Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures

Cell. 2020 Feb 20;180(4):655-665.e18. doi: 10.1016/j.cell.2020.01.008. Epub 2020 Jan 30.


Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with Gi, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.

Keywords: CB2-Gi; G protein-coupled receptor; activation; allosteric modulation; cannabinoid receptors; cholesterol; cryo-EM structures; crystal structure; subtype selectivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Animals
  • CHO Cells
  • Cannabinoid Receptor Agonists / chemistry
  • Cannabinoid Receptor Agonists / pharmacology*
  • Cannabinoids / chemistry
  • Cannabinoids / pharmacology
  • Cell Line, Tumor
  • Cholesterol / chemistry
  • Cholesterol / pharmacology
  • Cricetinae
  • Cricetulus
  • GTP-Binding Protein alpha Subunits, Gi-Go / chemistry*
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Humans
  • Molecular Dynamics Simulation
  • Receptor, Cannabinoid, CB1 / chemistry*
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / chemistry*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Sf9 Cells
  • Signal Transduction*
  • Spodoptera


  • Cannabinoid Receptor Agonists
  • Cannabinoids
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • HU 308
  • Cholesterol
  • GTP-Binding Protein alpha Subunits, Gi-Go