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Elife. 2019 Sep 30;8. pii: e48792. doi: 10.7554/eLife.48792.

Molecular mechanism of TRPV2 channel modulation by cannabidiol.

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Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Pfizer Research and Development, Groton, United States.
Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, United States.


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.


S. cerevisiae; TRP channels; cannabidiol; cryo-EM; ion channels; molecular biophysics; structural biology

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