IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v563y2018i7730d10.1038_s41586-018-0660-7.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-018-0660-7
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-018-0660-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. 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.
    3. 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.
    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.

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:563:y:2018:i:7730:d:10.1038_s41586-018-0660-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.