2H9I

Mycobacterium tuberculosis InhA bound with ETH-NAD adduct

2H9I の概要

• エントリーDOI: 10.2210/pdb2h9i/pdb
• 関連するPDBエントリー: 1ZID
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], {(2R,3S,4R,5R)-5-[(4S)-3-(AMINOCARBONYL)-4-(2-ETHYLISONICOTINOYL)PYRIDIN-1(4H)-YL]-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL}METHYL [(2R,3S,4R,5R)-5-(6-AMINO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL DIHYDROGEN DIPHOSPHATE (3 entities in total)
• 機能のキーワード: inha, ethionamide, eth, tuberculosis, oxidoreductase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29192.15

構造登録者

Wang, F.,Sacchettini, J.C. (登録日: 2006-06-09, 公開日: 2007-01-30, 最終更新日: 2023-08-30)

主引用文献

Wang, F.,Langley, R.,Gulten, G.,Dover, L.G.,Besra, G.S.,Jacobs, W.R.,Sacchettini, J.C.
Mechanism of thioamide drug action against tuberculosis and leprosy.
J.Exp.Med., 204:73-78, 2007

PubMed Abstract: Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target-drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.

PubMed: 17227913
DOI: 10.1084/jem.20062100

実験手法

X-RAY DIFFRACTION (2.2 Å)