Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline.
Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline.
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DOI：
10.1126/sciadv.1500106
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发表时间：
2015-05
期刊：
影响因子：
13.6
通讯作者：
Meier T
中科院分区：
文献类型：
--
作者：
Preiss L;Langer JD;Yildiz Ö;Eckhardt-Strelau L;Guillemont JE;Koul A;Meier T
抗结核药物贝达喹啉与分枝杆菌ATP合成酶转子结合的结构和抑制机制。耐多药结核病（MDR-TB）今天比人类历史上任何其他时期都更加普遍。贝达喹啉（BDQ）是一种新型的分枝杆菌特异性三磷酸腺苷（ATP）合成酶抑制剂，是近40年来第一个被批准用于治疗耐多药结核病的药物。这种杀菌化合物靶向分枝杆菌ATP合成酶的膜嵌入转子（c环），ATP合成酶是生成ATP所需的关键代谢酶。我们报告的X-射线晶体结构的分枝杆菌C9环没有和BDQ绑定在1.55-和1.7-<$的分辨率，分别。结构和支持功能分析揭示了BDQ如何通过多种相互作用与转子环特异性相互作用，从而完全覆盖C环的离子结合位点。这阻止了转子环作为离子穿梭器并停止ATP合酶的操作。这些结构解释了二芳基喹啉化学物质如何特异性地抑制分枝杆菌ATP合酶，从而使基于结构的药物设计能够对抗结核分枝杆菌和其他细菌病原体的下一代ATP合酶抑制剂。
Structure and inhibition mechanism of the anti-TB drug bedaquiline bound to the ATP synthase rotor from Mycobacteria. 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.