8G0C

Cryo-EM structure of TBAJ-876-bound Mycobacterium smegmatis ATP synthase rotational state 1 (backbone model)

8G0C の概要

• エントリーDOI: 10.2210/pdb8g0c/pdb
• EMDBエントリー: 29648 29649 29650 29651 29652 29653 29654 29655
• 分子名称: ATP synthase subunit alpha, MAGNESIUM ION, PHOSPHATE ION, ... (12 entities in total)
• 機能のキーワード: atp synthase, mycobacterial, inhibitor, tuberculosis, antibiotic, hydrolase, translocase-inhibitor complex, translocase/inhibitor
• 由来する生物種: Mycolicibacterium smegmatis MC2 155; 詳細
• タンパク質・核酸の鎖数: 20
• 化学式量合計: 555498.84

構造登録者

Courbon, G.M.,Rubinstein, J.L. (登録日: 2023-01-31, 公開日: 2023-02-15, 最終更新日: 2024-06-19)

主引用文献

Courbon, G.M.,Palme, P.R.,Mann, L.,Richter, A.,Imming, P.,Rubinstein, J.L.
Mechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines.
Embo J., 42:e113687-e113687, 2023

PubMed Abstract: Mycobacteria, such as Mycobacterium tuberculosis, depend on the activity of adenosine triphosphate (ATP) synthase for growth. The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase inhibitor, is an important medication for treatment of drug-resistant tuberculosis but suffers from off-target effects and is susceptible to resistance mutations. Consequently, both new and improved mycobacterial ATP synthase inhibitors are needed. We used electron cryomicroscopy and biochemical assays to study the interaction of Mycobacterium smegmatis ATP synthase with the second generation diarylquinoline TBAJ-876 and the squaramide inhibitor SQ31f. The aryl groups of TBAJ-876 improve binding compared with BDQ, while SQ31f, which blocks ATP synthesis ~10 times more potently than ATP hydrolysis, binds a previously unknown site in the enzyme's proton-conducting channel. Remarkably, BDQ, TBAJ-876, and SQ31f all induce similar conformational changes in ATP synthase, suggesting that the resulting conformation is particularly suited for drug binding. Further, high concentrations of the diarylquinolines uncouple the transmembrane proton motive force while for SQ31f they do not, which may explain why high concentrations of diarylquinolines, but not SQ31f, have been reported to kill mycobacteria.

PubMed: 37377118
DOI: 10.15252/embj.2023113687

実験手法

ELECTRON MICROSCOPY (2.8 Å)