Molecular mechanism of TRPV2 channel modulation by cannabidiol

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

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.

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

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Cannabidiol / pharmacology*
  • Cannabis / chemistry
  • Cryoelectron Microscopy
  • Humans
  • Hydrophobic and Hydrophilic Interactions / drug effects
  • Ligands
  • Lipids / chemistry*
  • Mutation / genetics
  • Protein Conformation, alpha-Helical / drug effects
  • Protein Structure, Secondary
  • Rats
  • TRPV Cation Channels / genetics*
  • TRPV Cation Channels / ultrastructure

Substances

  • Ligands
  • Lipids
  • TRPV Cation Channels
  • Trpv2 protein, rat
  • Cannabidiol

Associated data

  • PDB/PDB 6U84
  • PDB/PDB 6U86
  • PDB/PDB 6U8A
  • PDB/PDB 6U88