Asynchronous subunit transitions prime acetylcholine receptor activation

• 成果类型: Article
• 署名作者: Thompson, Mackenzie J.; Tessier, Christian J. G.; Ananchenko, Anna; Henault, Camille; Emlaw, Johnathon R.; Dehez, Francois; Zarkadas, Eleftherios; dacosta, Corrie J. B.; Nury, Hugues; Baenziger, John E.
• 署名单位: University of Ottawa; University of Ottawa; Centre National de la Recherche Scientifique (CNRS); Universite de Lorraine; European Molecular Biology Laboratory (EMBL); CEA; Communaute Universite Grenoble Alpes; Centre National de la Recherche Scientifique (CNRS); Universite Grenoble Alpes (UGA); CEA; Centre National de la Recherche Scientifique (CNRS); Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); University of California System; University of California Berkeley; Carleton University; Rockefeller University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adw1264
• 发表日期: 2026-01-01
• 页码: eadw1264
• 关键词: molecular-dynamics; nicotinic receptor; INTERMEDIATE STATES; software news; END-PLATE; binding; conformation; RESOLUTION; algorithm; mechanism

摘要

Communication at synapses is facilitated by postsynaptic receptors, which convert a chemical signal into an electrical response. For ligand-gated ion channels, agonist binding triggers rapid transitions through intermediate states leading to a transient open-pore conformation, with these transitions shaping the postsynaptic response. In this work, we determine structures of the muscle-type nicotinic acetylcholine receptor in unliganded, mono-liganded, and di-liganded states. Agonist binding to a single site stabilizes a closed structure where an entire principal agonist-binding subunit transitions to an active-like conformation, whereas the other unoccupied principal subunit remains inactive, albeit poised for activation. Uniting this intermediate structure with single-channel recordings informs a sequential activation mechanism where asynchronous subunit transitions prime the receptor for activation-a finding with implications for an entire superfamily of pentameric ligand-gated ion channels.