Cannabinoid receptor revealed

Two research groups have independently elucidated the first crystal structures of the cannabinoid receptor CB1, a cell-membrane protein involved in a host of appetite, pain-sensation, memory, and other physiological processes. The protein’s floppy movements between active and inactive states make it difficult to study, so Alexandros Makriyannis of Northeastern University and colleagues designed a strong inhibitor to bind and help immobilize CB1 to get a better glimpse of its structure (Cell 2016, DOI: 10.1016/j.cell.2016.10.004). Meanwhile, a team led by Daniel M. Rosenbaum of the University of Texas Southwestern Medical Center published a CB1 structure with slightly higher resolution, which they stabilized by binding the antiobesity drug taranabant (Nature 2016, DOI: 10.1038/nature20613). Because cannabinoids are quite varied themselves, Ken Mackie of Indiana University says the new papers “finally give us a clear sense of the nooks and crannies in CB1 that cannabinoids can interact with.” Despite some discrepancies, both groups discovered a binding pocket that allows lipophilic cannabinoid molecules to interact with the receptor. “A long-held hypothesis about how cannabinoids enter the receptor has now been proven,” says Patricia Reggio of the University of North Carolina, Greensboro. Reggio adds that the structural work could be a launching pad for designing new therapeutics targeting CB1.