Crystal structures of agonist-bound human cannabinoid receptor CB1

"Cannabinoid receptor 1 (CB1) is the primary target of the partial agonist 9-tetrahydrocannabinol (9-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 CB1agonist 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 BallesterosWeinstein 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 9-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."

Cannabinoid receptor 1 (CB1) binds the psychoactive partial agonist 9-THC. Two agonist-bound human CB1 crystal structures were determined with AM11542 and AM841. Agonist binding produces major conformational changes versus antagonist-bound CB1, including a 53% reduction in ligand-binding pocket volume and increased surface area at the G protein-binding region. A twin toggle switch formed by Phe2003.36 and Trp3566.48 is experimentally observed and appears essential for activation. The structures provide molecular details to predict binding modes of 9-THC, endogenous, and synthetic cannabinoids. Binding-pocket plasticity appears shared among some class A GPCRs, enabling design of diverse ligands with distinct pharmacology.

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