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Crystals of luxp and complexes thereofRelated Patent Categories: Chemistry: Natural Resins Or Derivatives; Peptides Or Proteins; Lignins Or Reaction Products Thereof, Proteins, I.e., More Than 100 Amino Acid ResiduesCrystals of luxp and complexes thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070185314, Crystals of luxp and complexes thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. patent application Ser. No. 10/227,400 filed Aug. 22, 2002 which claims benefit of U.S. Provisional Application Ser. No. 60/314,705, filed Aug. 24, 2001, all of which are hereby incorporated by reference in their entirety. [0002] This application is related to U.S. patent application Ser. No. 10/227,327 filed Aug. 22, 2002, which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [0004] 1. Field of the Invention [0005] This invention relates to the LuxP protein, and more particularly to a crystalline form of the LuxP protein having sufficient crystal quality to allow crystallographic data to be obtained, as well as to methods of structure-based drug design based on the crystollographic data. [0006] 2. Description of the Related Art [0007] Cell-cell communication in bacteria occurs through the exchange of extracellular signaling compounds called autoinducers. This process, termed quorum sensing, allows bacterial populations to coordinate gene expression. Community cooperation likely enhances the effectiveness of processes including bioluminescence, virulence factor expression, antibiotic production, and biofilm development. Unlike other autoinducers, which are specific to particular species of bacteria, a recently discovered autoinducer (AI-2) is produced by a large number of bacterial species. AI-2 has been proposed to serve as a universal signal for inter-species communication. [0008] AI-2 was originally identified in the bioluminescent marine bacterium Vibrio harveyi as one of two autoinducers that regulate light production in response to cell density. The synthase required for AI-2 production, LuxS, is widely conserved among gram-negative and-positive bacteria. Bacteria produce AI-2 from S-adenosylmethionine in several enzymatic steps, as shown in FIG. 1. Consumption of S-adenosylmethionine as a methyl donor produces S-adenosylhomocysteine, which undergoes hydrolysis catalyzed by the nucleosidase Pfs to yield adenine and S-ribosylhomocysteine. Subsequently LuxS catalyzes cleavage of S-ribosylhomocysteine to homocysteine and 4,5-dihydroxy-2,3-pentanedione, which can then cyclize either by itself or in an enzyme-mediated process. [0009] Detection of AI-2 by V. harveyi involves two proteins, LuxP and LuxQ. LuxP belongs to a large family of periplasmic binding proteins whose members bind diverse ligands, while LuxQ is a two-component hybrid sensor kinase embedded in the bacterial inner membrane. It is believed that LuxP is the primary AI-2 receptor, see X. Chen, S. Schauder, N. Potier, A. Van Dorsselaer, I. Pelczer, B. Bassler, and F. Hughson, "Structural Identification of a Bacterial Quorum-Sensing Signal Containing Boron," Nature, Vol. 415, pp. 545-549 (2002). In quorum sensing, the periplasmic LuxP-AI-2 complex likely interacts with LuxQ to transduce the autoinducer signal. However, heretofore LuxP has not been isolated in crystalline form suitable for structural determination by X-ray crystallography, and thus neither the crystal structure of LuxP nor the LuxP binding site for AI-2 were known prior to the instant invention. SUMMARY OF THE INVENTION [0010] A preferred embodiment provides a crystal comprising LuxP. The crystal may comprise a LuxP-ligand complex. Preferably, the ligand comprises boron and/or a furan moiety. AI-2 is an example of a preferred ligand. [0011] Another preferred embodiment provides a method of using the crystal to identify whether a ligand binds to LuxP, comprising: obtaining the atomic coordinates in the crystal of at least a selected portion of LuxP; using the atomic coordinates to model the selected portion; identifying a potential ligand; and docking the potential ligand to the selected portion of LuxP. Preferably, the selected portion comprises an amino acid residue selected from the group consisting of Trp 82, Gln 77, Ser 79, Asp 267, Thr 266, Trp 289, Arg 310, Arg 215, and Asn 159 according to Table 1. Another preferred embodiment provides ligands identified by this method. A pharmaceutical composition comprising such a ligand is another preferred embodiment, and methods of treating bacterial infections by administering such pharmaceutical compositions to humans are another preferred embodiment. [0012] These and other embodiments are described in greater detail below. BRIEF DESCRIPTION OF THE DRAWINGS [0013] Various aspects of the invention will be readily apparent from the following description and from the appended drawings, which are meant to illustrate and not to limit the invention, and wherein: [0014] FIG. 1 illustrates several steps in the pathway of the production of AI-2 from S-adenosylmethionine. [0015] FIG. 2 illustrates the structure of a LuxP-AI-2 complex. [0016] FIG. 3 shows the structure of LuxP and AI-2 at a binding site. [0017] FIG. 4 illustrates a route for the conversion of 4,5-dihydroxy-2,3-pentanedione to AI-2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0018] A preferred embodiment provides a crystal comprising LuxP (SEQ ID NO: 1). In this context, those skilled in the art will understand that the term "crystal" refers to an ordered arrangement of atoms, the crystal having an overall size and quality sufficient for the elucidation of the atomic arrangement by X-ray crystallography. Preferably, the crystal diffracts X-rays to a resolution of greater than about 5.0 Angstroms (.ANG.), more preferably greater than about 2.8 .ANG., even more preferably greater than about 1.5 .ANG.. Those skilled in the and that a resolution "greater than" a particular value means a resolution that numerically exceeds the recited value. For example, in the language of X-ray crystallography, a resolution 2.8 .ANG. is greater than a resolution of 5.0 .ANG.. Crystals comprising LuxP are preferably prepared by the methods described in the Examples below. The atomic coordinates for LuxP are preferably determined by X-ray crystallography of a crystal comprising LuxP, preferably by the methods described in the Examples below. A set of atomic coordinates obtained by these methods for a crystal comprising LuxP appears in Table 1. [0019] A preferred crystal comprises LuxP and a ligand. Preferably, the ligand comprises a furan moiety and/or a boron atom. In this context, those skilled in the art will understand that the term "ligand" refers to a molecule or ion that binds to LuxP. Preferably, binding between the ligand and LuxP occurs at a LuxP binding site. In this context, those skilled in the art will understand that the term "binding site" refers to a region of LuxP that favorably associates with a ligand, thus producing a LuxP-ligand complex in which the ligand binds relatively tightly to LuxP. Such strong binding may be produced, for example, when the shapes of the binding site and ligand are mutually compatible (e.g., "lock and key"), and/or when at least some of the ligand atoms are attracted to at least some of the LuxP atoms in the vicinity of the binding site by intermolecular forces, e.g., dipole-dipole interactions, Van der Waals attractions, hydrogen-bonding, etc. [0020] Binding sites have significant utility in fields such as drug discovery. The association of natural ligands with the binding sites of their corresponding proteins, enzymes or receptors is the basis of many biological mechanisms of action. Similarly, many drugs exert their biological effects through association with the binding sites of proteins, enzymes, and receptors. Such associations may occur with all or any parts of the binding site. An understanding of such associations enables the design of drugs having more favorable associations with their target proteins, enzymes or receptors, and thus, improved biological effects. Therefore, this information is valuable in designing potential inhibitors of the binding sites of biologically important targets. Continue reading about Crystals of luxp and complexes thereof... Full patent description for Crystals of luxp and complexes thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Crystals of luxp and complexes thereof patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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