Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

Yan Zhang, Bingfa Sun, Dan Feng, Hongli Hu, Matthew Chu, Qianhui Qu, Jeffrey T. Tarrasch, Shane Li, Tong Sun Kobilka, Brian K. Kobilka, Georgios Skiniotis
2017 Nature  
Glucagon-like peptide-1 (GLP-1) is a hormone with essential roles in regulating insulin secretion, carbohydrate metabolism and appetite. GLP-1 effects are mediated through binding to GLP-1R, a family B G protein-coupled receptor (GPCR) signaling primarily through the stimulatory G protein Gs. Family B GPCRs are important therapeutic targets, however our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we
more » ... the electron cryo-microscopy structure of the peptide-activated GLP-1R:Gs complex at near atomic resolution. The peptide is clasped between the N-terminal domain and transmembrane core of the receptor, further stabilized by extracellular loops. Conformational changes in the transmembrane domain result in a sharp kink in the middle of transmembrane helix 6, which pivots its intracellular half outward to accommodate the α5 helix of GαsRas. These results provide a structural framework for understanding family B receptor activation through hormone binding. GLP-1 is a hormone released from the gut in response to food intake and acts on GLP-1R to stimulate glucose-dependent insulin secretion from pancreatic β cells, reduce glucagon secretion from pancreatic α cells, as well as decrease gastric motility and appetite 1 . Given its Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.
doi:10.1038/nature22394 pmid:28538729 pmcid:PMC5587415 fatcat:cyx2nqh5o5gbfnfev5lnnx3dsu