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Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site

DOI: 10.1073/pnas.1600630113 DOI Help

Authors: Monica Kasbekar (National Center for Advancing Translational Sciences, National Institutes of Health; University of Cambridge) , Gerhard Fischer (University of Cambridge) , Bryan T. Mott (National Center for Advancing Translational Sciences, National Institutes of Health) , Adam Yasgar (National Center for Advancing Translational Sciences, National Institutes of Health) , Marko Hyvonen (University of Cambridge) , Helena I. M. Boshoff (National Institute of Allergy and Infectious Diseases, National Institutes of Health) , Chris Abell (University of Cambridge) , Clifton E. Barry (National Institute of Allergy and Infectious Diseases, National Institutes of Health) , Craig J. Thomas (National Center for Advancing Translational Sciences, National Institutes of Health)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 113 , PAGES 7503 - 7508

State: Published (Approved)
Published: July 2016
Diamond Proposal Number(s): 9537 , 14043

Abstract: Enzymes in essential metabolic pathways are attractive targets for the treatment of bacterial diseases, but in many cases, the presence of homologous human enzymes makes them impractical candidates for drug development. Fumarate hydratase, an essential enzyme in the tricarboxylic acid (TCA) cycle, has been identified as one such potential therapeutic target in tuberculosis. We report the discovery of the first small molecule inhibitor, to our knowledge, of the Mycobacterium tuberculosis fumarate hydratase. A crystal structure at 2.0-Å resolution of the compound in complex with the protein establishes the existence of a previously unidentified allosteric regulatory site. This allosteric site allows for selective inhibition with respect to the homologous human enzyme. We observe a unique binding mode in which two inhibitor molecules interact within the allosteric site, driving significant conformational changes that preclude simultaneous substrate and inhibitor binding. Our results demonstrate the selective inhibition of a highly conserved metabolic enzyme that contains identical active site residues in both the host and the pathogen.

Journal Keywords: allosteric regulation; selective inhibition; fumarate hydratase; Mycobacterium tuberculosis; TCA cycle

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography