Conformational transitions of the serotonin 5-HT3 receptor

Lucie Polovinkin, Ghérici Hassaine, Jonathan Perot, Emmanuelle Neumann, Anders A. Jensen, Solène N. Lefebvre, Pierre-Jean Corringer, Jacques Neyton (), Christophe Chipot, Francois Dehez, Guy Schoehn and Hugues Nury ()
Additional contact information
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
Francois Dehez: Université de Lorraine, CNRS, LPCT
Guy Schoehn: CNRS, Université Grenoble Alpes, CEA, IBS
Hugues Nury: CNRS, Université Grenoble Alpes, CEA, IBS

Nature, 2018, vol. 563, issue 7730, 275-279

Abstract: 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.

Keywords: Tropisetron; Allosteric Signal Transduction; Desensitized State; Voltage-clamp Fluorometry (VCF); Free-energy Landscape (search for similar items in EconPapers)
Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (4)

Downloads: (external link)
https://www.nature.com/articles/s41586-018-0672-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:563:y:2018:i:7730:d:10.1038_s41586-018-0672-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-018-0672-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().