New capsaicin analogs as molecular rulers to define the permissive conformation of the mouse TRPV1 ligand-binding pocket
- University of California, Davis, United States
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.
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All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Vladimir Yarov-Yarovoy
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.
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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New capsaicin analogs as molecular rulers to define the permissive conformation of the mouse TRPV1 ligand-binding pocket
eLife 9:e62039.
https://doi.org/10.7554/eLife.62039
