Poster Presentation 50th Lorne Proteins Conference 2025

Prolonged signaling of backbone-modified glucagon-like peptide-1 analogues with diverse receptor trafficking (#439)

Brian P Cary 1 2
  1. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Parkville, Vic, Australia
  2. Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia

The glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) is the target of blockbuster anti-obesity drugs, including peptides such as semaglutide and tirzepatide. GLP-1R has a complex signaling profile, and the effects of modulating this profile are not completely understood. Therefore, tools to dissect the receptor’s activities are desirable. Here, we report a pair of synthetic peptide agonists, both with sustained signaling capacities compared to GLP-1. Surprisingly, these two close analogues showed markedly distinct abilities to induce intracellular receptor trafficking. Structure-activity relationship studies, cryo-EM analysis, and molecular dynamics simulations shed light on the behavior of  GLP-1R in response to the new analogues. Collectively, our results support the hypothesis that peptide dynamics play a key role in signal transduction outcomes.

  1. Cary, B.P.; Hager, M. V.; Morris, R.K.; Belousoff, M.J.; Sexton, P.M.; Wootten, D.; Gellman, S.H. “Prolonged signaling of backbone-modified glucagon-like peptide-1 analogues with diverse receptor trafficking.” bioRxiv 2024, https://doi.org/10.1101/2024.04.17.589632. (preprint)