This page describes the structural basis for how glucagon-like peptide-1 receptor (GLP-1R), a class B1 G-protein-coupled receptors (GPCRs), is activated by both peptide ligands (GLP-1) and recently developed small-molecule antagonists (PF-06882961 and CHU-128). High-resolution cryo-EM structures reveal distinct ligand binding modes and explain why PF-06882961 mimics GLP-1 signaling more closely than CHU-128. This could be through water- mediated networks, TM6/TM7 rearrangements, biased agonism, and can have implications for oral drug design.
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Background
The glucagon-like peptide-1 receptor (GLP-1R) is a Class B1 GPCR essential for maintaining glucose homeostasis, regulating appetite, and supporting metabolic health. Activation of GLP-1R by the endogenous hormone GLP-1 enhances insulin secretion, slows gastric emptying, and promotes satiety.
Current GLP-1R therapeutics are peptide-based drugs, which are effective but require injection and often cause gastrointestinal side effects. These limitations have driven major interest in developing orally available small-molecule agonists capable of reproducing the beneficial actions of GLP-1.
Recent structural and pharmacological studies show that small molecules can bind and activate GLP-1R in ways that differ from peptide ligands. Some compounds, such as PF-06882961, closely mimic GLP-1–like signaling, while others exhibit strong pathway selectivity (biased agonism). Understanding these structural differences is crucial for designing next-generation oral GLP-1R agonists with improved efficacy, safety, and tolerability.
Pharmacalogical Profile of PF-06882961 and CHU-128
There are multiple GLP-1R pathways: cAMP, pERK1/2, intracellular calcium, β-arrestin recruitment, Gs conformational change, and receptor internalization. The small peptide agonists display different signalling behaviours across these pathways. Both non-peptides were potent and full agonists for cAMP production, showing ~30-fold lower potency than GLP-1 and similar ability to induce Gs activation. However, CHU-128 was inactive in every other pathway, even at high concentrations, indicating extreme Gs/cAMP bias.
In contrast, PF-06882961 activated all pathways, although with reduced potency. Quantitative modelling showed PF-06882961 has only subtle biased agonism compared to GLP-1, and in fact exhibits less bias than many clinically used peptide agonists. Despite CHU-128 having ~10-fold higher binding affinity than PF-06882961, PF-06882961 displays higher efficacy in cAMP signalling.
The data suggests that PF-06882961 behaves similarly to GLP-1 in overall signalling and receptor regulation, whereas CHU-128 displays narrow, cAMP-restricted profiles.These contrasting signaling behaviors make understanding the structural basis of how each small molecule engages GLP-1R of utmost importance.
Relevance
Structural highlights
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