6WTD

Monomer yeast ATP synthase Fo reconstituted in nanodisc with inhibitor of Bedaquiline bound

6WTD の概要

• エントリーDOI: 10.2210/pdb6wtd/pdb
• EMDBエントリー: 21894
• 分子名称: ATP synthase subunit 9, mitochondrial, ATP synthase protein 8, ATP synthase subunit a, ... (7 entities in total)
• 機能のキーワード: atp synthase, biosynthetic protein
• 由来する生物種: Saccharomyces cerevisiae (Baker's yeast); 詳細
• タンパク質・核酸の鎖数: 16
• 化学式量合計: 169263.47

構造登録者

Mueller, D.M.,Srivastava, A.P.,Symersky, J.,Luo, M.,Liao, M.F. (登録日: 2020-05-02, 公開日: 2020-08-26, 最終更新日: 2024-11-20)

主引用文献

Luo, M.,Zhou, W.,Patel, H.,Srivastava, A.P.,Symersky, J.,Bonar, M.M.,Faraldo-Gomez, J.D.,Liao, M.,Mueller, D.M.
Bedaquiline inhibits the yeast and human mitochondrial ATP synthases.
Commun Biol, 3:452-452, 2020

PubMed Abstract: 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.

PubMed: 32814813
DOI: 10.1038/s42003-020-01173-z

実験手法

ELECTRON MICROSCOPY (4.2 Å)