Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers

Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures...

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Veröffentlicht in:Nature communications 2021-02, Vol.12 (1), p.1074-1074, Article 1074
Hauptverfasser: Zhang, Yingyi, Dijkman, Patricia M., Zou, Rongfeng, Zandl-Lang, Martina, Sanchez, Ricardo M., Eckhardt-Strelau, Luise, Köfeler, Harald, Vogel, Horst, Yuan, Shuguang, Kudryashev, Mikhail
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Sprache:eng
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Zusammenfassung:Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT 3A serotonin receptor (5HT 3 R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT 3 R conformations in detergent, the lipid bilayer stabilises the receptor in a more tightly packed, ‘coupled’ state, involving a cluster of highly conserved residues. In consequence, the agonist-bound receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT 3 R by the membrane environment, and a model for asymmetric activation of the receptor. Pentameric ligand-gated ion channels (pLGICs) are key players in neurotransmission and have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. Here, the authors report structures of the pLGIC 5-HT 3A serotonin receptor reconstituted into lipid bilayer discs and reveal lipid–protein interactions as well as asymmetric activation of the homopentameric receptor.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-21016-7