Tethered Domains As Regulatory Elements

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DESCRIPTION (provided by applicant): Our work has contributed to the discovery of the ACT domain, a protein regulatory domain modulated by small molecules, and has produced the structure of the archetypical ACT domain. The goal of this research is to continue our investigation into the mechanism of regulation of proteins by the ACT domain and to relate this to the long term goals of this laboratory which are to determine the relationship between structure and function in conformationally regulated control mechanisms, to eventually relate that to the physiology and pathophysiology mediated by these enzymes and by analogous systems, and to eventually understand conformational mediated processes in proteins well enough to be able to apply basic principles to more complex systems. The specific aims will 1) elucidate the mechanism of the ACT domain in D-3- phosphoglycerate dehydrogenase (PGDN) from E. coli and M. tuberculosis, 2) elucidate the function of a new structural domain and small molecule binding site found in M. tuberculosis PGDH that may function in conjunction with the ACT domain, 3) determine the structure and function of human PGDH, and 4) screen the ligand binding sites of M. tuberculosis PGDH for the development of inhibitors that can be used to assess the role of PGDH in the metabolism of M. tuberculosis during its active, adaptive and persistent phases and that may eventually be used for the treatment of multi-drug resistant tuberculosis. The relevance of this work is 2-fold. First, the ACT domain is a newly recognized structural domain that functions in the regulation of many proteins. Determining its mechanism and the universality of its action among proteins will contribute to our understanding of protein regulation in physiology and disease as well as provide a potential new weapon for protein regulation in gene replacement therapy. Secondly, multi-drug resistant tuberculosis is a growing problem that impacts a large percentage of the world's population. Our observations that PGDH from M. tuberculosis is inhibited by L-serine and that PGDH from humans is not, may provide a new focus in drug development for treatment of tuberculosis.