New capsaicin analogs as molecular rulers to define the permissive conformation of the mouse TRPV1 ligand-binding pocket
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
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
- Stephan A. Pless, University of Copenhagen, Denmark
Version history
- Received: August 12, 2020
- Accepted: November 8, 2020
- Accepted Manuscript published: November 9, 2020 (version 1)
- 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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