1. Structural Biology and Molecular Biophysics
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New capsaicin analogs as molecular rulers to define the permissive conformation of the mouse TRPV1 ligand-binding pocket

  1. Simon Vu
  2. Vikrant Singh
  3. Heike Wulff
  4. Vladimir Yarov-Yarovoy
  5. Jie Zheng  Is a corresponding author
  1. University of California, Davis, United States
Research Article
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Cite this article as: eLife 2020;9:e62039 doi: 10.7554/eLife.62039

Abstract

The capsaicin receptor TRPV1 is an outstanding representative of ligand-gated ion channels in ligand selectivity and sensitivity. However, molecular interactions that stabilize the ligand-binding pocket in its permissive conformation, and how many permissive conformations the ligand-binding pocket may adopt, remain unclear. To answer these questions, we designed a pair of novel capsaicin analogs to increase or decrease the ligand size by about 1.5 Å without altering ligand chemistry. Together with capsaicin, these ligands form a set of molecular rulers for investigating ligand-induced conformational changes. Computational modeling and functional tests revealed that structurally these ligands alternate between drastically different binding poses but stabilize the ligand-binding pocket in nearly identical permissive conformations; functionally they all yielded a stable open state despite varying potencies. Our study suggests the existence of an optimal ligand-binding pocket conformation for capsaicin-mediated TRPV1 activation gating, and reveals multiple ligand-channel interactions that stabilize this permissive conformation.

Data availability

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

Article and author information

Author details

  1. Simon Vu

    Physiology and Membrane Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1529-8220
  2. Vikrant Singh

    Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Heike Wulff

    Pharmacology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Vladimir Yarov-Yarovoy

    Physiology and Membrane Biology, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2325-4834
  5. Jie Zheng

    Department of Physiology and Membrane Biology, University of California, Davis, Davis, United States
    For correspondence
    jzheng@ucdavis.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4161-627X

Funding

National Institutes of Health (R01NS103954)

  • Jie Zheng

National Institutes of Health (R01NS103954)

  • Vladimir Yarov-Yarovoy

American Heart Association (16PRE29340002)

  • Simon Vu

NIH Office of the Director (U54NS079202)

  • Heike Wulff

National Institute of Neurological Disorders and Stroke (U54NS079202)

  • Heike Wulff

NIH Office of the Director (U54NS079202)

  • Vikrant Singh

National Institute of Neurological Disorders and Stroke (U54NS079202)

  • Vikrant Singh

National Institutes of Health (R01GM132110)

  • Jie Zheng

National Institutes of Health (R01GM132110)

  • Vladimir Yarov-Yarovoy

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

Reviewing Editor

  1. Stephan A. Pless, University of Copenhagen, Denmark

Publication history

  1. Received: August 12, 2020
  2. Accepted: November 8, 2020
  3. Accepted Manuscript published: November 9, 2020 (version 1)
  4. Version of Record published: November 17, 2020 (version 2)

Copyright

© 2020, Vu 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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