来自结核分枝杆菌的 bd 氧化酶的冷冻电镜结构揭示了一个独特的结构框架,使合理的药物设计能够对抗结核病

The cryo-EM structure of the bd oxidase from M. tuberculosis reveals a unique structural framework and enables rational drug design to combat TB

 

 

 

Keywords:respiratory enzyme complex; cytochrome bd
关键词:呼吸酶复合物;细胞色素bd

非哺乳动物:真细菌
作者:Safarian S, Opel-Reading HK, Wu D, Mehdipour AR, Hards K, Harold LK, Radloff M, Stewart I, Welsch S, Hummer G, Cook GM, Krause KL, Michel H
出版期刊:《Nature Communications》 2021/9/2


Abstract:

New drugs are urgently needed to combat the global TB epidemic. Targeting simultaneously multiple respiratory enzyme complexes of Mycobacterium tuberculosis is regarded as one of the most effective treatment options to shorten drug administration regimes, and reduce the opportunity for the emergence of drug resistance. During infection and proliferation, the cytochrome bd oxidase plays a crucial role for mycobacterial pathophysiology by maintaining aerobic respiration at limited oxygen concentrations. Here, we present the cryo-EM structure of the cytochrome bd oxidase from M. tuberculosis at 2.5 Å. In conjunction with atomistic molecular dynamics (MD) simulation studies we discovered a previously unknown MK-9-binding site, as well as a unique disulfide bond within the Q-loop domain that defines an inactive conformation of the canonical quinol oxidation site in Actinobacteria. Our detailed insights into the long-sought atomic framework of the cytochrome bd oxidase from M. tuberculosis will form the basis for the design of highly specific drugs to act on this enzyme.

 

文章摘要:

抗击全球结核病疫情急需新药。同时靶向结核分枝杆菌的多种呼吸酶复合物被认为是缩短药物给药方案和减少耐药性出现机会的最有效治疗选择之一。在感染和增殖过程中,细胞色素 bd 氧化酶通过在有限的氧气浓度下维持有氧呼吸,对分枝杆菌的病理生理学起着至关重要的作用。在这里,我们展示了 2.5 Å 结核分枝杆菌细胞色素 bd 氧化酶的冷冻电镜结构。结合原子分子动力学 (MD) 模拟研究,我们发现了一个以前未知的 MK-9 结合位点,以及 Q 环结构域内的一个独特的二硫键,它定义了放线菌中典型的喹啉氧化位点的非活性构象。我们对来自结核分枝杆菌的细胞色素 bd 氧化酶的长期寻求的原子框架的详细见解将构成设计高度特异性药物以作用于这种酶的基础。

 


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