Transient receptor potential vanilloid (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 TRPV and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length rat TRPV channel in apo and CBD-bound states in nanodiscs by cryoelectron microscopy. We show that CBD interacts with TRPV through a hydrophobic pocket located between S and S helices of adjacent subunits, which differs from known ligand and lipid binding sites in other TRP channels. CBD-bound TRPV 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 TRPV 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.
|Original language||English (US)|
|State||Published - Sep 2019|
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)