Effects of Replacing a Central Glycine Residue in GLP‐1 on Receptor Affinity and Signaling Profile

Agonists of the glucagon‐like peptide‐1 receptor (GLP‐1R) are used to treat diabetes and obesity. Cryo‐EM structures indicate that GLP‐1 is completely α‐helical when bound to the GLP‐1R. The mature form of this hormone, GLP‐1(7‐36), contains a glycine residue near the center (Gly22). Since glycine has the second‐lowest α‐helix propensity among the proteinogenic α‐amino acid residues, and Gly22 does not appear to make direct contact with the receptor, we were motivated to explore the impact on agonist activity of altering the α‐helix propensity at this position. We examined GLP‐1 analogues in which Gly22 was replaced with L‐Ala, D‐Ala or β‐amino acid residues with varying helix propensities. The results suggest that the receptor is reasonably tolerant of variations in helix propensity, and that the functional receptor‐agonist complex may comprise a conformational spectrum rather than a single fixed structure.