The structures of the human cannabinoid receptor 1 (CB1) - the brain receptor that binds to Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive ingredient in marijuana - in complex with two synthetic cannabinoids have been solved. The study, published online in Nature this week, reveals new details of the activation mechanism of the CB1 receptor and thus the mode of action of Δ9-THC and other psychoactive cannabinoids. The findings could have implications for physiological studies, drug discovery and human health.
Marijuana has been used for medicinal and recreational purposes across various cultures for more than 5,000 years. Its main psychoactive ingredient is the cannabinoid Δ9-THC, which exerts its effects by activating CB1. This receptor is activated by the brain’s own endocannabinoid system and is a therapeutic target for pain management, epilepsy and obesity. To understand how CB1 elicits its diverse physiological effects, knowledge of how it binds to agonists, such as D9-THC, is necessary; previous studies that have reported the structure of CB1 bound to antagonists have provided insights into only the inactive state of the receptor.
Zhi-Jie Liu and colleagues solve the crystal structures of human CB1 in complex with two agonists (synthetic THC derivatives). They find a 53% reduction in the volume of the binding region of the agonist-bound structure compared to the antagonist-bound structure. This balloon-like flexibility of CB1 may help to explain how it can modulate such diverse physiological and psychological activities. The structure also reveals a ‘twin toggle switch’ that seems to be essential for activating the receptor.