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

Author

Listed:
  • Sandip Basak

    (Case Western Reserve University)

  • Yvonne Gicheru

    (Case Western Reserve University)

  • Shanlin Rao

    (University of Oxford)

  • Mark S. P. Sansom

    (University of Oxford)

  • Sudha Chakrapani

    (Case Western Reserve University
    School of Medicine, Case Western Reserve University)

Abstract

The 5-HT3A serotonin receptor1, a cationic pentameric ligand-gated ion channel (pLGIC), is the clinical target for management of nausea and vomiting associated with radiation and chemotherapies2. 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 Å and 3.89 Å 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 Å 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.

Suggested Citation

  • Sandip Basak & Yvonne Gicheru & Shanlin Rao & Mark S. P. Sansom & Sudha Chakrapani, 2018. "Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT3A receptor," Nature, Nature, vol. 563(7730), pages 270-274, November.
    • Handle: RePEc:nat:nature:v:563:y:2018:i:7730:d:10.1038_s41586-018-0660-7
    DOI: 10.1038/s41586-018-0660-7
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    Citations

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    Cited by:

    1. Maegan M Weltzin & Andrew A George & Ronald J Lukas & Paul Whiteaker, 2021. "Sleep-related hypermotor epilepsy associated mutations uncover important kinetic roles of α4β2- nicotinic acetylcholine receptor intracellular structures," PLOS ONE, Public Library of Science, vol. 16(3), pages 1-38, March.
    2. Eric Gibbs & Emily Klemm & David Seiferth & Arvind Kumar & Serban L. Ilca & Philip C. Biggin & Sudha Chakrapani, 2023. "Conformational transitions and allosteric modulation in a heteromeric glycine receptor," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Arvind Kumar & Kayla Kindig & Shanlin Rao & Afroditi-Maria Zaki & Sandip Basak & Mark S. P. Sansom & Philip C. Biggin & Sudha Chakrapani, 2022. "Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. 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.

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