 33 VAL 29 LYS 30 PRO 31 GLY 32 GLY 34 SER 35 ALA 36 PHE 37 ARG 56 Atoms within 15 A of Lys 33 VAL 5 ASN 6 GLN 27 HIS 28 VAL 29 LYS 30 PRO 31 GLY 32 GLY 34 SER 35 ALA 36 PHE 37 VAL 38 ARG 39 PHE 55 ARG 56 ALA 57 GLY 58 GLU 59 In another aspect, the present invention provides molecules or molecular complexes that are structurally homologous to an S. aureus EF-P molecule or molecular complex. In another aspect, the present invention provides a machine readable storage medium including the stmcture coordinates of all or a portion of an S. aureus EF-P molecule, molecular complex, a stmcturally homologous molecule or complex, including stmcturally equivalent structures, as defined herein, particularly a binding surface thereof, or a similarly shaped homologous binding surface. A storage medium encoded with these data is capable of displaying on a computer screen, or similar viewing device, a three-dimensional graphical representation of a molecule or molecular complex which comprises a binding surface or a similarly shaped homologous binding surface. In another aspect, the present invention provides a method for identifying inhibitors, ligands, and the like for an S aureus EF-P molecule by providing the coordinates of a molecule of S. aureus EF-P to a computerized modeling system; identifying chemical entities that are expected to bind to or interfere with the molecule (e.g., screening a small molecule library); and, optionally, procuring or synthesizing then assaying the compounds or analogues derived therefrom for bioactivity. In another aspect, the present invention provides methods for designing inhibitors, ligands, and the like by providing the coordinates of a molecule of S. aureus EF-P to a computerized modeling system; designing a chemical entity that is likely to bind to or interfere with the molecule; and optionally, synthesizing the chemical entity and assaying the chemical entity for bioactivity. In another aspect, the present invention provides inhibitors and ligands designed or identified by the above method. In one embodiment, a composition is provided that includes an inhibitor or ligand designed or identified by the above method. In another embodiment, the composition is a pharmaceutical composition. In another aspect, the present invention provides a method involving molecular replacement to obtain stmctural information about a molecule or molecular complex of unknown structure. The method includes crystallizing the molecule or molecular complex, generating an x-ray diffraction pattern from the crystallized molecule or molecular complex, and applying at least a portion of the EF-P stmcture coordinates set forth in Fig. 4 to the x-ray diffraction pattern to generate a three-dimensional electron density map of at least a portion of the molecule or molecular complex. In another aspect, the present invention provides a method for homology modeling an S. aureus EF-P homolog. DEFINITIONS Two crystallographic data sets (with stmcture factors F) are considered isomorphous if, after scaling, Δ F Σ I F,-F 2 F ∑ F* is less than about 35% for the reflections between 8 A and 4 A. ABBREVIATIONS The following abbreviations are used throughout this disclosure: Staphylococcus aureus elongation factor P (S. aureus EF-P) Isopropylthio-β-D-galactoside (IPTG). Dithiothreitol (DTT). Dimethyl sulfoxide (DMSO). Multiple anomalous dispersion (MAD). Polyethylene glycol (PEG) The following amino acid abbreviations are used throughout this disclosure: A = Ala = Alanine T = Thr = Threonine V = Val = Valine C = Cys = Cysteine L = Leu = Leucine Y = Tyr = Tyrosine I = lie = Isoleucine N = Asn = Asparagine P = Pro = Proline Q = Gin = Glutamine F = Phe = Phenylalanine D = Asp = Aspartic Acid W = Trp - Tryptophan E = Glu = Glutamic Acid M = Met = Methionine K = Lys = Lysine G = Gly - Glycine R = Arg = Arginine S = Ser = Serine H = His = Histidine BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a crystal of S. aureus elongation factor P grown in 0.1 M sodium acetate pH 5.4, 1% PEG 4000. The width of the crystal is approximately 0.350 mm. Figure 2 shows anomalous difference Patterson maps for selenomethionine EF-P at the inflection point of the selenium K edge (λ = 0.979746 A, 10- 1.9 A resolution), a) x Harker section, b) y Harker section, and c) z Harker section. Figure 3 shows electron density maps for EF-P for residues 73- 77 for a) multiple anomalous dispersion map after solvent flattening calculated to 2.3 A and b) the final 2F 0 -F C map calculated to 1.9 A resolution. Figure 4 lists the atomic structure coordinates for S. aureus EF-P as derived by x-ray diffraction from a crystal of that complex. The following abbreviations are used in Figure 1 : "Atom" refers to the element whose coordinates are measured. The second column defines the number of the atom in the stmcture. The letters in the third column define the element. The fourth and fifth columns define the amino acid and the number of the amino acid in the stmcture, respectively. "X, Y, Z" crystallographically define the atomic position of the element measured. "Occ" is an occupancy factor that refers to the fraction of the molecules in which each atom occupies the position specified by the coordinates. A value of " 1 " indicates that each atom has the same conformation, i.e., the same position, in all molecules of the crystal. "B" is a thermal factor that measures movement of the atom around its atomic center. Figure 5 shows stmcture and sequence of S. aureus EF-P by a) ribbon representation of the X-ray crystal stmcture of S. aureus EF-P, and b) the amino acid sequence of recombinant EF-P (SEQ ID NO:l, including a His 6 tag) with the beginning of each domain indicated by an arrow. Disordered residues are underlined. Figure 6 shows a secondary stmcture diagram for S. aureus EF- P. Figure 7 shows conserved secondary and tertiary stmcture between domains 2 and 3 of EF-P. Two views (a and b) of a superposition of domain 2 and domain 3 from S. aureus elongation factor P are shown. Figure 8 shows two stereoviews (a and b) of EF-P. Figure 9 shows a surface representation of S. aureus EF-P. Alternative views (a and b) of the surface charge density (180° apart) of elongation factor P are shown. Figure 10 shows a hypothetical superposition of EF-P and tRNA Bln from E. coli (tRNA from M.A. Rould et al., Science 246: 1135-42 (1989), PDB access code lgtr). a) ΕF-P is oriented with domain 3 at the anticodon stem and domain 1 at the acceptor stem, b) Another possible orientation of ΕF-P with domain 1 at the anticodon stem and domain 3 at the acceptor stem. Figure 11 shows a stmctural comparison and sequence alignment of ΕF-P homologs. The three solved structures from a) S. aureus, b) Methanococcus jannaschii, and c) Pyrobaculum aerophilum are shown, d) Sequence alignment of recombinant S. aureus ΕF-P (SΕQ ID NO:l, which includes a His 6 tag not present in the compared sequences) with four ΕF-P homologs: ΕF-P from E. coli (SΕQ ID NO:2), eIF5A from Methanococcus jannaschii (SΕQ ID NO:3), IF5A from Pyrobaculum aerophilum (SΕQ ID NO:4), and eIF5a from humans (SΕQ ID NO:5). Identical residues have been shaded or boxed. Figure 12 shows a superposition of S. aureus ΕF-P (dark) and eIF5 A from Methanococcus jannaschii (light), a) Alignment of domain 1 (residues 2-15, 19-33, 34-43, and 49-65 from S. aureus ΕF-P and residues 10- 23, 27-41, 43-52, 58-74 from M. jannaschii). b) Alignment of domain 2 (residues 66-95 and 99-128 from S. aureus ΕF-P and residues 75-103 and 104- 132 from M. jannaschii). Figure 13 shows the superposition of S. aureus ΕF-P (dark) and eIF5A from Pyrobaculum aerophilum (light), a) Alignment of domain 1 (residues 2-15, 19-33, 34-43, and 49-65 from S aureus ΕF-P and residues 11- 24, 28-42, 44-53, and 59-75 from P. aerophilum). b) Alignment of domain 2 (residues 66-95 and 99-128 from S. aureus ΕF-P and residues 76-105 and 109- 139 from P. aerophilum). Figure 14 shows certain residues of interest in S. aureus ΕF-P. Lys33 is the proposed site for post-translational modification based on the hypusine modification found in ΕF-P homologs in eukaryotic systems. Figure 15 lists the stmcture factors and multiple anomalous dispersion phases for the crystal stmcture of S. aureus EF-P (SEQ ID NO:l). "INDE" refers to the indices h, k, and 1 (columns 2, 3, and 4 respectively) of the lattice planes. "FOBS" refers to the stmcture factors of the observed reflections. "SIGMA" is the standard deviation for the observations. "PHAS" refers to the phase used for the observations. "FOM" refers to the figure of merit. DETAILED DESCRIPTION OF THE INVENTION Crystalline Form(s) and Method of Making Applicants have produced crystals comprising S. aureus EF-P which are suitable for x-ray crystallographic analysis. The three-dimensional stmcture of S aureus EF-P was solved using high resolution x-ray crystallography. Preferably, the crystal has orthorhombic space group symmetry P2-2-2,. More preferably, the crystal comprises rectangular shaped unit cells, each unit cell having the dimensions a, b, and c, wherein a is about 25 A to about 50 A, b is about 35 A to about 60 A, and c is about 85 A to about 110 A; and α = β = γ = 90°. The crystallized enzyme is a monomer and has one molecule in the asymmetric unit. Purified S. aureus EF-P at a concentration of about 1 mg/ml to about 50 mg/ml may be crystallized, for example, using the hanging drop procedure from a solution including about 0 wt. % to about 50 wt. % polyethylene glycol (PEG, preferably having a number average molecular weight between about 200 and about 20,000), 0 to about 20 wt. % DMSO, and buffered to a pH of about 3.5 to about 5.5. Use of a buffer having a pK a of between 2.5 and 6.5 is preferred. In a particularly preferred embodiment of the method, the buffer includes about 10 mM to about 300 mM sodium acetate. Variation in buffer and buffer pH as well as other additives such as PEG is apparent to those skilled in the art and may result in similar crystals. The invention further includes an S. aureus EF-P crystal or S. aureus EF-P/ligand crystal that is isomorphous with an S. aureus EF-P crystal characterized by a unit cell having the dimensions a, b, and c, wherein a is about 25 A to about 50 A, b is about 35 A to about 60 A, and c is about 85 A to about 110 A; and α = β = γ = 90°. X-ray Crystallographic Analysis Crystals of recombinant S. aureus EF-P (Figure 1) were obtained from a crystallization screening solution that contained 100 mM sodium acetate at pH 4.6 and 4% PEG 4000. The recombinant S. aureus EF-P used for crystallization contains a six-residue polyhistidine tag at the C-terminus in order to facilitate purification of the recombinant protein. Refinement of the conditions resulted in ideal crystal growth occurring at pH 5.2-5.4. Since there was no homologous stmcture available for molecular replacement, selenomethionine incoφorated EF-P was prepared by the downregulation of methionine (T.E. Benson et al, Nat. Struct. Biol 2:644-53 (1995); G.D. Van Duyne et al., J. Mol. Biol; 229:105-24 (1993)). Selenomethionine EF-P crystallized in a similar manner to the native protein and these crystals diffracted to 1.9 A resolution at the synchrotron (Advance Photon Source, Argonne, IL). The crystals belong to the orthorhombic space group P2-2-2, with cell constants a=37.5 A, b=47.3 A, c=97.5 A, α=β=γ=90°. Anomalous and dispersive difference Patterson maps (Figure 2) revealed two of the four potential selenium sites while a third site was found via cross difference Fourier methods. The fourth site could not be located by either method due to multiple conformations of the methionine as observed later in the electron density maps. Maximum likelihood phasing with solvent-flattening resulted in a disconnected but interpretable electron density map (Figure 3). The structure has been refined to an R-factor of 25.6% with a Free R-factor of 29.0%. Details of the stmcture determination and refinement are described in Tables 3 and 4. Table 3. Data collection and phasing statistics for EF-P. λ 1.0332 A λ 0.979746 A λ 0.979617 A (12000 eV) (12654.8 eV) (12656.5 eV) Resolution 1.9 A 1.9 A 1.9 A No. observations 105,951 106,013 104,323 No. unique refl. 12,373 14,350 14,349 % completeness 100% 100% 100% R sym 0.063 0.085 0.084 R cM]S acentrics - 0.587 0.605 IrC.,,**,,. anomalous 0.990 0.683 0.694 Phasing power centrics - 1.533 1.018 acentrics - 2.417 2.260 Mean figure of merit (to 1.9 A resolution) before solvent flattening 0.559 after solvent flattening 0.895 Table 4. Refinement Statistics for EF-P. R-factor Free R-factor No. of reflections 10-1.9 A F> 2σ 0.256 0.290 13,812 Bonds (A) Angles(°) r.m.s deviation from ideal geometry 0.011 1.508 Number of atoms Average B -factor Protein 1327 25.5 Waters 109 35.0 Total 1436 26.2 Each of the constituent amino acids of S. aureus EF-P is defined by a set of stmcture coordinates as set forth in Figure 4. The term "stmcture coordinates" refers to Cartesian coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of x-rays by the atoms (scattering centers) of an S. aureus EF-P complex in crystal form. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are then used to establish the positions of the individual atoms of the S. aureus EF-P protein or protein/ligand complex. Slight variations in stmcture coordinates can be generated by mathematically manipulating S. aureus EF-P stmcture coordinates. For example, the stmcture coordinates set forth in Figure 4 could be manipulated by crystallographic permutations of the stmcture coordinates, fractionalization of the stmcture coordinates, integer additions or subtractions to sets of the stmcture coordinates, inversion of the stmcture coordinates or any combination of the above. Alternatively, modifications in the crystal stmcture due to mutations, additions, substitutions, and/or deletions of amino acids, or other changes in any of the components that make up the crystal, could also yield variations in stmcture coordinates. Such slight variations in the individual coordinates will have little effect on overall shape. If such variations are within an acceptable standard error as compared to the original coordinates, the resulting three-dimensional shape is considered to be stmcturally equivalent. Structural equivalence is described in more detail below. It should be noted that slight variations in individual stmcture coordinates of the S aureus EF-P would not be expected to significantly alter the nature of chemical entities such as ligands that could associate with the binding surfaces. In this context, the phrase "associating with" refers to a condition of proximity between a chemical entity, or portions thereof, and an S. aureus EF-P molecule or portions thereof. The association may be non- covalent, wherein the juxtaposition is energetically favored by hydrogen bonding, van der Waals forces, or electrostatic interactions, or it may be covalent. Thus, for example, a ligand that bound to or interfered with a binding surface of S. aureus EF-P would also be expected to bind to or interfere with another binding surface whose stmcture coordinates define a shape that falls within the acceptable error. It will be readily apparent to those of skill in the art that the numbering of amino acids in other isoforms of S aureus EF-P may be different than that of S aureus EF-P expressed in E. coli. Overview of the Structure with Implications for Function Elongation factor P is primarily comprised of β strands organized into three distinct domains (Figures 5 and 6). Domain 1 contains four antiparallel β strands and a single turn of α helix. Domains two and three are both five stranded antiparallel β barrels similar to the putative oligonucleotide- oligosaccharide binding fold (A.G. Murzin, EMBO. J.; 12:861-67 (1993)). Domain 2 also contains a single turn of a 3, 0 helix between strands β7 and β8. Superposition of the C α from domains 2 and 3 resulted in an r.m.s. deviation of 1.55 A (Figure 7). Although there are several loop regions that are not conserved (including the absence of a tme helical region in domain 3), the general fold is maintained. This fold has been observed in many other proteins some of which bind RNA such as IF1 (M. Sette et al., EMBO. J.; 16:1436-43 (1997)), CspA (W. Jiang et al., J. Biol. Chem.; 272:196-202 (1997); H. Schindelin et al., Proc. Natl. Acad. Sci. U.S.A.; 91 :5119-23 (1994)) and EF-Tu (P. Nissen et al., Science; 270:1464-72 (1995)). This suggests that domains 2 and 3 of EF-P may play a role in interacting with RNA - probably either tRNA or rRNA. Other structures that utilize this putative oligonucleotide- oligosaccharide binding fold show specific interactions with their respective ligands with the loops between strands 1 and 2, strand 3 and the α helix, or strands 4 and 5 (A.G. Murzin, EMBO. J.; 12:861-67 (1993)). Identification of these residues within the two β barrels for EF-P reveals potential sites for interaction with RNA (Figure 8). Based on evidence from related structures, residues for S. aureus ER-P that could be involved in oligonucleotide binding include residues 77-80, 99-105, and 117-120 from domain 2 and residues 149- 150, 164-169, and 177-181 from domain 3. These residues correspond to the loop between strand 1 and strand 2, the loop from strand 3 through helix 1, and the loop between strand 4 and strand 5 in a model beta barrel oligonucleotide binding fold as described in A.G. Murzin, EMBO. J.; 12:861-67 (1993). An intriguing feature of EF-P is its polarity of surface charges as shown in a surface representation (Figure 9). Such polarity in a protein which most likely interacts with RNA suggests that the positively charged face of the protein (Figure 9a) would interact with the negatively charged oligonucleotide. In addition, this surface representation reveals that EF-P resembles the shape and dimensionality of tRNA (Figure 10) (M.A. Rould et al., Science 246:1135- 42 (1989)). This similarity in shape to tRNA may provide a hypothesis for the mechanism of action of EF-P. In models of translation, three distinct sites on the large subunit of the ribosome have been proposed - the P site for the tRNA containing the elongating amino acyl chain, the A site for the incoming tRNA and the E site for the deacylated tRNA. During the first step of translation the E site would be unoccupied since there is no tRNA which has yet been deacylated. One possibility is that EF-P could be binding in the E site during translation initiation to act as a mimic of a deacylated tRNA. This function might serve to bring the ribosome into a more active initial conformation which would enhance the synthesis of the first peptide bond. Comparison of EF-P to Related Structures Two related structures have been solved from archaebacteria ( jannaschii and P. aerophilum) which are more closely related to the human protein, eIF-5A (K.K. Kim et al., Proc. Natl. Acad. Sci. U.S.A; 95:10419-24 (1998); T.S. Peat et al., Structure; 6:1207-14 (1998)). These archaebacterial proteins contain homology to domains 1 and 2 of the bacterial EF-P, but domain 3 is surprisingly absent (Figure 11). While it is not apparent why domain 3 is absent in the archaebacteria and eukaryotic sequences but is present in E. coli and S. aureus EF-P, the similarity of domain 3 to domain 2 and the oligonucleotide binding fold suggests the interaction with rRNA or tRNA may be somewhat different for E. coli and S. aureus. Superposition of domain 1 from S aureus and M. jannaschii gave a r.m.s.d. for C α atoms of 2.02 A and superposition of domain 2 of these two stmctures gave a r.m.s.d. for C α atoms of 3.02 A. Superposition of domain 1 from S. aureus and P. aerophilum gave a r.m.s.d. for C α atoms of 3.29 A and superposition of domain 2 of these two stmctures gave a r.m.s.d. for C α atoms of 4.25 A. While there is good agreement for each domain individually, the relative orientation of domains 1 and 2 is quite flexible as illustrated in Figures 12 and 13. A second crystal form of eIF5A from M. jannaschii has been solved which reveals some flexibility in the relative orientation of domains 1 and 2 (K.K. Kim et al., Proc. Natl. Acad. Sci. U.S.A; 95:10419-24 (1998)). Since we have only solved one crystal, it is unclear how flexible this linker is for S. aureus EF-P. The stmctures of S. aureus, M. jannaschii, and P. aerophilum possess a highly conserved motif within domain 1 - xKxGKGxA - which has been identified in yeast and human as a site for post-translational modification of the second lysine to N ε -(4-aminobutyl)lysine (also called deoxyhypusine). This modification has been shown to be essential for cell viability in yeast (J. Schnier et al., Mol. Cell. Biol; 11:3105-14 (1991)) and occurs only with eIF5A by the enzyme deoxyhypusine synthase (D.I. Liao et al., Stmcture; 6:23-32 (1998)). The location of this conserved loop in EF-P is between β2 and β3 with K33 of S. aureus EF-P being the conserved residue which is modified in eukaryotic EF-P homologs. This exposed lysine is illustrated in Figure 14 projecting out from this loop. In bacteria, hypusination of the homologous EF-P K33 amino acid has not been observed, and, in fact, analysis of the electron density for this residue in S. aureus EF-P does not reveal evidence of a post translational modification in this recombinant protein. Similar investigation of the electron density for the EF-P homologs from archaebacteria did not reveal any modification (K.K. Kim et al, Proc. Natl. Acad. Sci. U.S.A; 95:10419-24 (1998); T.S. Peat et al., Stmcture; 6:1207-14 (1998)). Mass spectrometry of the S. aureus EF-P sample (both methionine and selenomethionine) did not reveal any additional mass that would be accounted for by a post-translational modification. Since S. aureus EF-P was purified from an EF-P overexpression strain, it is possible that the modification pathway was overwhelmed and unable to sufficiently carry out the post-translational modification. There is also no direct evidence that hypusination occurs in bacteria, and it may be that another type of modification is incorporated for S. aureus EF-P. Binding Surfaces and Other Structural Features Applicants' invention has provided, for the first time, information about the shape and stmcture of a putative oligonucleotide binding surface of S. aureus EF-P. Binding surfaces are of significant utility in fields such as dmg discovery. The association of natural ligands or substrates with the binding surfaces of their corresponding receptors or enzymes is the basis of many biological mechanisms of action. Similarly, many d gs exert their biological effects through association with the binding surfaces of receptors and enzymes. Such associations may occur with all or any parts of the binding surface. An understanding of such associations helps lead to the design of d gs having more favorable associations with their target, and thus improved biological effects. Therefore, this information is valuable in designing potential inhibitors of S. aureus EF-P-like binding surfaces, as discussed in more detail below. A "molecular complex" means a protein in colvalent or non- covalent association with a chemical entity. The term "binding surface" as used herein, refers to a region of a molecule or molecular complex, that, as a result of its shape, favorably associates with another chemical entity. The amino acid constituents of an S. aureus EF-P oligonucleotide binding surface as defined herein, as well as selected constituent atoms thereof, are positioned in three dimensions in accordance with the stmcture coordinates listed in Figure 4. In one aspect, the stmcture coordinates defining the binding surface of S aureus EF-P include stmcture coordinates of substantially all atoms in the constituent amino acids; in another aspect, the stmcture coordinates of the binding surface include stmcture coordinates of just the backbone atoms of the constituent atoms. A specific chemical entity may bind to any of the amino acid surface residues of S. aureus EF-P as listed in Table 1. Preferably, the surface residues that comprise the binding surface include amino acid K33. Even more preferably, the surface residues that comprise the binding surface include residues whose backbone atoms are situated within 4 A, preferably within 7 A, more preferably within 10 A, and most preferably within 15 A of K33 as listed in Table 2. The term "S. aureus EF-P-like binding surface" refers to a portion of a molecule or molecular complex whose shape is sufficiently similar to at least a portion of a binding surface of S aureus EF-P as to be expected to bind common or stmcturally related ligands. A stmcturally equivalent binding surface is defined by a root mean square deviation from the structure coordinates of the backbone atoms of the amino acids that make up the binding surfaces in S aureus EF-P (as set forth in Figure 4) of at most about 1.9 A. How this calculation is obtained is described below. Accordingly, the invention thus provides molecules or molecular complexes comprising an S. aureus EF-P oligonucleotide binding surface or S. aureus EF-P-like binding surface, as defined by the sets of stmcture coordinates described above. Three-Dimensional Configurations X-ray stmcture coordinates define a unique configuration of points in space. Those of skill in the art understand that a set of stmcture coordinates for protein or a protein/ligand complex, or a portion thereof, define a relative set of points that, in turn, define a configuration in three dimensions. A similar or identical configuration can be defined by an entirely different set of coordinates, provided the distances and angles between coordinates remain essentially the same. In addition, a scalable configuration of points can be defined by increasing or decreasing the distances between coordinates by a scalar factor while keeping the angles essentially the same. The present invention thus includes the scalable three- dimensional configuration of points derived from the stmcture coordinates of at least a portion of an S. aureus EF-P molecule or molecular complex, as listed in Figure 4, as well as stmcturally equivalent configurations, as described below. Preferably, the scalable three-dimensional configuration includes points derived from stmcture coordinates representing the locations of a plurality of the amino acids defining the S. aureus EF-P binding surface. In one embodiment, the scalable three-dimensional configuration includes points derived from stmcture coordinates representing the locations the backbone atoms of a plurality of amino acids defining the S. aureus EF-P binding surface, preferably those amino acids listed in Table 1. In another embodiment, the scalable three- dimensional configuration includes points derived from stmcture coordinates representing the locations of the side chain and the backbone atoms (other than hydrogens) of a plurality of the amino acids defining the S aureus EF-P binding surface, preferably those amino acids listed in Table 1. Alternatively, the scalable three-dimensional configuration of points are derived from stmcture coordinates representing the locations of backbone and, optionally, side chain atoms (other than hydrogens) of amino acids within 4 A, preferably within 7 A, more preferably within 10 A, and most preferably within 15 A of Lys33 as shown in Table 2. Likewise, the invention also includes the scalable three- dimensional configuration of points derived from stmcture coordinates of molecules or molecular complexes that are stmcturally homologous to S. aureus EF-P, as well as stmcturally equivalent configurations. Stmcturally homologous molecules or molecular complexes are defined below. Advantageously, stmcturally homologous molecules can be identified using the stmcture coordinates of S. aureus EF-P (Figure 4) according to a method of the invention. The configurations of points in space derived from stmcture coordinates according to the invention can be visualized as, for example, a holographic image, a stereodiagram, a model or a computer-displayed image, and the invention thus includes such images, diagrams or models. Structurally Equivalent Crystal Structures Various computational analyses can be used to determine whether a molecule or the binding surface portion thereof is "stmcturally equivalent," defined in terms of its three-dimensional stmcture, to all or part of S. aureus EF-P or its binding surfaces. Such analyses may be carried out in current software applications, such as the Molecular Similarity application of QUANTA (Molecular Simulations Inc., San Diego, CA) version 4.1, and as described in the accompanying User's Guide. The Molecular Similarity application permits comparisons between different stmctures, different conformations of the same stmcture, and different parts of the same stmcture. The procedure used in Molecular Similarity to compare stmctures 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 stmcture is identified by a name. One stmcture is identified as the target (i.e., the fixed stmcture); all remaining stmctures are working stmctures (i.e., moving structures). Since atom equivalency within QUANTA is defined by user input, for the purpose of this invention equivalent atoms are defined as protein backbone atoms (N, Cα, C, and O) for all conserved residues between the two stmctures being compared. A conserved residue is defined as a residue that is stmcturally or functionally equivalent. Only rigid fitting operations are considered. When a rigid fitting method is used, the working stmcture is translated and rotated to obtain an optimum fit with the target stmcture. The fitting operation uses an algorithm that computes the optimum translation and rotation to be applied to the moving stmcture, 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 molecule or molecular complex or binding surface thereof, or any portion thereof, that has a root mean square deviation of conserved residue backbone atoms (N, Cα, C, O) of less than about 1.9 A, when superimposed on the relevant backbone atoms described by the reference stmcture coordinates listed in Figure 4, is considered "stmcturally equivalent" to the reference molecule. That is to say, the crystal stmctures of those portions of the two molecules are substantially identical, within acceptable error. Particularly preferred stmcturally equivalent molecules or molecular complexes are those that are defined by the entire set of structure coordinates in Figure 4, ± a root mean square deviation from the conserved backbone atoms of those amino acids of not more than 1.9 A. More preferably, the root mean square deviation is less than about 1.0 A. The term "root mean square deviation" means the square root of the arithmetic mean of the squares of the deviations. It is a way to express the deviation or variation from a trend or object. For purposes of this invention, the "root mean square deviation" defines the variation in the backbone of a protein from the backbone of S. aureus EF-P or a binding surface portion thereof, as defined by the stmcture coordinates of S. aureus EF-P described herein. Machine Readable Storage Media Transformation of the stmcture coordinates for all or a portion of S. aureus EF-P or the S. aureus EF-P/ligand complex, for stmcturally homologous molecules as defined below, or for the stmctural equivalents of any of these molecules or molecular complexes as defined above, into three- dimensional graphical representations of the molecule or complex can be conveniently achieved through the use of commercially-available software. The nvention thus further provides a machine-readable 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 any of the molecule or molecular complexes of this invention that have been described above. In a preferred embodiment, the machine-readable data storage medium comprises 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 all or any parts of an S. aureus EF-P binding surface or an S. aureus EF-P-like binding surface, as defined above. In another preferred embodiment, the machine-readable data storage medium is capable of displaying a graphical three-dimensional representation of a molecule or molecular complex defined by the stmcture coordinates of all of the amino acids in Figure 4, ± a root mean square deviation from the backbone atoms of said amino acids of not more than 1.9 A. In an alternative 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 stmcture coordinates set forth in Figure 4, and which, when using a machine programmed with instmctions 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 stmcture coordinates corresponding to the second set of machine readable data. For example, a system for reading a data storage medium may include a computer 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 display devices (e.g., cathode-ray tube ("CRT") displays, light emitting diode ("LED") displays, liquid crystal displays ("LCDs"), electroluminescent displays, vacuum fluorescent displays, field emission displays ("FEDs"), plasma displays, projection panels, etc.), one or more user input devices (e.g., keyboards, microphones, mice, touch screens, etc.), one or more input lines, and one or more output lines, all of which are interconnected by a conventional bidirectional system bus. The system may be a stand-alone computer, or may be networked (e.g., through local area networks, wide area networks, intranets, extranets, or the internet) to other systems (e.g., computers, hosts, servers, etc.). The system may also include additional computer controlled devices such as consumer electronics and appliances. Input hardware may be coupled to the computer by input lines and 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. Alternatively or additionally, the input hardware may comprise CD-ROM drives or disk drives. In conjunction with a display terminal, a keyboard may also be used as an input device. Output hardware may be coupled to the computer by output lines and may similarly be implemented by conventional devices. By way of example, the output hardware may include a display device for displaying a graphical representation of a binding surface of this invention 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, a CPU coordinates the use of the various input and output devices, coordinates data accesses from mass storage devices, 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. Such programs are discussed in reference to the computational methods of dmg discovery as described herein. References to components of the hardware system are included as appropriate throughout the following description of the data storage medium. Machine-readable storage devices useful in the present invention include, but are not limited to, magnetic devices, electrical devices, optical devices, and combinations thereof. Examples of such data storage devices include, but are not limited to, hard disk devices, CD devices, digital video disk devices, floppy disk devices, removable hard disk devices, magneto-optic disk devices, magnetic tape devices, flash memory devices, bubble memory devices, holographic storage devices, and any other mass storage peripheral device. It should be understood that these storage devices include necessary hardware (e.g., drives, controllers, power supplies, etc.) as well as any necessary media (e.g., disks, flash cards, etc.) to enable the storage of data. Structurally Homologous Molecules, Molecular Complexes, and Crystal Structures The stmcture coordinates set forth in Figure 4 can be used to aid in obtaining stmctural information about another crystallized molecule or molecular complex. The method of the invention allows determination of at least a portion of the three-dimensional stmcture of molecules or molecular complexes which contain one or more stmctural features that are similar to structural features of S. aureus EF-P. These molecules are referred to herein as "stmcturally homologous" to S. aureus EF-P. Similar stmctural features can include, for example, regions of amino acid identity, conserved active site or binding site motifs, and similarly arranged secondary stmctural elements (e.g., α helices and β sheets). Optionally, structural homology is determined by aligning the residues of the two amino acid sequences to optimize the number of identical amino acids along the lengths of their sequences; gaps in either or both sequences are permitted in making the alignment in order to optimize the number of identical amino acids, although the amino acids in each sequence must nonetheless remain in their proper order. Preferably, two amino acid sequences are compared using the Blastp program, version 2.0.9, of the BLAST 2 search algorithm, as described by Tatiana et al., FEMS Microbiol Lett 174, 247-50 (1999), and available at http://www.ncbi.nlm.nih.gov/gorf/bl2.html. Preferably, the default values for all BLAST 2 search parameters are used, including matrix = BLOSUM62; open gap penalty = 11, extension gap penalty = 1, gap x_dropoff = 50, expect = 10, wordsize = 3, and filter on. In the comparison of two amino acid sequences using the BLAST search algorithm, structural similarity is referred to as "identity." Preferably, a stmcturally homologous molecule is a protein that has an amino acid sequence sharing at least 65%) identity with a native or recombinant amino acid sequence of S. aureus EF-P (for example, SEQ ID NO: 1). More preferably, a protein that is stmcturally homologous to S. aureus EF-P includes at least one contiguous stretch of at least 50 amino acids that shares at least 80%) amino acid sequence identity with the analogous portion of the native or recombinant S. aureus EF-P (for example, SEQ ID NO: 1). Methods for generating stmctural information about the stmcturally homologous molecule or molecular complex are well- known and include, for example, molecular replacement techniques. Therefore, in another embodiment this invention provides a method of utilizing molecular replacement to obtain structural information about a molecule or molecular complex whose stmcture is unknown comprising the steps of: (a) crystallizing the molecule or molecular complex of unknown structure; (b) generating an x-ray diffraction pattern from said crystallized molecule or molecular complex; and (c) applying at least a portion of the stmcture coordinates set forth in Figure 4 to the x-ray diffraction pattern to generate a three-dimensional electron density map of the molecule or molecular complex whose stmcture is unknown. By using molecular replacement, all or part of the stmcture coordinates of S aureus EF-P or the S. aureus EF-P/ligand complex as provided by this invention (for example as set forth in Figure 4) can be used to determine the structure of a crystallized molecule or molecular complex whose stmcture is unknown more quickly and efficiently than attempting to determine such information ab initio. Molecular replacement provides an accurate estimation of the phases for an unknown stmcture. Phases are a factor in equations used to solve crystal stmctures that cannot be determined directly. Obtaining accurate values for the phases, by methods other than molecular replacement, is a time- consuming process that involves iterative cycles of approximations and refinements and greatly hinders the solution of crystal stmctures. However, when the crystal stmcture of a protein containing at least a stmcturally homologous portion has been solved, the phases from the known stmcture provide a satisfactory estimate of the phases for the unknown stmcture. Thus, this method involves generating a preliminary model of a molecule or molecular complex whose stmcture coordinates are unknown, by orienting and positioning the relevant portion of S. aureus EF-P according to Figure 4 within the unit cell of the crystal of the unknown molecule or molecular complex so as best to account for the observed x-ray diffraction pattern of the crystal of the molecule or molecular complex whose stmcture is unknown. Phases can then be calculated from this model and combined with the observed x-ray diffraction pattern amplitudes to generate an electron density map of the structure whose coordinates are unknown. This, in turn, can be subjected to any well-known model building and stmcture refinement techniques to provide a final, accurate stmcture of the unknown crystallized molecule or molecular complex (E. Lattman, "Use of the Rotation and Translation Functions," in Meth. Enzymol., 115, pp. 55-77 (1985); M.G. Rossman, ed., "The Molecular Replacement Method," Int. Sci. Rev. Ser., No. 13, Gordon & Breach, New York (1972)). Stmctural information about a portion of any crystallized molecule or molecular complex that is sufficiently stmcturally homologous to a portion of S. aureus EF-P can be resolved by this method. In addition to a molecule that shares one or more stmctural features with S aureus EF-P as described above, a molecule that has similar bioactivity, such as the same substrate specificity or ligand binding activity as S. aureus EF-P, may also be sufficiently stmcturally homologous to S aureus EF-P to permit use of the stmcture coordinates of S aureus EF-P to solve its crystal stmcture. In a preferred embodiment, the method of molecular replacement is utilized to obtain stmctural information about a molecule or molecular complex, wherein the molecule or molecular complex comprises at least one S. aureus EF-P subunit or homolog. A "subunit" of S. aureus EF-P is an S. aureus EF-P molecule that has been truncated at the N-terminus or the C-terminus, or both. In the context of the present invention, a "homolog" of S. aureus EF-P is a protein that contains one or more amino acid substitutions, deletions, additions, or rearrangements with respect to the amino acid sequence of S. aureus EF-P, but that, when folded into its native conformation, exhibits or is reasonably expected to exhibit at least a portion of the tertiary (three- dimensional) structure of S. aureus EF-P. For example, stmcturally homologous molecules can contain deletions or additions of one or more contiguous or noncontiguous amino acids, such as a loop or a domain. Stmcturally homologous molecules also include "modified" S. aureus EF-P molecules that have been chemically or enzymatically derivatized at one or more constituent amino acid, including side chain modifications, backbone modifications, and N- and C- terminal modifications including acetylation, hydroxylation, methylation, amidation, and the attachment of carbohydrate or lipid moieties, cofactors, and the like. A heavy atom derivative of S. aureus EF-P is also included as an S. aureus EF-P homolog. The term "heavy atom derivative" refers to derivatives of S. aureus EF-P produced by chemically modifying a crystal of S. aureus EF-P. In practice, a crystal is soaked in a solution containing heavy metal atom salts, or organometallic compounds, e.g., lead chloride, gold thiomalate, thiomersal or uranyl acetate, which can diffuse through the crystal and bind to the surface of the protein. The location(s) of the bound heavy metal atom(s) can be determined by x-ray diffraction analysis of the soaked crystal. This information, in turn, is used to generate the phase information used to constmct three-dimensional stmcture of the protein (T.L. Blundell and N.L. Johnson, Protein Crystallography, Academic Press (1976)). Because S aureus EF-P can crystallize in more than one crystal form, the stmcture coordinates of S. aureus EF-P as provided by this invention are particularly useful in solving the stmcture of other crystal forms of S. aureus EF-P or S. aureus EF-P complexes. The stmcture coordinates of S. aureus EF-P as provided by this invention are particularly useful in solving the stmcture of S. aureus EF-P mutants. Mutants may be prepared, for example, by expression of S. aureus EF- P cDNA previously altered in its coding sequence by oligonucleotide-directed mutagenesis. Mutants may also be generated by site-specific incorporation of unnatural amino acids into EF-P proteins using the general biosynthetic method of C.J. Noren et al., Science, 244:182-188 (1989). In this method, the codon encoding the amino acid of interest in wild-type S. aureus EF-P is replaced by a "blank" nonsense codon, TAG, using oligonucleotide-directed mutagenesis. A suppressor tRNA directed against this codon is then chemically aminoacylated in vitro with the desired unnatural amino acid. The aminoacylated tRNA is then added to an in vitro translation system to yield a mutant S. aureus EF-P with the site-specific incorporated unnatural amino acid. Selenocysteine or selenomethionine may be incorporated into wild-type or mutant S. aureus EF-P by expression of S aureus EF-P-encoding cDNAs in auxotrophic E. coli strains (W.A. Hendrickson et al., EMBO J., 9(5): 1665-1672 (1990)). In this method, the wild-type or mutagenized S. aureus EF-P cDNA may be expressed in a host organism on a growth medium depleted of either natural cysteine or methionine (or both) but enriched in selenocysteine or selenomethionine (or both). Alternatively, selenomethionine analogues may be prepared by down regulation methionine biosynthesis. (T.E. Benson et al., Nat. St ct. Biol., 2:644-53 (1995); G.D. Van Duyne et al., J. Mol. Biol. 229:105-24 (1993)). The stmcture coordinates of S. aureus EF-P in Figure 4 are also particularly useful to solve the stmcture of crystals of S. aureus EF-P, S. aureus EF-P mutants or S aureus EF-P homologs co-complexed with a variety of chemical entities. This approach enables the determination of the optimal sites for interaction between chemical entities, including candidate S. aureus EF-P inhibitors. Potential sites for modification within the various binding site of the molecule can also be identified. This information provides an additional tool for determining the most efficient binding interactions, for example, increased hydrophobic interactions, between S. aureus EF-P and a chemical entity. For example, high resolution x-ray diffraction data collected from crystals exposed to different types of solvent allows the determination of where each type of solvent molecule resides. Small molecules that bind tightly to those sites can then be designed and synthesized and tested for their S. aureus EF-P inhibition activity. All of the complexes referred to above may be studied using well-known x-ray diffraction techniques and may be refined versus 1.5-3 A resolution x-ray data to an R value of about 0.20 or less using computer software, such as X-PLOR (Yale University, 81992, distributed by Molecular Simulations, Inc.; see, e.g., Blundell & Johnson, supra; Meth. Enzymol., Vol. 114 & 115, H.W. Wyckoff et al., eds., Academic Press (1985)). This information may thus be used to optimize known S. aureus EF-P inhibitors, and more importantly, to design new S aureus EF-P inhibitors. The invention also includes the unique three-dimensional configuration defined by a set of points defined by the stmcture coordinates for a molecule or molecular complex stmcturally homologous to S. aureus EF-P as determined using the method of the present invention, structurally equivalent configurations, and magnetic storage media comprising such set of stmcture coordinates. Further, the invention includes structurally homologous molecules as identified using the method of the invention. Homology Modeling Using homology modeling, a computer model of an S aureus EF-P homolog can be built or refined without crystallizing the homolog. First, a preliminary model of the S aureus EF-P homolog is created by sequence alignment with S. aureus EF-P, secondary structure prediction, the screening of stmctural libraries, or any combination of those techniques. Computational software may be used to carry out the sequence alignments and the secondary stmcture predictions. Stmctural incoherences, e.g., stmctural fragments around insertions and deletions, can be modeled by screening a stmctural library for peptides of the desired length and with a suitable conformation. For prediction of the side chain conformation, a side chain rotamer library may be employed. If the S. aureus EF-P homolog has been crystallized, the final homology model can be used to solve the crystal stmcture of the homolog by molecular replacement, as described above. Next, the preliminary model is subjected to energy minimization to yield an energy minimized model. The energy minimized model may contain regions where stereochemistry restraints are violated, in which case such regions are remodeled to obtain a final homology model. The homology model is positioned according to the results of molecular replacement, and subjected to further refinement comprising molecular dynamics calculations. Rational Drug Design Computational techniques can be used to screen, identify, select and/or design chemical entities capable of associating with S. aureus EF-P or stmcturally homologous molecules. Knowledge of the stmcture coordinates for S. aureus EF-P permits the design and/or identification of synthetic compounds and/or other molecules which have a shape complementary to the conformation of the S. aureus EF-P binding site. In particular, computational techniques can be used to identify or design chemical entities, such as inhibitors, agonists and antagonists, that associate with an S. aureus EF-P binding surface or an S. aureus EF-P-like binding surface. Inhibitors may bind to or interfere with all or a portion of the binding surface of S. aureus EF-P, and can be competitive, non-competitive, or uncompetitive inhibitors; or interfere with dimerization by binding at the interface between the two monomers. For example, inhibitors that are bound to a binding surface of S. aureus EF-P may interfere with binding of S aureus EF-P to a ribosomal protein or ribosomal RNA during translation. Once identified and screened for biological activity, these inhibitors/agonists/antagonists may be used therapeutically or prophylactically to block S. aureus EF-P activity and, thus, inhibit growth of the bacteria or cause its death. Structure-activity data for analogs of ligands that bind to or interfere with S. aureus EF-P or S. aureus EF-P-like binding surfaces can also be obtained computationally. The term "chemical entity," as used herein, refers to chemical compounds, complexes of two or more chemical compounds, and fragments of such compounds or complexes. Chemical entities that are determined to associate with S. aureus EF-P are potential drug candidates. Data stored in a machine-readable storage medium that is capable of displaying a graphical three-dimensional representation of the stmcture of S. aureus EF-P or a stmcturally homologous molecule, as identified herein, or portions thereof may thus be advantageously used for dmg discovery. The stmcture coordinates of the chemical entity are used to generate a three- dimensional image that can be computationally fit to the three-dimensional image of S. aureus EF-P or a structurally homologous molecule. The three- dimensional molecular stmcture encoded by the data in the data storage medium can then be computationally evaluated for its ability to associate with chemical entities. When the molecular structures encoded by the data is displayed in a graphical three-dimensional representation on a computer screen, the protein stmcture can also be visually inspected for potential association with chemical entities. One embodiment of the method of dmg design involves evaluating the potential association of a known chemical entity with S. aureus EF-P or a stmcturally homologous molecule, particularly with an S. aureus EF- P binding surface or S. aureus EF-P-like binding surface. The method of dmg design thus includes computationally evaluating the potential of a selected chemical entity to associate with any of the molecules or molecular complexes set forth above. This method comprises the steps of: (a) employing computational means to perform a fitting operation between the selected chemical entity and a binding surface 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 surface. In another embodiment, the method of dmg design involves computer-assisted design of chemical entities that associate with S. aureus EF- P, its homologs, or portions thereof. Chemical entities can be designed in a step-wise fashion, one fragment at a time, or may be designed as a whole or "de novo." To be a viable dmg candidate, the chemical entity identified or designed according to the method must be capable of structurally associating with at least part of an S. aureus EF-P or S. aureus EF-P-like binding surfaces, and must be able, sterically and energetically, to assume a conformation that allows it to associate with the S. aureus EF-P or S. aureus EF-P-like binding surface. Non-covalent molecular interactions important in this association include hydrogen bonding, van der Waals interactions, hydrophobic interactions, and electrostatic interactions. Conformational considerations include the overall three-dimensional structure and orientation of the chemical entity in relation to the binding surface, and the spacing between various functional groups of an entity that directly interact with the S aureus EF-P-like binding surface or homologs thereof. Optionally, the potential binding of a chemical entity to an S. aureus EF-P or S aureus EF-P-like binding surface is analyzed using computer modeling techniques prior to the actual synthesis and testing of the chemical entity. If these computational experiments suggest insufficient interaction and association between it and the S. aureus EF-P or S. aureus EF-P-like binding surface, testing of the entity is obviated. However, if computer modeling indicates a strong interaction, the molecule may then be synthesized and tested for its ability to bind to or interfere with an S. aureus EF-P or S. aureus EF-P- like binding surface, binding assays to determine if a compound actually binds to S. aureus EF-P can also be performed and are well known in the art. binding assays may employ kinetic or thermodynamic methodology using a wide variety of techniques including, but not limited to, microcalorimetry, circular dichroism, capillary zone electrophoresis, nuclear magnetic resonance spectroscopy, fluorescence spectroscopy, and combinations thereof. One skilled in the art may use one of several methods to screen chemical entities or fragments for their ability to associate with an S. aureus EF- P or S. aureus EF-P-like binding surface. This process may begin by visual inspection of, for example, an S aureus EF-P or S aureus EF-P-like binding surface on the computer screen based on the S. aureus EF-P stmcture coordinates in Figure 4 or other coordinates which define a similar shape generated from the machine-readable storage medium. Selected fragments or chemical entities may then be positioned in a variety of orientations, or docked, within the binding surface. Docking may be accomplished using software such as QUANTA and SYBYL, followed by energy minimization and molecular dynamics with standard molecular mechanics forcefields, such as CHARMM and AMBER. Specialized computer programs may also assist in the process of selecting fragments or chemical entities. Examples include GRID (P.J. Goodford, J. Med. Chem. 28:849-857 (1985); available from Oxford University, Oxford, UK); MCSS (A. Miranker et al., Proteins: Struct. Funct. Gen., 11 :29-34 (1991); available from Molecular Simulations, San Diego, CA); AUTODOCK (D.S. Goodsell et al., Proteins: Struct. Funct. Genet. 8:195-202 (1990); available from Scripps Research Institute, La Jolla, CA); and DOCK (I.D. Kuntz et al., J. Mol. Biol. 161 :269-288 (1982); available from University of California, San Francisco, CA). Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound or complex. Assembly may be preceded by visual inspection of the relationship of the fragments to each other on the three-dimensional image displayed on a computer screen in relation to the structure coordinates of S aureus EF-P. This would be followed by manual model building using software such as QUANTA or SYBYL (Tripos Associates, St. Louis, MO). Useful programs to aid one of skill in the art in connecting the individual chemical entities or fragments include, without limitation, CAVEAT (P.A. Bartlett et al., in Molecular Recognition in Chemical and Biological Problems," Special Publ., Royal Chem. Soc, 78:182-196 (1989); G. Lauri et al., J. Comput. Aided Mol. Des. 8:51-66 (1994); available from the University of California, Berkeley, CA); 3D database systems such as ISIS (available from MDL Information Systems, San Leandro, CA; reviewed in Y.C. Martin, J. Med. Chem. 35:2145-2154 (1992)); and HOOK (M.B. Eisen et al., Proteins: Struc, Funct., Genet. 19:199-221 (1994); available from Molecular Simulations, San Diego, CA). S aureus EF-P binding compounds may be designed "de novo" using either an empty binding site or optionally including some portion(s) of a known inhibitor(s). There are many de novo ligand design methods including, without limitation, LUDI (H.-J. Bohm, J. Comp. Aid. Molec. Design. 6:61-78 (1992); available from Molecular Simulations Inc., San Diego, CA); LEGEND (Y. Nishibata et al., Tetrahedron, 47:8985 (1991); available from Molecular Simulations Inc., San Diego, CA); LeapFrog (available from Tripos Associates, St. Louis, MO); and SPROUT (V. Gillet et al., J. Comput. Aided Mol. Design 7:127-153 (1993); available from the University of Leeds, UK). Once a compound has been designed or selected by the above methods, the efficiency with which that entity may bind to or interfere with an S. aureus EF-P or S. aureus EF-P-like binding surface may be tested and optimized by computational evaluation. For example, an effective S. aureus EF-P or S. aureus EF-P-like binding surface inhibitor must preferably demonstrate a relatively small difference in energy between its bound and free states (i.e., a small deformation energy of binding). Thus, the most efficient S. aureus EF-P or S. aureus EF-P-like binding surface inhibitors should preferably be designed with a deformation energy of binding of not greater than about 10 kcal/mole; more preferably, not greater than 7 kcal/mole. S aureus EF-P or S. aureus EF-P-like binding surface inhibitors may interact with the binding surface in more than one conformation that is similar in overall binding energy. In those cases, the deformation energy of binding is taken to be the difference between the energy of the free entity and the average energy of the conformations observed when the inhibitor binds to the protein. An entity designed or selected as binding to or interfering with an S. aureus EF-P or S aureus EF-P-like binding surface may be further computationally optimized so that in its bound state it would preferably lack repulsive electrostatic interaction with the target enzyme and with the surrounding water molecules. Such non-complementary electrostatic interactions include repulsive charge-charge, dipole-dipole, and charge-dipole interactions. Specific computer software is available in the art to evaluate compound deformation energy and electrostatic interactions. Examples of programs designed for such uses include: Gaussian 94, revision C (M.J. Frisch, Gaussian, Inc., Pittsburgh, PA 81995); AMBER, version 4.1 (P. A. Kollman, University of California at San Francisco, 81995); QUANTA CHARMM (Molecular Simulations, Inc., San Diego, CA 81995); Insight II/Discover (Molecular Simulations, Inc., San Diego, CA 81995); DelPhi (Molecular Simulations, Inc., San Diego, CA 81995); and AMSOL (Quantum Chemistry Program Exchange, Indiana University). These programs may be implemented, for instance, using a Silicon Graphics workstation such as an Indigo 2 with "IMPACT" graphics. Other hardware systems and software packages will be known to those skilled in the art. Another approach encompassed by this invention is the computational screening of small molecule databases for chemical entities or compounds that can bind in whole, or in part, to a S. aureus EF-P or S. aureus EF-P-like binding surface. In this screening, the quality of fit of such entities to the binding site may be judged either by shape complementarity or by estimated interaction energy (E.C. Meng et al., J. Comp. Chem., 13, pp. 505-524 (1992)). This invention also enables the development of chemical entities that can isomerize to short-lived reaction intermediates in the chemical reaction of a substrate or other compound that binds to or interferes with or with S. aureus EF-P. Time-dependent analysis of stmctural changes in S. aureus EF-P during its interaction with other molecules is carried out. The reaction intermediates of S. aureus EF-P can also be deduced from the reaction product in co-complex with S. aureus EF-P. Such information is useful to design improved analogs of known S. aureus EF-P inhibitors or to design novel classes of inhibitors based on the reaction intermediates of the S. aureus EF-P and inhibitor co-complex. This provides a novel route for designing S. aureus EF-P inhibitors with both high specificity and stability. Yet another approach to rational dmg design involves probing the S. aureus EF-P crystal of the invention with molecules comprising a variety of different functional groups to determine optimal sites for interaction between candidate S. aureus EF-P inhibitors and the protein. For example, high resolution x-ray diffraction data collected from crystals soaked in or co- crystallized with other molecules allows the determination of where each type of solvent molecule sticks. Molecules that bind tightly to those sites can then be further modified and synthesized and tested for their EF-P inhibitor activity (J. Travis, Science, 262:1374 (1993)). In a related approach, iterative dmg design is used to identify inhibitors of S. aureus EF-P. Iterative drag design is a method for optimizing associations between a protein and a compound by determining and evaluating the three-dimensional structures of successive sets of protein/compound complexes. In iterative drag design, crystals of a series of protein/compound complexes are obtained and then the three-dimensional stmctures of each complex is solved. Such an approach provides insight into the association between the proteins and compounds of each complex. This is accomplished by selecting compounds with inhibitory activity, obtaining crystals of this new protein/compound complex, solving the three dimensional structure of the complex, and comparing the associations between the new protein/compound complex and previously solved protein/compound complexes. By observing how changes in the compound affected the protein/compound associations, these associations may be optimized. A compound that is identified or designed as a result of any of these methods can be obtained (or synthesized) and tested for its biological activity, e.g., inhibition of S aureus EF-P activity. Pharmaceutical Compositions Pharmaceutical compositions of this invention comprise an inhibitor of S. aureus EF-P activity identified according to the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The term "pharmaceutically acceptable carrier" refers to a carrier(s) that is "acceptable" in the sense of being compatible with the other ingredients of a composition and not deleterious to the recipient thereof. Optionally, the pH of the formulation is adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. Methods of making and using such pharmaceutical compositions are also included in the invention. The pharmaceutical compositions of the invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. Oral administration or administration by injection is preferred. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrastemal, intrathecal, intralesional, and intracranial injection or infusion techniques. Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 75 mg/kg body weight per day of the S. aureus EF-P inhibitory compounds described herein are useful for the prevention and treatment of S aureus EF-P mediated disease. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of admimstration. A typical preparation will contain from about 5% to about 95%) active compound (w/w). Preferably, such preparations contain from about 20% to about 80% active compound. In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be constmed as limiting the scope of the invention in any way. EXAMPLES Example 1: Analysis of the Structure of S. aureus EF-P Expression of EF-P and Incorporation of Selenomethionine The Escherichia coli construct Ml 5 (pREP4) (pQE-60 EF-P) which expresses S. aureus EF-P was obtained from Human Genome Sciences. Various genes and polypeptides derived from S. aureus are published in WO 0012678. For preparation of the selenomethionine analog of EF-P, the construct was grown in a minimal salts medium, M9, which contained glucose and NH 4 C1 as the sources of carbon and nitrogen. Endogenous methionine biosynthesis was then inhibited while adding an excess of selenomethionine to the growth medium just prior to IPTG induction of EF-P synthesis (T.E. Benson et al., Nat. Struct. Biol 2:644-53 (1995); G.D. Van Duyne et al., J. Mol. Biol; 229:105-24 (1993)). The formulation of basal M9 media was Na 2 HPO 4 , 6 g; KH 2 PO 4 , 3 g; NH 4 C1, 1.0 g; and NaCl, 0.5 g per L of deionized water. The pH was adjusted to 7.4 with concentrated KOH and the medium was sterilized by autoclaving. Prior to inoculation, the following filter sterilized solutions were added per L of basal medium: 1M MgSO 4 , 1.0 ml; 1M CaCl 2 , 0.1 ml; trace metal salts solution, 0.1 ml, 10 mM thiamin, 1.0 ml; and 20% glucose, 20 ml. The trace metal salts solution contained per L of deionized water: MgCl 2 " 6H 2 O, 39.44 g; MnSO 4 H 2 O, 5.58 g; FeSO 4 - 7H 2 O, 1.11 g; N^MoO, • 2H 2 O, 0.48 g; CaCl 2 , 0.33 g; NaCl, 0.12 g; and ascorbic acid, 1.0 g. Filter sterilized ampicillin and kanamycin were added to the medium at final concentrations of 100 μg/ml and 30 μg/ml, respectively. Fermentations were prepared in 100 ml volumes of M9 medium contained in 500 ml wide mouth flasks. A 0.1 ml aliquot of the stock culture was inoculated into the medium and allowed to grow at 37°C for 18 - 20 hours with a shaking rate of 200 rpm. The seed culture was harvested by centrifugation and then resuspended in an equal volume of M9 medium. The resuspended seed was used to inoculate expression fermentations at a rate of 3%. For expression, the culture was grown under the same conditions to an A 600 of 0.6. At this point, methionine biosynthesis was down regulated by the addition of L-lysine, L-threonine, and L-phenylalanine at a final concentration for each of 100 μg/ml and L-leucine, L-isoleucine, and L-valine at 50 μg/ml each. D,L-selenomethionine was added simultaneously to a final concentration of 100 μg/ml. After 15 - 20 minutes, protein expression was induced by addition of IPTG (isopropyl thio-β-D-galactosidase, Gibco BRL) to 1 mM. Growth of the culture was continued for an additional 3 hours until an A 600 of 2.0 - 2.2. Cells were then harvested by centrifugation and frozen at -80°C. Under these conditions, the average yield of cell paste was 4.0 g/L and approximately 20 mg/L of selenomethionine EF-P was produced. Purification of Selenomethionine EF-P E. coli cell paste resulting from 1 liter of induced cell culture was resuspended in 25 mL of buffer A (50 mM Tris pH 7.6 containing 300 mM NaCl and 10% glycerol). 10 mg of DNAse I and 1 Complete™ protease inhibitor tablet was added to the suspension. The cells were then lysed by passing the suspension three times through a French Press (Spectronic Instmments, Rochester, NY) at a pressure of 1000 PSI using a chilled 40 mL high pressure cell. The soluble cytosol was prepared from the lysate by ultracentrifugation at 100,000 x g for 60 min at 4°C. Benzonase (25μL) was added to the cytosol to remove any residual polynucleotides. The clarified cytosol was injected onto a HRlO/10 FPLC column (Pharmacia Biotech, Piscataway, NJ) packed with Ni-NTA Superflow resin (Qiagen, Chatsworth, CA) which had been previously equilibrated in buffer A. All of the column chromatography was performed on an AKTA 100 Explorer biochromatography system (Pharmacia Biotech, Piscataway, NJ) at a flow rate of 1 mL/minute. After injection, the column was rinsed with buffer A until the absorbance at 280 nm of the column eluate was less than 0.1 AUFS. The material was then eluted from the column by a linear gradient of buffer B (500 mM imidazole in buffer A). The gradient consisted of 0-8% buffer B in 20 minutes, followed by a 10 minute segment of 8% buffer B, and then a linear gradient of 8-100% buffer B over 20 minutes. The column was washed with 100% buffer B for 30 minutes. 4 mL fractions were collected starting at the beginning of the gradient. Selected fractions were analyzed by SDS-PAGE for purity before making the final pool for crystallographic studies. In a manner similar to that for selenomethionine EF-P, S. aureus EF-P was prepared and purified. Protein Crystallization The final purified EF-P protein sample was exchanged into 10 mM Tris pH 7.6 (5 mM DTT was added for selenomethionine EF-P) and concentrated to 12 mg/mL for crystallization experiments. Initial crystals of EF-P were obtained from a standard library of crystallization screening solutions - Hampton Screen 1, condition 37, 0.1 M sodium acetate pH 4.6, 8% PEG 4000. Optimization of the crystallization condition was conducted using EF-P at a concentration of 12 mg/ml. Crystals grew best at 0.1 M sodium acetate pH 5.2-5.4 and 1-4% PEG 4000. The crystals were grown by vapor diffusion in hanging drops by the addition of a 1 :1 starting ratio of protein to well solution. Since the pH of the crystallization buffer was at or very near the pi of the protein, protein precipitation was always observed after adding well solution to the protein solution. Over the course of equilibration, the protein resolubilized and eventually crystallized during a period of 1-5 days. Subsequently, it was determined that EF-P crystals could be grown by vapor diffusion in sitting drops where no well solution was added to the protein drop and equilibration occurred through the vapor phase overnight (this method avoided the initial precipitation event before crystal formation). Because of the lack of access to coordinates for either one of the eIF5A stmctures during the early stages of this project, selenomethionine EF-P was overexpressed by downregulating methionine biosynthesis (T.E. Benson et al., Nat. Struct. Biol 2:644-53 (1995); G.D. Van Duyne et al., J. Mol. Biol; 229:105-24 (1993)) and purified using immobilized metal affinity chromatography (see above). The purified selenomethionine EF- P was maintained in 50 mM Tris pH 7.8 and 5 mM DTT. Crystals of the selenomethionine EF-P grew in a manner similar to the methionine EF-P. Crystals grown under these conditions diffracted to 1.9 A resolution at the synchrotron. Data Collection and Structure Determination. Multiwavelength anomalous dispersion data was collection at the Advanced Photon Source located at Argonne National Labs in Argonne, IL on beamline 17-ID on the sodium acetate crystal form. Complete data sets were collected at three different wavelengths - one remote, low energy wavelength (1.0332 A), one wavelength at the inflection point of the selenium X-ray fluorescence spectrum where the dispersive differences would be maximal (0.979746 A) and one wavelength at the peak of the X-ray fluorescence spectrum where the anomalous differences would be maximal (0.979617 A). Each of these individual data sets was indexed and integrated separately (see Table 1 for integration statistics). The data sets were scaled to each other using the program SCALEIT in the CCP4 Program Suite (Collaborative Computational Project N4, Acta Cryst; D50:760-63 (1994)). Patterson maps initially revealed only two of the four selenium sites. Solution of the Patterson function was complicated by the presence of a cross vector between the two top selenium sites on a Harker section. Cross difference Fourier maps revealed a weaker third selenium site that indeed corresponded to a selenomethionine position in the EF-P structure. Heavy atom refinement and phase calculations carried out in MLPHARE (Z. Otwinowski, in Isomorphous Replacement and Anomalous Scattering 80-86 (W. Wolf et al., eds., SERC Daresbury Laboratory, Warrington, 1991) and subsequently followed by solvent flattening in DM (K.D. Cowtan & P. Main, Acta Cryst.; D49:148-57 (1993)) yielded electron density maps that were severely disconnected. At this point in the structure solution after investigating several alternative space groups, heavy atom refinement and phase calculations were conducted using SHARP (E. La Fortelle et al., A Maximum-Likelihood Heavy- Atom Parameter Refinement and Phasing Program for the MIR and MAD Methods, P. Bourne & K. Watenpaugh, eds., Crystallographic Computing 7 (1997)). Phases calculated in SHARP were solvent flattened using the program SOLOMON (Collaborative Computational Project N4, Acta Cryst.; D50:760-63 (1994)) and gave a significantly improved electron density map. At this stage in the stmcture solution, the coordinates for eIF5A from M. jannaschii became available and greatly aided the process of model building. Model building was done using the program CHAIN ( J.S. Sack, J. Mol. Graph; 6:224-25 (1988)) and LORE (B.C. Finzel, Meth. Enzymol.; 277:230-42 (1997)). Refinement was carried out with XPLOR98 (A.T. Brunger, X-PLOR version 3.1: A system for X-ray Crystallography and NMR, New Haven: Yale Univ. Press (1992)) incorporating bulk solvent correction during the refinement (J.S. Jiang & A.T. Brunger, J. Mol. Biol; 243:100-15 (1994)). Progress of the refinement was monitored by a decrease in both the R-factor and Free R-factor. Stereochemistry of the model was checked using PROCHECK (R.A. Laskowski et al., Journal of Applied Crystallography; 26:283-91 (1993)) revealing no residues in disallowed regions of the Ramachandran plot. Figures 3 and 10 were made using SETOR (S.N. Evans, J. Mol. Graphics; 11 :134-38 (1993)) and figures 5, 7, 8, 11-14 were produced in MOLSCRIPT (P. Kraulis, J. Appl. Cryst.; 24:946-50 (1991)).

Claims: What is claimed is: 1. A molecule or molecular complex comprising at least a portion of an S. aureus EF-P or EF-P-like binding surface, wherein the binding surface comprises amino acids selected from the surface residues listed in Table 1 , the binding surface defined by a set of points having a root mean square deviation of less than about 1.9 A from points representing the backbone atoms of amino acids Val 29, Lys30, Pro31, Gly32, Lys 33, Gly 34, Ser 35, and Ala 36 as represented by the stmcture coordinates listed in Figure 4. 2. The molecule or molecular complex of claim 1 , wherein the binding surface is defined by a set of points having a root mean square deviation of less than about 1.9 A from points representing the backbone atoms of amino acids within about 15 A of Lys33 as listed in Table 2 and as represented by the stmcture coordinates listed in Figure 4. 3. A molecule or molecular complex that is stmcturally homologous to an S. aureus EF-P molecule or molecular complex, wherein the S aureus EF-P molecule or molecular complex is represented by stmcture coordinates listed in Figure 4. 4. A scalable three dimensional configuration of points, at least a portion of said points derived from stmcture coordinates of at least a portion of an S. aureus EF-P molecule or molecular complex listed in Figure 4 comprising amino acids Val 29, Lys30, Pro31, Gly32, Lys 33, Gly 34, Ser 35, and Ala 36. 5. The scalable three dimensional configuration of points of claim 4, substantially all of said points derived from stmcture coordinates of an S. aureus EF-P molecule or molecular complex listed in Figure 4. 6. The scalable three dimensional configuration of points of claim 4 wherein at least a portion of the points derived from the S. aureus EF-P stmcture coordinates are derived from stmcture coordinates representing the locations of at least the backbone atoms of amino acids defining an S. aureus EF-P or EF-P- like binding surface, the binding surface comprising amino acids listed in Table 1. 7. The scalable three dimensional configuration of points of claim 4 wherein the binding surface comprises amino acids within about 15 A of Lys33 as listed in Table 2. 8. The scalable three dimensional configuration of points of claim 4 displayed as a holographic image, a stereodiagram, a model or a computer-displayed image. 9. A scalable three dimensional configuration of points, at least a portion of the points derived from stmcture coordinates of at least a portion of a molecule or a molecular complex that is stmcturally homologous to an S. aureus EF-P molecule or molecular complex and comprises an EF-P or EF-P-like binding surface comprising the amino acids selected from the surface residues listed in Table 1. 10. The scalable three-dimensional configuration of points of claim 9 displayed as a holographic image, a stereodiagram, a model or a computer-displayed image. 11. A machine-readable data storage medium comprising a data storage material encoded with machine readable data which, when using a machine programmed with instmctions for using said data, is capable of displaying a graphical three-dimensional representation of at least one molecule or molecular complex selected from the group consisting of: (i) a molecule or molecular complex comprising at least a portion of an S. aureus EF-P or EF-P-like binding surface comprising amino acids selected from the surface residues listed in Table 1 , the binding surface defined by a set of points having a root mean square deviation of less than about 1.9 A from points representing the backbone atoms of amino acids Val 29, Lys30, Pro31, Gly32, Lys 33, Gly 34, Ser 35, and Ala 36 as represented by structure coordinates listed in Figure 4; and (ii) a molecule or molecular complex comprising at least a portion of an S. aureus EF-P molecule comprising amino acids within about 15 A of Lys33 as listed in Table 2, the EF-P molecule defined by a set of points having a root mean square deviation of less than about 1.9 A from points representing the backbone atoms of said amino acids as represented by stmcture coordinates listed in Figure 4; and (iii) a molecule or molecular complex that is stmcturally homologous to an S. aureus EF-P molecule or molecular complex, wherein the S aureus EF-P molecule or molecular complex is represented by stmcture coordinates listed in Figure 4. 12. 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 stmcture 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 stmctural coordinates for S. aureus EF-P listed in Figure 4; and said second set of data comprises an x-ray diffraction pattern of a molecule or molecular complex of unknown stmcture. PAGE INTENTIONALLY LEFT BLANK 13. A method for obtaining stmctural information about a molecule or a molecular complex of unknown stmcture comprising: crystallizing the molecule or molecular complex; generating an x-ray diffraction pattern from the crystallized molecule or molecular complex; applying at least a portion of the stmcture coordinates set forth Figure 4 to the x-ray diffraction pattern to generate a three-dimensional electron density map of at least a portion of the molecule or molecular complex whose stmcture is unknown. 14. A method for homology modeling an S. aureus EF-P homolog comprising: aligning the amino acid sequence of an S aureus EF-P homolog with the amino acid sequence of an S. aureus EF-P molecule and incorporating the sequence of the S. aureus EF-P homolog into a model of S. aureus EF-P derived from structure coordinates set forth in Figure 4 to yield a preliminary model of the S. aureus EF-P homolog; subjecting the preliminary model to energy minimization to yield an energy minimized model; remodeling regions of the energy minimized model where stereochemistry restraints are violated to yield a final model of the S. aureus EF-P homolog. 15. A computer-assisted method for identifying an inhibitor of S. aureus EF-P activity comprising: supplying a computer modeling application with a set of stmcture coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of an S. aureus EF-P or EF-P-like binding surface, the binding surface comprising amino acid surface residues listed in Table 1; supplying the computer modeling application with a set of structure coordinates of a chemical entity; and determining whether the chemical entity is an inhibitor expected to bind to or interfere with the molecule or molecular complex, wherein binding to or interfering with the molecule or molecular complex is indicative of potential inhibition of S. aureus EF-P activity. 16. The method of claim 15 wherein the binding surface comprises amino acids selected from the surface residues listed in Table 1, the binding surface being further defined by a set of points having a root mean square deviation of less than about 1.9 A from points representing the backbone atoms of amino acids Val 29, Lys30, Pro31, Gly32, Lys 33, Gly 34, Ser 35, and Ala 36 as represented by structure coordinates listed in Figure 4. 17. The method of claim 15 wherein determining whether the chemical entity is an inhibitor expected to bind to or interfere with the molecule or molecular complex comprises performing a fitting operation between the chemical entity and the binding surface of the molecule or molecular complex, followed by computationally analyzing the results of the fitting operation to quantify the association between the chemical entity and the binding surface. 18. The method of claim 15 further comprising screening a library of chemical entities. 19. A computer-assisted method for designing an inhibitor of S. aureus EF-P activity comprising: supplying a computer modeling application with a set of stmcture coordinates of a molecule or molecular complex to, the molecule or molecular complex comprising at least a portion of an S. aureus EF-P or EF-P-like binding surface, the binding surface comprising amino acid surface residues listed in Table 1; supplying the computer modeling application with a set of structure coordinates for a chemical entity; evaluating the potential binding interactions between the chemical entity and binding surface of the molecule or molecular complex; structurally modifying the chemical entity to yield a set of structure coordinates for a modified chemical entity; and determining whether the modified chemical entity is an inhibitor expected to bind to or interfere with the molecule or molecular complex, wherein binding to or interfering with the molecule or molecular complex is indicative of potential inhibition of S aureus EF-P activity. 20. The method of claim 19 wherein the binding surface comprises amino acids selected from the surface residues listed in Table 1, the binding surface being defined by a set of points having a root mean square deviation of less than about 1.9 A from points representing the backbone atoms of amino acids Nal 29, Lys30, Pro31, Gly32, Lys 33, Gly 34, Ser 35, and Ala 36 as represented by stmcture coordinates listed in Figure 4. 21. The method of claim 19 wherein determining whether the modified chemical entity is an inhibitor expected to bind to or interfere with the molecule or molecular complex comprises performing a fitting operation between the chemical entity and the binding surface of the molecule or molecular complex, followed by computationally analyzing the results of the fitting operation to quantify the association between the chemical entity and the binding surface. 22. The method of claim 19 wherein the set of stmcture coordinates for the chemical entity is obtained from a chemical fragment library 23. A computer-assisted method for designing an inhibitor of S. aureus EF-P activity de novo comprising: supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of an S aureus EF-P or EF-P-like binding surface, wherein the binding surface comprises amino acid surface residues listed in Table 1; computationally building a chemical entity represented by set of stmcture coordinates; and determining whether the chemical entity is an inhibitor expected to bind to or interfere with the molecule or molecular complex, wherein binding to or interfering with the molecule or molecular complex is indicative of potential inhibition of S aureus EF-P activity. 24. The method of claim 23 wherein the binding surface comprises amino acids selected from the surface residues listed in Table 1 , the binding surface being defined by a set of points having a root mean square deviation of less than about 1.9 A from points representing the backbone atoms of amino acids Val 29, Lys30, Pro31, Gly32, Lys 33, Gly 34, Ser 35, and Ala 36 as represented by structure coordinates listed in Figure 4. 25. The method of claim 23 wherein determining whether the chemical entity is an inhibitor expected to bind to or interfere with the molecule or molecular complex comprises performing a fitting operation between the chemical entity and the binding surface of the molecule or molecular complex, followed by computationally analyzing the results of the fitting operation to quantify the association between the chemical entity and the binding surface. 26. A method for making an inhibitor of S. aureus EF-P activity, the method comprising chemically or enzymatically synthesizing a chemical entity to yield an inhibitor of S aureus EF-P activity, the chemical entity having been identified during a computer-assisted process comprising supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a S aureus EF-P or EF-P-like binding surface; supplying the computer modeling application with a set of structure coordinates of a chemical entity; and determining whether the chemical entity is expected to bind to or interfere with the molecule or molecular complex at the binding surface, wherein binding to or interfering with the molecule or molecular complex is indicative of potential inhibition of S. aureus EF-P activity. 27. A method for making an inhibitor of S. aureus EF-P activity, the method comprising chemically or enzymatically synthesizing a chemical entity to yield an inhibitor of S. aureus EF-P activity, the chemical entity having been designed during a computer-assisted process comprising supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a S aureus EF-P or EF-P-like binding surface; supplying the computer modeling application with a set of structure coordinates for a chemical entity; evaluating the potential binding interactions between the chemical entity and binding surface of the molecule or molecular complex; stmcturally modifying the chemical entity to yield a set of structure coordinates for a modified chemical entity; and determining whether the chemical entity is expected to bind to or interfere with the molecule or molecular complex at the binding surface, wherein binding to or interfering with the molecule or molecular complex is indicative of potential inhibition of S aureus EF-P activity. 28. A method for making an inhibitor of S. aureus EF-P activity, the method comprising chemically or enzymatically synthesizing a chemical entity to yield an inhibitor of S. aureus EF-P activity, the chemical entity having been designed during a computer-assisted process comprising supplying a computer modeling application with a set of stmcture coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a S aureus EF-P or EF-P-like binding surface; computationally building a chemical entity represented by set of stmcture coordinates; and determining whether the chemical entity is expected to bind to or interfere with the molecule or molecular complex at the binding surface, wherein binding to or interfering with the molecule or molecular complex is indicative of potential inhibition of S aureus EF-P activity. 29. An inhibitor of S. aureus EF-P activity identified, designed or made according to the method of any of the claims 15, 19, 23, 26, 27, or 28. 30. A composition comprising an inhibitor of S. aureus EF-P activity identified, designed or made according to the method of any of claims 15, 19, 23, 26, 27, or 28. 31. A pharmaceutical composition comprising an inhibitor of S. aureus EF-P activity identified or designed according to the method of any of claims 15, 19, 23, 26, 27, or 28.or a salt thereof, and pharmaceutically acceptable carrier. 32. A method for crystallizing an S. aureus EF-P molecule or molecular complex comprising: preparing purified S. aureus EF-P at a concentration of about 1 mg/ml to about 50 mg/ml; and crystallizing S. aureus EF-P from a solution including about 0 wt. % to about 50 wt. % polyethylene glycol, 0 to about 20 wt. % DMSO, and buffered to a pH of about 3.5 to about 5.5. 33. A crystal of S. aureus EF-P. 34. The crystal of claim 33 having the orthorhombic space group symmetry P2.2.2,. 35. The crystal of claim 33 comprising a unit cell having dimensions of a, b, and c; wherein a is about 25 A to about 50 A, b is about 35 A to about 60 A, and c is about 85 A to about 110 A; and α = β = γ = 90°. 36. The crystal of claim 33 comprising atoms arranged in a spatial relationship represented by the stmcture coordinates listed in Figure 4. 37. The crystal of claim 33 having an S. aureus EF-P amino acid sequence SEQ ID NO:l. 38. The crystal of claim 33 having an S. aureus EF-P amino acid sequence SEQ ID NO: 1, except that at least one methionine is replaced with selenomethionine.

Inventors: BENSON TIMOTHY E, BENSON, TIMOTHY, E.
Applicants: BENSON TIMOTHY E, UPJOHN CO, BENSON, TIMOTHY, E., PHARMACIA & UPJOHN COMPANY
Application year: 2000
Main classification: C07K14
IPC codes: A61K45, A61P31, A61P43, C07K1, C07K14, C12P1