Abstract
Cannabinoid receptor 1 (CB(1)) is the primary target of the partial agonist Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the psychoactive constituent of marijuana(1). Here we report two agonist-bound crystal structures of human CB(1) in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841). The two CB(1)-agonist complexes reveal important conformational changes in the overall structure relative to the antagonist-bound state(2), 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 numbering(3)) is experimentally observed and seems to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB(1) and provide a molecular basis for predicting the binding modes of Δ(9)-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB(1) 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.