9GY6

Mycobacterial cytochrome bc1:aa3 with inhibitor

これはPDB形式変換不可エントリーです。

9GY6 の概要

• エントリーDOI: 10.2210/pdb9gy6/pdb
• EMDBエントリー: 51689
• 分子名称: Cytochrome bc1 complex Rieske iron-sulfur subunit, DUF5130 domain-containing protein, Superoxide dismutase [Cu-Zn], ... (25 entities in total)
• 機能のキーワード: membrane protein, inhibitor complex, mycobacterium, cytochrome bc, oxidoreductase
• 由来する生物種: Mycolicibacterium smegmatis MC2 155; 詳細
• タンパク質・核酸の鎖数: 22
• 化学式量合計: 707791.26

構造登録者

lamers, M.H.,Verma, A.K. (登録日: 2024-10-01, 公開日: 2025-04-09, 最終更新日: 2025-07-02)

主引用文献

Verma, A.K.,Kim, R.Q.,Lamprecht, D.A.,Aguilar-Perez, C.,Wong, S.,Veziris, N.,Aubry, A.,Bartolome-Nebreda, J.M.,Carbajo, R.J.,Wetzel, J.,Lamers, M.H.
Structural and mechanistic study of a novel inhibitor analogue of M. tuberculosis cytochrome bc 1 :aa 3 .
NPJ Drug Discov, 2:6-6, 2025

PubMed Abstract: Drug-resistant tuberculosis (TB) continues to challenge treatment options, necessitating the exploration of new compounds of novel targets. The mycobacterial respiratory complex cytochrome bc:aa has emerged as a promising target, exemplified by the success of first-in-class inhibitor Q203 in phase 2 clinical trials. However, to fully exploit the potential of this target and to identify the best-in-class inhibitor more compounds need evaluation. Here, we introduce JNJ-2901, a novel Q203 analogue, that demonstrates activity against multidrug-resistant clinical strains at sub-nanomolar concentration and 4-log reduction in bacterial burden in a mouse model of TB infection. Inhibitory studies on purified enzymes validate the nanomolar inhibitions observed in mycobacterial cells. Additionally, cryo-EM structure analysis of cytochrome bc:aa bound to JNJ-2901 reveals the binding pocket at the menaquinol oxidation site (Qp), akin to other substate analogue inhibitors like Q203 and TB47. Validation of the binding site is further achieved by generating and isolating the JNJ-2901 resistant mutations in , followed by purification and resistance analysis of the resistant cytochrome bc:aa complex. Our comprehensive work lays the foundation for further clinical validations of JNJ-2901.

PubMed: 40191462
DOI: 10.1038/s44386-025-00008-3

実験手法

ELECTRON MICROSCOPY (3.1 Å)