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 Phe2003.36 and Trp3566.48 (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.
