Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex

Cell. 2020 Feb 20;180(4):645-654.e13. doi: 10.1016/j.cell.2020.01.007. Epub 2020 Jan 30.


Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 activation and signaling are poorly understood but critical for drug design. Here we report the cryo-EM structure of the human CB2-Gi signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and Gi coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system.

Keywords: 3D Structure of Cannabinoid Receptor CB2; Activation Mechanisms of CB2 and CB1; Agonist-bound CB2- Gi Signaling Complex; CB2 Agonist; CB2 Coupling Specificity for Gi; CB2 Drug Discovery; CB2 Inverse Agonist; Cryo-EM structure; Gi Coupling Versatility; Residual Energy Contribution.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • CHO Cells
  • Cannabinoid Receptor Agonists / chemical synthesis
  • Cannabinoid Receptor Agonists / pharmacology
  • Cannabinoid Receptor Antagonists / chemical synthesis
  • Cannabinoid Receptor Antagonists / pharmacology
  • Cricetinae
  • Cricetulus
  • Cryoelectron Microscopy
  • GTP-Binding Protein alpha Subunits, Gi-Go / chemistry*
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Humans
  • Molecular Docking Simulation
  • Protein Binding
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB2 / chemistry*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Sf9 Cells
  • Signal Transduction*
  • Spodoptera


  • Cannabinoid Receptor Agonists
  • Cannabinoid Receptor Antagonists
  • Receptor, Cannabinoid, CB2
  • GTP-Binding Protein alpha Subunits, Gi-Go