As a component of the Tuberculosis Structural Genomics Consortium, this project will focus on structural and biochemical characterization of key metabolic and biosynthetic enzymes in three broad categories. 1) We will determine the structures of several enzymes involved in energy production, given the need of the organism to adapt to metabolism of different carbon sources inside host macrophages, especially enzymes at key choice points where flux of metabolites between pathways is controlled. 2) We will determine the structures of enzymes required for biosynthesis of essential amino acids and co-factors, which are thought to be restricted in the nutrient-limiting environment of the phagosome. 3) Finally, we will determine the structures of enzymes that synthesize mycolic acids, polyketides, and other lipid components of the cell wall. Each of these pathways represents a critical vulnerability in the organism that could be exploited for future drug discovery. Our goal is not just to solve the structures of these proteins, but also to obtain co-crystal structures of complexes with inhibitors, which provides important information on active-site interactions for subsequent drug design. Hence, for most of our targets, we will perform screening of small-molecule libraries to identify inhibitors as ligands for co-crystallization. The inhibitory compounds we discover will also be useful as chemical tools of value for many other purposes, such as probing function in cell and validating essentiality by chemical knock-down. All structural and chemical data generated will be made available to the public to stimulate future drug discovery for tuberculosis.
The protein crystal structures we propose to solve will not only contribute to our understanding of the function and role of these proteins in M. tuberculosis, but they will also provide important structural information for future drug discovery. Structures of complexes with inhibitors are needed to reveal active-site interactions for designing more potent drugs.
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