Molecular mechanism of TRPV2 channel modulation by cannabidiol

Pumroy, R. A.; Samanta, A.; Liu, Y.; Hughes, T. E. T.; Zhao, S.; Yudin, Y.; Huynh, K. W.; Zhou, Z. H.; Rohacs, T.; Han, S.; Moiseenkova-Bell, V. Y.

doi:10.1101/521880

bioRxiv · 10.1101/521880

Molecular mechanism of TRPV2 channel modulation by cannabidiol

Pumroy, R. A.·Samanta, A.·Liu, Y.·Hughes, T. E. T.·Zhao, S.·Yudin, Y.·Huynh, K. W.·Zhou, Z. H.·Rohacs, T.·Han, S.·Moiseenkova-Bell, V. Y.

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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 a potent activator of TRPV2 and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length TRPV2 channel in a CBD-bound state in detergent and in PI(4,5)P2 enriched nanodiscs by cryo-electron microscopy. 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. Comparison between apo- and two CBD-bound TRPV2 structures reveals that the S4-S5 linker plays a critical role in channel gating upon CBD binding. The TRPV2 \"vanilloid\" pocket, which is critical for ligand-dependent gating in other TRPV channels, stays unoccupied by annular lipids, PI(4,5)P2, or CBD. Together these results provide a foundation to further understand TRPV channel gating properties and their divergent physiological functions and to accelerate structure-based drug design.

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Pumroy, R. A., Samanta, A., Liu, Y., Hughes, T. E. T., Zhao, S., Yudin, Y., Huynh, K. W., Zhou, Z. H., Rohacs, T., Han, S., Moiseenkova-Bell, V. Y.. 2019-01-16. Molecular mechanism of TRPV2 channel modulation by cannabidiol. https://doi.org/10.1101/521880

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