Crystal structures of agonist-bound human cannabinoid receptor CB₁

Cannabinoid receptor 1 (CB₁) is the primary target of the partial agonist Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the psychoactive constituent of marijuana¹. Here we report two agonist-bound crystal structures of human CB₁ in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841). The two CB₁-agonist complexes reveal important conformational changes in the overall structure relative to the antagonist-bound state², including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G protein-binding region. Furthermore, a twin toggle switch of Phe200^3.36 and Trp356^6.48 (where the superscripts denote Ballesteros-Weinstein numbering³) is experimentally observed and seems to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB₁ and provide a molecular basis for predicting the binding modes of Δ⁹-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB₁ seems to be a common feature among certain class A G protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.