α-Helix or β-Turn? An Investigation into N-Terminally Constrained Analogues of Glucagon-like Peptide 1 (GLP-1) and Exendin-4

• DOI: 10.1021/acs.biochem.8b00105
• Publication Date: 2018-06-07T15:04:53Z
• Authors: Alberto Oddo; Sofia Mortensen; Henning Thøgersen; Leonardo De Maria; Stephanie Hennen; James N. McGuire; Jacob Kofoed; Lars Linderoth; Steffen Reedtz-Runge
• Keywords: Turn (biochemistry); Helix (gastropod)

Peptide agonists acting on the glucagon-like peptide 1 receptor (GLP-1R) promote glucose-dependent insulin release and therefore represent important therapeutic agents for type 2 diabetes (T2D). Previous data indicated that an N-terminal II β-turn motif might be feature GLP-1R. In contrast, recent publications reporting structure of full-length GLP-1R have shown N-terminus receptor-bound in α-helical conformation. To reconcile these conflicting results, we prepared N-terminally constrained analogues (GLP-1) exendin-4 evaluated their affinity functionality vitro; then examined crystal structures complex with extracellular domain used molecular modeling dynamics simulations further investigations. We report peptides' N-termini all determined adopted a conformation, but vitro potency varied several thousand-fold across series. Potency correlated better α-helicity our computational model, although found energy barrier between two mentioned conformations is low most potent flexibility highlighted by simulations.