Structural basis of endogenous lipid recognition and G protein selectivity in GPR119

G protein-coupled receptors (GPCRs) often engage multiple intracellular transducers, yet the structural basis by which endogenous ligands influence G protein selectivity remains poorly understood. GPR119 is a lipid-activated receptor expressed in pancreatic β-cells and enteroendocrine L-cells, where it regulates glucose-dependent insulin and incretin secretion, making it a promising therapeutic target for metabolic disease. Here, we present cryo-electron microscopy structures of GPR119 bound to its endogenous lipid agonist oleoylethanolamide (OEA) in complex with G _s and G _q proteins. These structures reveal that OEA occupies a deeply buried orthosteric pocket but adopts distinct conformations in the two signaling states. Structural and functional analyses further identify an extended TM5 helix that stabilizes the receptor-G _s interface and acts as a key determinant of G-protein subtype selectivity. Together, these findings provide mechanistic insights into endogenous lipid-driven multi-transducer signaling and establish a structural framework for the development of pathway-selective GPR119 therapeutics.