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标题：Structure of the ATP synthase from Mycobacterium smegmatis provides targets for treating tuberculosis
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作者：Martin G. Montgomery ; Jessica Petri ; Tobias E. Spikes 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：47
DOI：10.1073/pnas.2111899118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance As the world tackles the COVID-19 pandemic, other widespread infectious diseases, including tuberculosis (TB), take their toll on humans, and those with TB are more likely to die from COVID-19 infection. Bedaquiline (BD), an anti-TB drug, combats multidrug-resistant Mycobacterium tuberculosis by preventing a molecular machine known as the adenosine triphosphate (ATP) synthase from generating ATP, the fuel needed to keep it alive. However, BD-resistant strains of M. tuberculosis have arisen. Here, we describe features of the mycobacterial ATP synthase that are not present in the human enzyme. Potentially these features can be exploited for the development of new anti-TB drugs unrelated to BD to prevent and cure TB by inhibiting the formation of ATP by the pathogen. The structure has been determined by electron cryomicroscopy of the adenosine triphosphate (ATP) synthase from Mycobacterium smegmatis. This analysis confirms features in a prior description of the structure of the enzyme, but it also describes other highly significant attributes not recognized before that are crucial for understanding the mechanism and regulation of the mycobacterial enzyme. First, we resolved not only the three main states in the catalytic cycle described before but also eight substates that portray structural and mechanistic changes occurring during a 360° catalytic cycle. Second, a mechanism of auto-inhibition of ATP hydrolysis involves not only the engagement of the C-terminal region of an α-subunit in a loop in the γ-subunit, as proposed before, but also a “fail-safe” mechanism involving the b′-subunit in the peripheral stalk that enhances engagement. A third unreported characteristic is that the fused bδ-subunit contains a duplicated domain in its N-terminal region where the two copies of the domain participate in similar modes of attachment of the two of three N-terminal regions of the α-subunits. The auto-inhibitory plus the associated “fail-safe” mechanisms and the modes of attachment of the α-subunits provide targets for development of innovative antitubercular drugs. The structure also provides support for an observation made in the bovine ATP synthase that the transmembrane proton-motive force that provides the energy to drive the rotary mechanism is delivered directly and tangentially to the rotor via a Grotthuss water chain in a polar L-shaped tunnel.
关键词：mycobacteria; ATP synthase; structure; regulation; rotary mechanism