1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics

High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition

  1. Sandip Basak
  2. Arvind Kumar
  3. Steven Ramsey
  4. Eric Gibbs
  5. Abhijeet Kapoor
  6. Marta Filizola
  7. Sudha Chakrapani  Is a corresponding author
  1. Case Western Reserve University, United States
  2. Icahn School of Medicine at Mount Sinai, United States
https://doi.org/10.7554/eLife.57870
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  1. Sandip Basak
  2. Arvind Kumar
  3. Steven Ramsey
  4. Eric Gibbs
  5. Abhijeet Kapoor
  6. Marta Filizola
  7. Sudha Chakrapani
(2020)
High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition
eLife 9:e57870.
https://doi.org/10.7554/eLife.57870
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Abstract

Serotonin receptors (5-HT3AR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HT3AR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HT3AR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HT3AR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition.

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All data generated or analysed during this study are included in the manuscript and supporting files.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Sandip Basak

    Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Arvind Kumar

    Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8421-8669

  3. Steven Ramsey

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Eric Gibbs

    Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Abhijeet Kapoor

    2Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3606-3463

  6. Marta Filizola

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Sudha Chakrapani

    Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, United States
    For correspondence
    Sudha.chakrapani@case.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0722-2338

Funding

National Institute of General Medical Sciences (R01GM108921,R01GM131216,R35GM134896)

  • Sudha Chakrapani

American Heart Association (17POST33671152)

  • Sandip Basak

American Heart Association (20POST35210394)

  • Arvind Kumar

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Cynthia M Czajkowski, University of Wisconsin, Madison, United States

Version history

  1. Received: April 15, 2020
  2. Accepted: October 15, 2020
  3. Accepted Manuscript published: October 16, 2020 (version 1)
  4. Version of Record published: November 10, 2020 (version 2)

Copyright

© 2020, Basak et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sandip Basak
  2. Arvind Kumar
  3. Steven Ramsey
  4. Eric Gibbs
  5. Abhijeet Kapoor
  6. Marta Filizola
  7. Sudha Chakrapani
(2020)
High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition
eLife 9:e57870.
https://doi.org/10.7554/eLife.57870

Share this article

https://doi.org/10.7554/eLife.57870

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