Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT3A receptor

Article

关键词: NICOTINIC ACETYLCHOLINE-RECEPTOR;    SINGLE-CHANNEL CONDUCTANCE;    X-RAY-STRUCTURE;    5-HYDROXYTRYPTAMINE TYPE-3;    LIGAND RECOGNITION;    DESENSITIZATION;    LOOP;    PORE;    MECHANISM;    DOMAIN;   

DOI  :  10.1038/s41586-018-0660-7

来源: SCIE

【 摘 要 】

The 5-HT3A serotonin receptor(1), a cationic pentameric ligand-gated ion channel (pLGIC), is the clinical target for management of nausea and vomiting associated with radiation and chemotherapies(2). Upon binding, serotonin induces a global conformational change that encompasses the ligand-binding extracellular domain (ECD), the transmembrane domain (TMD) and the intracellular domain (ICD), the molecular details of which are unclear. Here we present two serotonin-bound structures of the full-length 5-HT3A receptor in distinct conformations at 3.32 angstrom and 3.89 angstrom resolution that reveal the mechanism underlying channel activation. In comparison to the apo 5-HT3A receptor, serotonin-bound states underwent a large twisting motion in the ECD and TMD, leading to the opening of a 165 angstrom permeation pathway. Notably, this motion results in the creation of lateral portals for ion permeation at the interface of the TMD and ICD. Combined with molecular dynamics simulations, these structures provide novel insights into conformational coupling across domains and functional modulation.

【 授权许可】

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