Evolutionarily conserved residues at glucagon-like peptide-1 (GLP-1) receptor core confer ligand-induced receptor activation

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play important roles in insulin secretion through their receptors, GLP1R and GIPR. Although GLP-1 and GIP are attractive candidates for treatment of type 2 diabetes and obesity, little is known regarding the molecular interaction of these peptides with the heptahelical core domain of their receptors. These core domains are important not only for specific ligand binding but also for ligand-induced receptor activation. Here, using chimeric and point-mutated GLP1R/GIPR, we determined that evolutionarily conserved amino acid residues such as Ile¹⁹⁶ at transmembrane helix 2, Leu ²³² and Met²³³ at extracellular loop 1, and Asn ³⁰² at extracellular loop 2 of GLP1R are responsible for interaction with ligand and receptor activation. Application of chimeric GLP-1/GIP peptides together with molecular modeling suggests that His¹ of GLP-1 interacts with Asn³⁰² of GLP1R and that Thr⁷ of GLP-1 has close contact with a binding pocket formed by Ile¹⁹⁶, Leu ²³², and Met²³³ of GLP1R. This study may provide critical clues for the development of peptide and/or nonpeptide agonists acting at GLP1R.