Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor–Gs complex

The structure of the glucagon-like peptide 1 receptor (GLP-1R) with its biased agonist exendin-P5 sheds light on both receptor activation and the mechanism of biased agonism. The glucagon-like peptide 1 receptor (GLP-1R) is a key target for the treatment of type 2 diabetes and obesity. Recently, biased agonists—ligands that selectively activate primarily one signalling pathway—have been identified. One of these, exendin-P5, is biased for G-protein signalling, increasing adipogenesis—the generation of fat cells—and is more effective at correcting hyperglycaemia than other agonists. Here, Patrick Sexton and colleagues report the structure of the human GLP-1R in complex with exendin-P5 and the G-protein heterotrimer determined from cryo-electron microscopy. Not only does this work reveal more detailed structural information about the receptor complex and its activation, it also proposes a basis for biased agonism, in the interactions with both the ligand and the G protein. The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity1. Endogenous and mimetic GLP-1 peptides exhibit biased agonism—a difference in functional selectivity—that may provide improved therapeutic outcomes1. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a Gαs heterotrimer, determined at a global resolution of 3.3 Å. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-bound structure and previous GLP-1-bound GLP-1 receptor structure2. At the intracellular face, there was a six-degree difference in the angle of the Gαs–α5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the Gαs protein. Our structure provides insights into the molecular basis of biased agonism.