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

Yingyi Zhang, Patricia M. Dijkman, Rongfeng Zou, Martina Zandl-Lang, Ricardo M. Sanchez, Luise Eckhardt-Strelau, Harald Köfeler, Horst Vogel, Shuguang Yuan () and Mikhail Kudryashev ()
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Yingyi Zhang: Max Planck Institute of Biophysics
Patricia M. Dijkman: Max Planck Institute of Biophysics
Rongfeng Zou: Research Center for Computer-Aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Martina Zandl-Lang: Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz
Ricardo M. Sanchez: Max Planck Institute of Biophysics
Luise Eckhardt-Strelau: Max Planck Institute of Biophysics
Harald Köfeler: Core Facility Mass Spectrometry, ZMF, Medical University of Graz
Horst Vogel: Research Center for Computer-Aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Shuguang Yuan: Research Center for Computer-Aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Mikhail Kudryashev: Max Planck Institute of Biophysics

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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-HT3A serotonin receptor (5HT3R) 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 5HT3R 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 5HT3R by the membrane environment, and a model for asymmetric activation of the receptor.

Date: 2021
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DOI: 10.1038/s41467-021-21016-7

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