Prolonged signaling of backbone-modified glucagon‐like peptide‐ 1 analogues with diverse receptor trafficking
Year: 2025
Type: article
Abstract: Signal duration and subcellular location are emerging as important facets of G protein-coupled receptor (GPCR) function. The glucagon-like peptide-1 receptor (GLP-1R), a clinically relevant class B1 GPCR, stimulates production of the second messenger cAMP upon activation by the native hormone, GLP-1. cAMP production continues after the hormone-receptor complex has been internalized via endocytosis. Here, we report GLP-1 analogues that induce prolonged signaling relative to GLP-1. A single β-amino acid substitution at position 18, with the residue derived from ( S , S )- trans -2-aminocyclopentanecarboxylic acid (ACPC), enhances signaling duration with retention of receptor endocytosis. Pairing ACPC at position 18 with a second substitution, α-aminoisobutyric acid (Aib) at position 16, abrogates endocytosis, but prolonged signaling is maintained. Prolonged signaling is sensitive to the structure of the β residue at position 18. Cryo-electron microscopy (cryo-EM) structures of two GLP-1 analogues bound to the GLP- 1R:Gs complex suggest substantial alterations to bound peptide structure and dynamics compared to the GLP-1:GLP-1R complex. These structural findings strengthen an emerging view that agonist dynamics in the receptor-bound state influence signaling profile. Our results advance understanding of the structural underpinnings of receptor activation and introduce new tools for exploring the impact of spatiotemporal signaling profiles following GLP-1R activation.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: National Science Foundation, University of Wisconsin-Madison, Monash University, University of Melbourne, Department of Health and Aged Care, Australian Government, Department of Education and Training, National Institutes of Health, Medical Research Council, Australian Research Council, National Health and Medical Research Council, National Institute of General Medical Sciences, National Science Foundation Graduate Research Fellowship Program
Awards: Graduate Research Fellowship Program (GRFP), G1104264917, G1274928169, Molecular control of efficacy at glucagon family of receptors, Mechanistic understanding of biased agonism and dimerisation for co-targeting incretin receptors for metabolic diseases, G1686957331, G2134840038, G2337776100, G237404272, G2560624041, Novel targeting of the glucagon family of G protein-coupled receptors, Collaborative Research: Social Networks and Microfinance, G3981254544, Translating membrane proteins into therapeutics; from bedside to bench, G4934850370, Processes mediated by polypeptides, G5232483184, G5317223370, ARC Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery, G6686301362, Improving translational understanding of the most abundant therapeutic target class, G7294385387, G7450968682, Structure, function and modulation of peptide hormone G protein-coupled receptors (GPCRs), G7869431301, G8064552963, G843635962, G8767588413, G9000023674, G9000029677, G9000035331, G9000069240, G9000331062
OpenAlex ID: W4409045737