The glucagon-like peptide-1 receptor binding site for the N-terminus of GLP-1 requires polarity at Asp198 rather than negative charge.
The mutation of Asp198 to Asn in the receptor for glucagon-like peptide-1(7-36)amide (GLP-1) had no effect upon GLP-1 affinity whereas substitution with Ala greatly reduced affinity, demonstrating the importance of polarity rather than negative charge at Asp198. However, the Asp198-Ala mutation had less effect upon the affinity of Exendin-4, a peptide agonist that has been shown previously not to require its N-terminus for high affinity. Moreover, the affinity of a truncated GLP-1 analogue lacking the first eight residues was not affected by the Asp198-Ala mutation, demonstrating that Asp198 is required for maintaining the binding site of the N-terminal region of GLP-1.
López de Maturana
Rakel
R
School of Biomedical Sciences, University of Leeds, UK.
Donnelly
Dan
D
D001224:Aspartic Acid / Q000378:metabolism*; D002460:Cell Line; D005934:Glucagon / Q000737:chemistry / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism*; D011869:Radioligand Assay; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*
C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D011498:Protein Precursors; D018027:Receptors, Glucagon; D001224:Aspartic Acid; D052216:Glucagon-Like Peptide 1; D005934:Glucagon