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.
Disease
Relevance
Structural highlights
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