Molecular mechanism of TRPV2 channel modulation by cannabidiol
- University of Pennsylvania, United States
- Pfizer Research and Development, United States
- New Jersey Medical School, Rutgers, the State University of New Jersey, United States
Abstract
Transient receptor potential vanilloid 2 (TRPV2) plays a critical role in neuronal development, cardiac function, immunity, and cancer. Cannabidiol (CBD), the non-psychotropic therapeutically active ingredient of Cannabis sativa, is an activator of TRPV2 and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length rat TRPV2 channel in apo and CBD-bound states in nanodiscs by cryo-electron microscopy. We show that CBD interacts with TRPV2 through a hydrophobic pocket located between S5 and S6 helices of adjacent subunits, which differs from known ligand and lipid binding sites in other TRP channels. CBD-bound TRPV2 structures revealed that the S4-S5 linker plays a critical role in channel gating upon CBD binding. Additionally, nanodiscs permitted us to visualize two distinct TRPV2 apo states in a lipid environment. Together these results provide a foundation to further understand TRPV channel gating, their divergent physiological functions, and to accelerate structure-based drug design.
Data availability
cryoEM maps have been deposited in the Electron Microscopy Data Bank under the following accession codes: EMD-20677, EMD-20678, EMD-20686, EMD-20682The models built into the cryoEM maps have been deposited into the Protein Data Bank under the following accession codes: 6U84, 6U85, 6U8A, 6U88The maps and models analyzed in this study are included with the manuscript and supporting files.
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Apo full-length rat TRPV2 in nanodiscs, state 1Electron Microscopy Data Bank, EMD-20677.
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Apo full-length rat TRPV2 in nanodiscs, state 1Protein Data Bank, PDB 6U84.
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Apo full-length rat TRPV2 in nanodiscs, state 2Electron Microscopy Data Bank, EMD-20678.
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Apo full-length rat TRPV2 in nanodiscs, state 2Protein Data Bank, PDB 6U86.
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CBD-bound full-length rat TRPV2 in nanodiscs, state 1Electron Microscopy Data Bank, EMD-20686.
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CBD-bound full-length rat TRPV2 in nanodiscs, state 1Protein Data Bank, PDB 6U8A.
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CBD-bound full-length rat TRPV2 in nanodiscs, state 2Electron Microscopy Data Bank, EMD-20682.
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CBD-bound full-length rat TRPV2 in nanodiscs, state 2Protein Data Bank, PDB 6U88.
Article and author information
Author details
Vera Y Moiseenkova-Bell
Funding
National Institutes of Health (R01GM129357)
- Vera Y Moiseenkova-Bell
National Institutes of Health (R01GM103899)
- Vera Y Moiseenkova-Bell
National Institutes of Health (R01 NS055159)
- Tibor Rohacs
National Institutes of Health (R01GM093290)
- Tibor Rohacs
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Pumroy 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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Molecular mechanism of TRPV2 channel modulation by cannabidiol
eLife 8:e48792.
https://doi.org/10.7554/eLife.48792
