小柯机器人

加拿大儿童病医院John L. Rubinstein研究组的一项最新研究，揭示了与结核药物苯达喹啉结合的分枝杆菌ATP合酶的结构。该研究于2020年12月9日发表于《自然》。

他们确定了耻垢分枝杆菌ATP合酶的单独和与苯达喹啉联合使用的冷冻电镜结构。无药物结构表明，α-亚基的钩状延伸可防止酶逆向运行，从而抑制ATP水解并在低氧条件下保持能量。 苯达喹啉结合在ATP合酶中诱导大的构象变化，在亚基a和c的界面上产生紧密的结合口袋，这说明该药物具有作为结核病抗生素的效力。

据了解，结核病-世界上主要的传染病死亡原因-对目前的一线抗生素抗性越来越强。结核分枝杆菌（引起结核病）可以在低能条件下存活，从而使感染保持休眠状态并降低其对许多抗生素的敏感性。苯达喹啉于2005年从针对耻垢分枝杆菌的表型筛选中鉴定出的先导化合物开发而成。该药物甚至可以对潜在的结核分枝杆菌感染进行治疗，并已成为治疗多药耐药和广泛耐药的结核病的基石。苯达喹啉靶向分枝杆菌ATP合酶，这是专性有氧分枝杆菌属中的必不可少的酶，但是如何结合完整的酶尚不清楚。

附：英文原文

Title: Structure of mycobacterial ATP synthase bound to the tuberculosis drug bedaquiline

Author: Hui Guo, Gautier M. Courbon, Stephanie A. Bueler, Juntao Mai, Jun Liu, John L. Rubinstein

Issue&Volume: 2020-12-09

Abstract: Tuberculosis—the world’s leading cause of death by infectious disease—is increasingly resistant to current first-line antibiotics1. The bacterium Mycobacterium tuberculosis (which causes tuberculosis) can survive low-energy conditions, allowing infections to remain dormant and decreasing their susceptibility to many antibiotics2. Bedaquiline was developed in 2005 from a lead compound identified in a phenotypic screen against Mycobacterium smegmatis3. This drug can sterilize even latent M. tuberculosis infections4 and has become a cornerstone of treatment for multidrug-resistant and extensively drug-resistant tuberculosis1,5,6. Bedaquiline targets the mycobacterial ATP synthase3, which is an essential enzyme in the obligate aerobic Mycobacterium genus3,7, 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 α-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.

DOI: 10.1038/s41586-020-3004-3

Source: https://www.nature.com/articles/s41586-020-3004-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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