Cryo-EM Structure of the Activated GLP-1 Receptor in Complex with a G Protein

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 the GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR) that signals primarily through the stimulatory G protein Gs. Class 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 report the cryo-electron microscopy structure of the peptide-activated GLP-1R–Gs complex at near atomic resolution. The peptide is clasped between the N-terminal domain and the transmembrane core of the receptor, and 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 the Ras-like domain of Gs. These results provide a structural framework for understanding class B GPCR activation through hormone binding. The structure of the GLP-1 receptor complexed with its ligand offers insight into the mechanism of class B G-protein-coupled receptor activation. The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) belong to the class B G-protein-coupled receptor family and have opposing physiological roles in glucose homeostasis and insulin release. As such, they are important in regulating metabolism and appetite and offer significant treatment possibilities for type 2 diabetes. However, as yet, no full-length structures of these receptors have been solved. Three papers in this issue of Nature report the structure of GLP-1R. Ray Stevens and colleagues describe the crystal structure of the human GLP-1R transmembrane domain in an inactive state in complex with negative allosteric modulators. Fiona Marshall and colleagues describe the active-state full-length receptor in complex with truncated peptide agonists, which have potent activity in mice on oral administration. Georgios Skiniotis, Brian Kobilka and colleagues describe the cryo-electron microscopy structure of an unmodified GLP-1R in complex with its endogenous peptide ligand, GLP-1, and the heterotrimeric G protein. Finally, in a fourth paper in this week's issue of Nature, Beili Wu and colleagues report the crystal structure of the full-length GCGR in an inactive conformation. Taken together, these studies provide key insights into the activation and signalling mechanisms of class B receptors and provide therapeutic opportunities for targeting this receptor family.