The receptor activated by GLP-1 is a target for drugs that treat type 2 diabetes and obesity. Since glycine has a low α-helix propensity, and Gly22 of GLP-1 does not contact the receptor, we replaced Gly22 with residues that have a higher or lower helix propensity. Most substitutions had little effect on receptor affinity or activation and raised the possibility that the receptor-bound state of agonist peptides encompasses a broader conformational envelope.

Abstract

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.