4V1G

Crystal structure of a mycobacterial ATP synthase rotor ring

4V1G の概要

• エントリーDOI: 10.2210/pdb4v1g/pdb
• 関連するPDBエントリー: 4V1F 4V1H
• 分子名称: F0F1 ATP SYNTHASE SUBUNIT C, octyl beta-D-glucopyranoside (3 entities in total)
• 機能のキーワード: hydrolase, f1fo-atp synthase rotor membrane protein structure
• 由来する生物種: MYCOBACTERIUM PHLEI
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 26713.13

構造登録者

Preiss, L.,Yildiz, O.,Meier, T. (登録日: 2014-09-26, 公開日: 2015-05-20, 最終更新日: 2024-01-10)

主引用文献

Preiss, L.,Langer, J.D.,Yildiz, O.,Eckhardt-Strelau, L.,Guillemont, J.E.G.,Koul, A.,Meier, T.
Structure of the Mycobacterial ATP Synthase Fo Rotor Ring in Complex with the Anti-Tb Drug Bedaquiline.
Sci.Adv., 1:106-, 2015

PubMed Abstract: Multidrug-resistant tuberculosis (MDR-TB) is more prevalent today than at any other time in human history. Bedaquiline (BDQ), a novel Mycobacterium-specific adenosine triphosphate (ATP) synthase inhibitor, is the first drug in the last 40 years to be approved for the treatment of MDR-TB. This bactericidal compound targets the membrane-embedded rotor (c-ring) of the mycobacterial ATP synthase, a key metabolic enzyme required for ATP generation. We report the x-ray crystal structures of a mycobacterial c9 ring without and with BDQ bound at 1.55- and 1.7-Å resolution, respectively. The structures and supporting functional assays reveal how BDQ specifically interacts with the rotor ring via numerous interactions and thereby completely covers the c-ring's ion-binding sites. This prevents the rotor ring from acting as an ion shuttle and stalls ATP synthase operation. The structures explain how diarylquinoline chemicals specifically inhibit the mycobacterial ATP synthase and thus enable structure-based drug design of next-generation ATP synthase inhibitors against Mycobacterium tuberculosis and other bacterial pathogens.

PubMed: 26601184
DOI: 10.1126/SCIADV.1500106

実験手法

X-RAY DIFFRACTION (1.55 Å)