Evolutionarily Conserved Residues at Glucagon-like Peptide-1 (GLP-1) Receptor Core Confer Ligand-induced Receptor Activation

Abstract

Background: Little is known regarding the molecular interaction between GLP-1 and its receptor. Conclusion:Evolutionarily conserved residues at the GLP1R core confer ligand-induced receptor activation. Significance: This study may provide critical clues for development of peptide and/or nonpeptide agonists acting at GLP1R.

Ligand Binding Pocket Formed by Evolutionarily Conserved Residues in the Glucagon-like Peptide-1 (GLP-1) Receptor Core Domain

“…This is likely due to a relatively high degree (47%) of sequence similarity between ECL3 of GLP1R and that of GIPR. Indeed, the ECL3 regions of GLP1R and its paralogous receptors GIPR, GLP2R, GCGR, and GCRPR exhibit considerable similarities in amino acid length and sequence (32). In our previous study with GLP1R/GIPR chimeric receptors, we were unable to identify the residues in GLP1R ECL3 that interact with the peptide ligand.…”

“…Although GLP-1 and its related peptides share a high degree of sequence identity and structural similarity, they generally exhibit specific binding to their own receptors with some crossreactivity toward paralogous receptors (32,52). This observation suggests that there are distinct amino acid residues among paralogs of the peptide and receptor that mediate selective interactions with their own partners.…”

“…Recently, by using chimeric GLP1R/GIPR together with chimeric GLP-1/GIP peptides, we identified interactions of His 1 and Thr 7 of GLP-1 with Ile 196 /Lys 197 at TMH2, Met 233 at ECL1, and Asn 302 at ECL2 of GLP1R (32). These results demonstrated the evolutionary pressure to conserve critical residues for ligand binding and activation of GLP1R (33).…”

“…The peptide ligands for these receptors showed significantly altered potencies and affinities for the receptor chimera (32), demonstrating that residues in TMH2, ECL1, and ECL2 contribute to interactions between GLP-1 and GLP1R. However, exchanging ECL3 of GLP1R with that of GIPR did not affect the potency of GLP-1.…”

“…Thus, replacing Leu 379 in GLP2R with an Ala, which has a shorter side chain, may affect the structure of the binding pocket. Alanine scanning of GLP-2 showed that the residues at positions 2, 5, 6, and 17 are important for receptor activation (62), indicating that receptor-interacting residues in GLP-2 differ from those of GLP- , and Asn 302 in GLP1R (32,32), this study sheds light on the mechanism underlying the high affinity interaction between the GLP-1 peptide family and the binding pocket in the receptor that is formed by evolutionarily conserved residues. Identifying the structure of the ligand-binding pocket is important for in silico virtual screening of small molecules that activate GLP1R, which could be further developed by medicinal chemistry in treatments for diabetes and obesity.…”