|Nature. 2016 Nov 16. doi: 10.1038/nature20613. [Epub ahead of print]|
High-resolution crystal structure of the human CB1 cannabinoid receptor.
Shao Z1, Yin J1, Chapman K1, Grzemska M1, Clark L1, Wang J2, Rosenbaum DM1.
1Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
2Green Center for Systems Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
The human cannabinoid G-protein-coupled receptors (GPCRs) CB1 and CB2 mediate the functional responses to the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG), as well as the widely consumed plant (phyto)cannabinoid ?9-tetrahydrocannabinol (THC)1. The cannabinoid receptors have been the targets of intensive drug discovery efforts owing to the therapeutic potential of modulators for controlling pain2, epilepsy3, obesity4, and other maladies. Although much progress has recently been made in understanding the biophysical properties of GPCRs, investigations of the molecular mechanisms of the cannabinoids and their receptors have lacked high-resolution structural data. We used GPCR engineering and lipidic cubic phase (LCP) crystallization to determine the structure of the human CB1 receptor bound to the inhibitor taranabant at 2.6?Å resolution. The extracellular surface of CB1, including the highly conserved membrane-proximal amino-terminal (N-terminal) region, is distinct from other lipid-activated GPCRs and forms a critical part of the ligand binding pocket. Docking studies further demonstrate how this same pocket may accommodate the cannabinoid agonist THC. Our CB1 structure provides an atomic framework for studying cannabinoid receptor function, and will aid the design and optimization of cannabinoid system modulators for therapeutic ends.