The UCLA project develops and applies structural and bioinformatic tools for the discovery of protein drug targets anddrugs against tuberculosis. We have developed the database for the TB Structural Genomics Consortium. Thiscontains a wealth of information on the genome and proteome of Mycobacterium tuberculosis, which is open toresearchers world wide to aid them in their structural studies of MTb proteins. Improvements to the database willenhance the ease with which scientists can view and update information about each protein. The information willinclude the complete history of experiments on each protein, as the project moves from cloning and expression, throughpurification, crystallization, structure determination, and drug discovery. The database will also incorporate newbioinformatics methods being developed at UCLA. These include methods for inferring the biological function ofproteins from their structures by the server ProKnow and for inferring biological function from genome sequences fromthe database ProLinks. A new method for inferring biological function from combined genome sequences andmicroarray data will be developed to aid consortium members in selecting the most effective targets for structuralstudies in the effort to determine drugs.Structural studies of Mtb proteins at UCLA will focus on secreted, regulatory, and metabolic proteins. These proteinsare involved in the invasion of host cells by Mtb, in the protection of Mtb against host cell defenses, in survival of Mtband are thus potential protein drug targets. Secreted proteins of Mtb in particular are excellent anti- Mtb drug targetsbecause drugs inhibiting these proteins do not have to penetrate the waxy cell wall of Mtb. Structures of each of theseprotein targets can then be screened in silico against ligands, in collaboration with Dr. James Sacchettini's laboratory.Predicted ligands will be co-crystallized for further structural studies. Potential inhibitors will be studied in collaborationwith Dr. William Jacobs' laboratory to see if they prevent growth of Mtb within a mouse model.Each protein whose structure we determine, we will also characterize biochemically. Developing an in vitro assay willallow high-throughput in vitro drug screening, continuing our collaboration with the Southern Research Institute. All leadcompounds will be cocrystallized with its target protein for structural studies. Where functions of proteins are unknown,our bioinformatics tools may predict a function, which will then be verified experimentally, to move the protein into thedrug discovery pipeline. Dozens of MTb proteins are in the UCLA pipeline, with some half dozen at the stage ofcrystals.
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