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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 displayed 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. PF-06882961 also had only subtle biased agonism compared to GLP-1. 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 signalling behaviours make understanding the structural basis of how each small molecule engages GLP-1R of utmost importance.

Structural Basis of GLP-1R Activation by Peptide and Small Molecule Agonists

High-resolution cryo-EM structures of human GLP-1R in complex with GLP-1, PF-06882961, or CHU-128 gave an understanding of how these agonists engage and activate the receptor.

The GLP-1 bound receptor showed extensive peptide interactions across the transmembrane pocket, extracellular loops, and a deep water-mediated hydrogen-bond network critical for receptor activation.

Binding of the Small Molecule Agonists seemed more superficial but was still distinct.

CHU-128 occupied a planar orientation with limited overlap to the peptide and failed to engage key TM7 and water-network interactions, whereas PF-06882961 adopted a deeper, elongated structure that overlapped the GLP-1 N-terminal binding region and stabilised a rich structural water network similar to that observed for the peptide. This differential binding might explain why PF-06882961 has a broad signalling profile like GLP-1.

Structural highlights

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