5JFO

Structure of the M.tuberculosis enoyl-reductase InhA in complex with GSK625

5JFO の概要

• エントリーDOI: 10.2210/pdb5jfo/pdb
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl}-5-[(1S)-1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine, ... (4 entities in total)
• 機能のキーワード: antitubercular, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 118544.39

構造登録者

Gulten, G.,Sacchettini, J.C. (登録日: 2016-04-19, 公開日: 2016-08-10, 最終更新日: 2023-09-27)

主引用文献

Martinez-Hoyos, M.,Perez-Herran, E.,Gulten, G.,Encinas, L.,Alvarez-Gomez, D.,Alvarez, E.,Ferrer-Bazaga, S.,Garcia-Perez, A.,Ortega, F.,Angulo-Barturen, I.,Rullas-Trincado, J.,Blanco Ruano, D.,Torres, P.,Castaneda, P.,Huss, S.,Fernandez Menendez, R.,Gonzalez Del Valle, S.,Ballell, L.,Barros, D.,Modha, S.,Dhar, N.,Signorino-Gelo, F.,McKinney, J.D.,Garcia-Bustos, J.F.,Lavandera, J.L.,Sacchettini, J.C.,Jimenez, M.S.,Martin-Casabona, N.,Castro-Pichel, J.,Mendoza-Losana, A.
Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor.
Ebiomedicine, 8:291-301, 2016

PubMed Abstract: Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.

PubMed: 27428438
DOI: 10.1016/j.ebiom.2016.05.006

実験手法

X-RAY DIFFRACTION (2.907 Å)