A model for receptor-peptide binding at the glucagon-like peptide-1 (GLP-1) receptor through the analysis of truncated ligands and receptors.
1. The receptor for glucagon-like peptide-1 (GLP-1) can be activated by both its physiological hormone and a peptide discovered in the venom of the Gila Monster, exendin-4, which shows promise as an antidiabetic agent. 2. Exendin-4 displays receptor-binding properties not observed for GLP-1. Firstly, exendin-4 can be truncated by up to eight residues at its N-terminus without a significant loss of affinity. Secondly, exendin-4 maintains high affinity for the isolated N-terminal domain of the receptor, suggesting that exendin-4 makes additional contacts with this domain of the receptor, which nullify the requirement for ligand-receptor interactions involving the extracellular loops and/or transmembrane helices of the receptor's core domain. 3. In order to further understand the nature of the receptor-peptide interaction, a variety of full length and truncated peptide analogues were used to quantify the contribution of each distinct region of exendin-4 and GLP-1 to receptor affinity. 4. Our data show that, for both exendin-4 and GLP-1, the primary interaction is between the putative helical region of the peptide and the extracellular N-terminal domain of the receptor. 5. However, we demonstrate that the contribution to receptor affinity provided by the N-terminal segment of GLP-1 is greater than that of exendin-4, while the C-terminal nine residue extension of exendin-4, absent in GLP-1, forms a compensatory interaction with the N-terminal domain of the receptor. 6. We describe a peptide-receptor binding model to account for these data.
Al-Sabah
Suleiman
S
School of Biomedical Sciences, University of Leeds, Worsley Building, Leeds LS2 9JT, U.K.
Donnelly
Dan
D
D000595:Amino Acid Sequence; D002460:Cell Line; D000077270:Exenatide; D005934:Glucagon / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014688:Venoms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide