User:Ananya Narayanan/Sandbox 1

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.

You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

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

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.