Structure of mycobacterial ATP synthase bound to the tuberculosis drug bedaquiline
Structure of mycobacterial ATP synthase bound to the tuberculosis drug bedaquiline
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DOI：
10.1038/s41586-020-3004-3
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发表时间：
2020-12-09
期刊：
影响因子：
64.8
通讯作者：
Rubinstein, John L.
中科院分区：
文献类型：
--
作者：
Guo, Hui;Courbon, Gautier M.;Rubinstein, John L.
耻垢分枝杆菌ATP合酶的结构提供了对该酶如何通过ATP水解的自抑制来保存能量以及贝达喹啉（一种用于治疗多药耐药结核病的药物）的作用机制的深入了解。肺结核是世界上由感染性疾病引起的主要死亡原因，对当前一线抗生素的耐药性越来越强（1）。结核分枝杆菌（导致结核病）可以在低能量条件下存活，使感染保持休眠状态，并降低对许多抗生素的敏感性（2）。贝达喹啉于2005年由在针对耻垢分枝杆菌的表型筛选中鉴定出的一种先导化合物开发而来（3）。这种药甚至能消灭潜伏的M。结核感染（4），并已成为治疗耐多药和广泛耐药结核病的基石（1，5，6）。贝达喹啉靶向分枝杆菌ATP合酶（3），这是专性需氧分枝杆菌属的必需酶（3，7），但其如何结合完整的酶尚不清楚。本文测定了M.单独的和与贝达喹啉的复合物的smegastrin ATP合酶。无药物结构表明，α亚基的钩状延伸阻止酶反向运行，抑制ATP水解并在缺氧条件下保存能量。贝达喹啉结合诱导ATP合酶的大的构象变化，在亚基a和c的界面处产生紧密的结合口袋，这解释了这种药物作为结核病抗生素的效力。
Structures of Mycobacterium smegmatis ATP synthase provide insights into how the enzyme conserves energy by autoinhibition of ATP hydrolysis and the mechanism of action of bedaquiline, a drug used in treatment of multidrug-resistant tuberculosis.Tuberculosis-the world's leading cause of death by infectious disease-is increasingly resistant to current first-line antibiotics(1). The bacterium Mycobacterium tuberculosis (which causes tuberculosis) can survive low-energy conditions, allowing infections to remain dormant and decreasing their susceptibility to many antibiotics(2). Bedaquiline was developed in 2005 from a lead compound identified in a phenotypic screen against Mycobacterium smegmatis(3). This drug can sterilize even latent M. tuberculosis infections(4) and has become a cornerstone of treatment for multidrug-resistant and extensively drug-resistant tuberculosis(1,5,6). Bedaquiline targets the mycobacterial ATP synthase(3), which is an essential enzyme in the obligate aerobic Mycobacterium genus(3,7), but how it binds the intact enzyme is unknown. Here we determined cryo-electron microscopy structures of M. smegmatis ATP synthase alone and in complex with bedaquiline. The drug-free structure suggests that hook-like extensions from the alpha-subunits prevent the enzyme from running in reverse, inhibiting ATP hydrolysis and preserving energy in hypoxic conditions. Bedaquiline binding induces large conformational changes in the ATP synthase, creating tight binding pockets at the interface of subunits a and c that explain the potency of this drug as an antibiotic for tuberculosis.