The primary ligand-binding interaction at the GLP-1 receptor is via the putative helix of the peptide agonists

The N-terminal domain of the GLP-1 receptor binds the putative helical region of the peptide agonists, GLP-1 and exendin-4. Here we demonstrate that this interaction also determines the magnitude of a separate interaction between the N-terminus of these peptides and the receptor's core domain. Enhancing the pre-formation of the C-terminal Trp-Cage motif of exendin-4, a motif critical for high-affinity binding, results in no improvement in receptor affinity, suggesting that this motif forms after the initial peptide-receptor binding event.