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Conformational transitions of the serotonin 5-HT3 receptor

Author

Listed:
  • Lucie Polovinkin

    (CNRS, Université Grenoble Alpes, CEA, IBS)

  • Ghérici Hassaine

    (Theranyx)

  • Jonathan Perot

    (CNRS, Université Grenoble Alpes, CEA, IBS)

  • Emmanuelle Neumann

    (CNRS, Université Grenoble Alpes, CEA, IBS)

  • Anders A. Jensen

    (University of Copenhagen)

  • Solène N. Lefebvre

    (Channel Receptors Unit, CNRS UMR 3571, Institut Pasteur)

  • Pierre-Jean Corringer

    (Channel Receptors Unit, CNRS UMR 3571, Institut Pasteur)

  • Jacques Neyton

    (CNRS, Université Grenoble Alpes, CEA, IBS)

  • Christophe Chipot

    (Université de Lorraine, CNRS, LPCT
    Laboratoire International Associé CNRS and University of Illinois at Urbana-Champaign
    University of Illinois at Urbana-Champaign)

  • Francois Dehez

    (Université de Lorraine, CNRS, LPCT
    Laboratoire International Associé CNRS and University of Illinois at Urbana-Champaign)

  • Guy Schoehn

    (CNRS, Université Grenoble Alpes, CEA, IBS)

  • Hugues Nury

    (CNRS, Université Grenoble Alpes, CEA, IBS)

Abstract

The serotonin 5-HT3 receptor is a pentameric ligand-gated ion channel (pLGIC). It belongs to a large family of receptors that function as allosteric signal transducers across the plasma membrane1,2; upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions that result in transient opening of a pore permeable to ions. 5-HT3 receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression3. In spite of several reported pLGIC structures4–8, no clear unifying view has emerged on the conformational transitions involved in channel gating. Here we report four cryo-electron microscopy structures of the full-length mouse 5-HT3 receptor in complex with the anti-emetic drug tropisetron, with serotonin, and with serotonin and a positive allosteric modulator, at resolutions ranging from 3.2 Å to 4.5 Å. The tropisetron-bound structure resembles those obtained with an inhibitory nanobody5 or without ligand9. The other structures include an ‘open’ state and two ligand-bound states. We present computational insights into the dynamics of the structures, their pore hydration and free-energy profiles, and characterize movements at the gate level and cation accessibility in the pore. Together, these data deepen our understanding of the gating mechanism of pLGICs and capture ligand binding in unprecedented detail.

Suggested Citation

  • Lucie Polovinkin & Ghérici Hassaine & Jonathan Perot & Emmanuelle Neumann & Anders A. Jensen & Solène N. Lefebvre & Pierre-Jean Corringer & Jacques Neyton & Christophe Chipot & Francois Dehez & Guy S, 2018. "Conformational transitions of the serotonin 5-HT3 receptor," Nature, Nature, vol. 563(7730), pages 275-279, November.
  • Handle: RePEc:nat:nature:v:563:y:2018:i:7730:d:10.1038_s41586-018-0672-3
    DOI: 10.1038/s41586-018-0672-3
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    Citations

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    Cited by:

    1. 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.
    2. Mackenzie J. Thompson & Farid Mansoub Bekarkhanechi & Anna Ananchenko & Hugues Nury & John E. Baenziger, 2024. "A release of local subunit conformational heterogeneity underlies gating in a muscle nicotinic acetylcholine receptor," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Vasyl Bondarenko & Marta M. Wells & Qiang Chen & Tommy S. Tillman & Kevin Singewald & Matthew J. Lawless & Joel Caporoso & Nicole Brandon & Jonathan A. Coleman & Sunil Saxena & Erik Lindahl & Yan Xu &, 2022. "Structures of highly flexible intracellular domain of human α7 nicotinic acetylcholine receptor," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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