Asymmetric gating of a homopentameric ion channel GLIC revealed by cryo- EM

• 成果类型: Article
• 署名作者: Li, Zhuowen; Bharambe, Nikhil; Lande, Kashmiri Manishrao; Feddersen, Bjarne; Balakrishna, Asha Manikkoth; Biggin, Philip C.; Sahu, Giriraj; Basak, Sandip
• 署名单位: Nanyang Technological University; Indian Institute of Science (IISC) - Bangalore; University of Oxford; Nanyang Technological University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2512811122
• 发表日期: 2025-10-28
• 页码: e2512811122
• 关键词: ligand-gated Ion channel; cryo-em; MD simulations; nanodisc; patch-clamp; GUI MEMBRANE-BUILDER; x-ray-structure; molecular-dynamics; Conformational transitions; brownian dynamics; structural basis; PARTIAL AGONIST; CYS-LOOP; mechanism; gromacs

摘要

Pentameric ligand- gated ion channels (pLGICs) are vital neurotransmitter receptors that are key therapeutic targets for neurological disorders. Although the high- resolution structures of these channels have been elucidated, capturing their dynamic conformational transitions remains challenging due to the transient nature of intermediate states. In this study, we investigated a prokaryotic proton- gated pLGIC, GLIC. In our cryo- EM data at pH 4.0, we identified and segregated asymmetric particles, which we precisely aligned to resolve high- resolution structures of several previously unresolved asymmetric intermediate states, in addition to symmetric closed and open states. Detailed structural analysis revealed systematic conformational changes at individual subunits driving the channel opening. Molecular dynamics simulations were used to assign the functional states. We further examined the roles of the F116 and Y251 residues, located at the domain interface, playing a central role in interdomain communication. In addition, demonstrated their importance in channel gating. Together, these results shed light on vation, offering a deeper mechanistic understanding of asymmetric gating in pLGICs.