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 {beta}-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 Gs and Gq 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-Gs 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.
Kim, D., Ranjbar, M., Raskovalov, A., Song, P., Salve, J., Katritch, V., Cherezov, V.
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