5F92

Fumarate hydratase of Mycobacterium tuberculosis in complex with formate

Summary for 5F92

• Entry DOI: 10.2210/pdb5f92/pdb
• Related: 5F91
• Descriptor: Fumarate hydratase class II, FORMIC ACID, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: hydratase, metabolism, tuberculosis, lyase
• Biological source: Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)
• Cellular location: Cytoplasm : P9WN92
• Total number of polymer chains: 4
• Total formula weight: 210926.61

Authors

Kasbekar, M.,Fischer, G.,Mott, B.T.,Yasgar, A.,Hyvonen, M.,Boshoff, H.I.,Abell, C.,Barry, C.E.,Thomas, C.J. (deposition date: 2015-12-09, release date: 2016-06-22, Last modification date: 2024-03-06)

Primary citation

Kasbekar, M.,Fischer, G.,Mott, B.T.,Yasgar, A.,Hyvonen, M.,Boshoff, H.I.,Abell, C.,Barry, C.E.,Thomas, C.J.
Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site.
Proc.Natl.Acad.Sci.USA, 113:7503-7508, 2016

PubMed 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.

PubMed: 27325754
DOI: 10.1073/pnas.1600630113

Experimental method

X-RAY DIFFRACTION (1.859 Å)