In this Cell paper, the team of scientists led by the iHuman Institute of ShanghaiTech University determined and analyzed the high-resolution structure of human cannabinoid receptor 1 (CB1), which is the most highly expressed G protein-coupled receptors (GPCRs) in the human central nervous system and is the target of one of the longest used herbs in human history. In this study, the scientists presented the 2.8 ? crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist with a long half-life and is potentially useful in the treatment of addiction disorders. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids.
This work will enhance our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.