Inhibition mechanism of potential antituberculosis compound lansoprazole sulfide

• 成果类型: Article
• 署名作者: Kovalova, Terezia; Krol, Sylwia; Gamiz-Hernandez, Ana P.; Sjostrand, Dan; Kaila, Ville R. I.; Brzezinski, Peter; Hogbom, Martin
• 署名单位: Stockholm University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14609
• DOI: 10.1073/pnas.2412780121
• 发表日期: 2024-11-19
• 关键词: respiratory supercomplex; software news; cryo-em; complex

摘要

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 inhibberculosis 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 III2IV2 of plex. We show that LPZS binds to the Qo cavity of the mycobacterial supercomplex, inhibiting the quinol substrate oxidation process and the activity of the enzyme. We 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.