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

Author

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  • Yingyi Zhang

    (Max Planck Institute of Biophysics
    Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University of Frankfurt
    Biological Cryo-EM Center, Hong Kong University of Science and Technology, Clear Water Bay)

  • Patricia M. Dijkman

    (Max Planck Institute of Biophysics
    Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University of Frankfurt
    Max Planck Institute of Biochemistry
    Institute of Neuropathology, University Medical Center)

  • 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
    Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University of Frankfurt)

  • 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
    Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • 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
    Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University of Frankfurt)

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.

Suggested Citation

  • Yingyi Zhang & Patricia M. Dijkman & Rongfeng Zou & Martina Zandl-Lang & Ricardo M. Sanchez & Luise Eckhardt-Strelau & Harald Köfeler & Horst Vogel & Shuguang Yuan & Mikhail Kudryashev, 2021. "Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21016-7
    DOI: 10.1038/s41467-021-21016-7
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    Cited by:

    1. Xiaofen Liu & Weiwei Wang, 2023. "Asymmetric gating of a human hetero-pentameric glycine receptor," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Vikram Dalal & Mark J. Arcario & John T. Petroff & Brandon K. Tan & Noah M. Dietzen & Michael J. Rau & James A. J. Fitzpatrick & Grace Brannigan & Wayland W. L. Cheng, 2024. "Lipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Nikhil Bharambe & Zhuowen Li & David Seiferth & Asha Manikkoth Balakrishna & Philip C. Biggin & Sandip Basak, 2024. "Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. John T. Petroff & Noah M. Dietzen & Ezry Santiago-McRae & Brett Deng & Maya S. Washington & Lawrence J. Chen & K. Trent Moreland & Zengqin Deng & Michael Rau & James A. J. Fitzpatrick & Peng Yuan & Th, 2022. "Open-channel structure of a pentameric ligand-gated ion channel reveals a mechanism of leaflet-specific phospholipid modulation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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