ATP synthase, F0 complex, subunit J / ATP synthase protein 8, fungal type / ATP synthase, F0 complex, subunit F, mitochondria, fungi / ATP synthase j chain / Fungal ATP synthase protein 8 (A6L) / Mitochondrial F1-F0 ATP synthase subunit F of fungi / ATP synthase, F0 complex, subunit B/MI25 / ATP synthase, F0 complex, subunit B / Mitochondrial ATP synthase B chain precursor (ATP-synt_B) / ATP synthase, F0 complex, subunit D, mitochondrial ...ATP synthase, F0 complex, subunit J / ATP synthase protein 8, fungal type / ATP synthase, F0 complex, subunit F, mitochondria, fungi / ATP synthase j chain / Fungal ATP synthase protein 8 (A6L) / Mitochondrial F1-F0 ATP synthase subunit F of fungi / ATP synthase, F0 complex, subunit B/MI25 / ATP synthase, F0 complex, subunit B / Mitochondrial ATP synthase B chain precursor (ATP-synt_B) / ATP synthase, F0 complex, subunit D, mitochondrial / ATP synthase D chain, mitochondrial (ATP5H) / ATP synthase, F0 complex, subunit D superfamily, mitochondrial / ATP synthase, F0 complex, subunit A, bacterial/mitochondria / ATP synthase, F0 complex, subunit A / ATP synthase, F0 complex, subunit A, active site / ATP synthase, F0 complex, subunit A superfamily / ATP synthase A chain / ATP synthase a subunit signature. / ATP synthase, F0 complex, subunit C / F1F0 ATP synthase subunit C superfamily / ATP synthase, F0 complex, subunit C, DCCD-binding site / ATP synthase c subunit signature. / V-ATPase proteolipid subunit C-like domain / F/V-ATP synthase subunit C superfamily / ATP synthase subunit C 類似検索 - ドメイン・相同性
ATP synthase subunit a / ATP synthase protein 8 / ATP synthase subunit 4, mitochondrial / ATP synthase subunit d, mitochondrial / ATP synthase subunit 9, mitochondrial / ATP synthase subunit J, mitochondrial / ATP synthase subunit f, mitochondrial 類似検索 - 構成要素
National Institutes of Health/National Library of Medicine (NIH/NLM)
R01GM66223
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35GM131731
米国
引用
ジャーナル: Commun Biol / 年: 2020 タイトル: Bedaquiline inhibits the yeast and human mitochondrial ATP synthases. 著者: Min Luo / Wenchang Zhou / Hiral Patel / Anurag P Srivastava / Jindrich Symersky / Michał M Bonar / José D Faraldo-Gómez / Maofu Liao / David M Mueller / 要旨: Bedaquiline (BDQ, Sirturo) has been approved to treat multidrug resistant forms of Mycobacterium tuberculosis. Prior studies suggested that BDQ was a selective inhibitor of the ATP synthase from M. ...Bedaquiline (BDQ, Sirturo) has been approved to treat multidrug resistant forms of Mycobacterium tuberculosis. Prior studies suggested that BDQ was a selective inhibitor of the ATP synthase from M. tuberculosis. However, Sirturo treatment leads to an increased risk of cardiac arrhythmias and death, raising the concern that this adverse effect results from inhibition at a secondary site. Here we show that BDQ is a potent inhibitor of the yeast and human mitochondrial ATP synthases. Single-particle cryo-EM reveals that the site of BDQ inhibition partially overlaps with that of the inhibitor oligomycin. Molecular dynamics simulations indicate that the binding mode of BDQ to this site is similar to that previously seen for a mycobacterial enzyme, explaining the observed lack of selectivity. We propose that derivatives of BDQ ought to be made to increase its specificity toward the mycobacterial enzyme and thereby reduce the side effects for patients that are treated with Sirturo.