STRUCTURE DETERMINATION OF RV2996C/NADH, AND RV2513

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mycobacterium tuberculosis(TB) is a human pathogen causing the disease, tuberculosis, killing over 2 million people per year. It is the No. 1 infectious killer of adults in the world. As part of the TB Structural Genomics Consortium (TBSGC) funded by the NIH¿s Protein Structure Initiative, our main goal is to determine unique and/or functionally important TB proteins to help understand TB physiology and to help establish the foundation of anti-TB drug development. We recently crystallized two new TB target proteins. (1) Rv2996C, a D-3-phosphoglycerate dehydrogenase, or serA, is a key enzyme in intermediary metabolism and respiration of TB. It contains ATP/GTP-binding site motif A (P-loop), D-isomer specific 2-hydroxyacid dehydrogenases NAD-binding signature and D-isomer specific 2-hydroxyacid dehydrogenases signature. Similar structures are available but its NADH bound form has not been unveiled. Structure of this will help understand the biochemistry in Serine synthesis in TB and provide chemical basis in designing inhibitors. (2) Rv2513, a conserved hypothetical protein essential to TB¿s growth. This will lead to a new structure crucial to TB¿s life cycle. The new structure may contain important clue to the function of this new target.