Structural dynamics underlying agonist activation of a GLP-1R-Gs precoupled complex

Authors

Sys, J., Ho, J. D., Showalter, A. D., Yu, A.-P., Wainscott, D. B., Laos, V., Broughton, H., Sloop, K. W., Espada, A., Reading, E.

Abstract

G-protein-coupled receptors (GPCRs) act as allosteric transmembrane signalling machines, generating distinct cellular responses depending on the conformational states induced by ligand binding. The glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR central to insulin secretion and body-weight regulation, is a key therapeutic target for obesity-associated metabolic disease. Here, we used hydrogen-deuterium exchange mass spectrometry to characterize ligand-evoked structural dynamics within a pre-coupled GLP-1R-Gs protein complex. Non-peptide agonists Chu-128 and danuglipron elicited overlapping dynamic perturbation profiles, with distinct drug-specific effects within the transmembrane bundle. In contrast, the natural GLP-1 hormone produced a weaker stabilizing effect on receptor backbone dynamics, while its inactive metabolite exerted opposing localised destabilization. Notably, both peptides uniquely modulated the highly flexible G-protein switch III loop, a key mediator of downstream signalling. These findings pinpoint areas where structural dynamics shape agonist efficacy and facilitate functional dynamics-integrated drug discovery of non-peptide agonists.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Aug 2026.

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