9FTZ

CIII2/CIV respiratory supercomplex from Mycobacterium smegmatis with lansoprazole sulfide

これはPDB形式変換不可エントリーです。

9FTZ の概要

• エントリーDOI: 10.2210/pdb9ftz/pdb
• 関連するPDBエントリー: 9FU0
• EMDBエントリー: 50752
• 分子名称: Cytochrome bc1 complex cytochrome c subunit, Uncharacterized protein MSMEG_4692/MSMEI_4575, LpqE protein, ... (31 entities in total)
• 機能のキーワード: respiratory supercomplex, membrane protein, actinobacteria, electron transport
• 由来する生物種: Mycolicibacterium smegmatis; 詳細
• タンパク質・核酸の鎖数: 15
• 化学式量合計: 521382.97

構造登録者

Kovalova, T.,Krol, S.,Gamiz-Hernandez, A.,Sjostrand, D.,Kaila, V.,Brzezinski, P.,Hogbom, M. (登録日: 2024-06-25, 公開日: 2024-11-20, 最終更新日: 2024-11-27)

主引用文献

Kovalova, T.,Krol, S.,Gamiz-Hernandez, A.P.,Sjostrand, D.,Kaila, V.R.I.,Brzezinski, P.,Hogbom, M.
Inhibition mechanism of potential antituberculosis compound lansoprazole sulfide.
Proc.Natl.Acad.Sci.USA, 121:e2412780121-e2412780121, 2024

PubMed Abstract: Tuberculosis is one of the most common causes of death worldwide, with a rapid emergence of multi-drug-resistant strains underscoring the need for new antituberculosis drugs. Recent studies indicate that lansoprazole-a known gastric proton pump inhibitor and its intracellular metabolite, lansoprazole sulfide (LPZS)-are potential antituberculosis compounds. Yet, their inhibitory mechanism and site of action still remain unknown. Here, we combine biochemical, computational, and structural approaches to probe the interaction of LPZS with the respiratory chain supercomplex IIIIV of , a close homolog of supercomplex. We show that LPZS binds to the Q cavity of the mycobacterial supercomplex, inhibiting the quinol substrate oxidation process and the activity of the enzyme. We solve high-resolution (2.6 Å) cryo-electron microscopy (cryo-EM) structures of the supercomplex with bound LPZS that together with microsecond molecular dynamics simulations, directed mutagenesis, and functional assays reveal key interactions that stabilize the inhibitor, but also how mutations can lead to the emergence of drug resistance. Our combined findings reveal an inhibitory mechanism of LPZS and provide a structural basis for drug development against tuberculosis.

PubMed: 39531492
DOI: 10.1073/pnas.2412780121

実験手法

ELECTRON MICROSCOPY (2.6 Å)