5F91

Fumarate hydratase of Mycobacterium tuberculosis in complex with formate and allosteric modulator (N-(5-(azepan-1-ylsulfonyl)-2-methoxyphenyl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide)

5F91 の概要

• エントリーDOI: 10.2210/pdb5f91/pdb
• 関連するPDBエントリー: 5F92
• 分子名称: Fumarate hydratase class II, ~{N}-[5-(azepan-1-ylsulfonyl)-2-methoxy-phenyl]-2-(4-oxidanylidene-3~{H}-phthalazin-1-yl)ethanamide, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: allostery, inhibitor, hydratase, metabolism, tuberculosis, modulation, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)
• 細胞内の位置: Cytoplasm : P9WN92
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 211641.75

構造登録者

Kasbekar, M.,Fischer, G.,Mott, B.T.,Yasgar, A.,Hyvonen, M.,Boshoff, H.I.,Abell, C.,Barry, C.E.,Thomas, C.J. (登録日: 2015-12-09, 公開日: 2016-06-22, 最終更新日: 2023-09-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.998 Å)