Journal of the American Chemical SocietySep 12, 2024

Activation of the Class B Glucagon-like Peptide 1 Receptor Begins with G Protein Binding and Changes Guided by Its Front Domain

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 20, 2026

Abstract

The proposed mechanism for GLP-1 receptor activation involves a GLP-1R-GP precoupled complex that remains inactive until an agonist binds.

GLP-1 receptor (GLP-1R) activation may occur through a G protein-first mechanism, as supported by extensive atomistic simulations.
The GLP-1R is hypothesized to form a complex with the G protein at the cell membrane before ligand binding, making it preactivated but still inactive.
The complex maintains a conformation typical of activated GLP-1R, yet it does not initiate signaling until an agonist is present.
A novel N-terminus domain-swing mechanism is proposed, where the extracellular domain of GLP-1R helps position the peptide agonist for binding.
These insights could aid in the design of new GLP-1R medications with improved efficacy and reduced side effects.

Simplified

Recently, there has been a great deal of excitement about new glucagon-like peptide 1 receptor (GLP-1R) agonists (e.g., semaglutide and tirzepatide) that have received FDA approval for type 2 diabetes and obesity. Although effective, these drugs come with side effects that limit their use. While research efforts continue to focus intensively on long-lasting, orally administered GLP-1R medications with fewer side effects, a major impediment to developing improved GLP-1R medications is that the mechanism by which an agonist activates GLP-1R to imitate signaling is not known. Here we present and validate the G protein (GP)-first mechanism for the GLP-1R supported by extensive atomistic simulations. We propose that GLP-1R is preactivated through the formation of a GLP-1R-GP precoupled complex at the cell membrane prior to ligand binding. Despite a transmembrane helix 6 (TM6)-bentout conformation characteristic of activated GLP-1R, this precoupled complex remains unactivated until an agonist binds to elicit signaling. Notably, this new hypothesis offers a unified and predictive model for the activities of a series of full and partial agonists, including the peptides ExP5, GLP-1(7-36), and GLP-1(9-36). Most surprisingly, our simulations reveal an N-terminus domain (NTD)-swing/agonist-insertion mechanism wherein the long extracellular NTD of GLP-1R tightly holds the C-terminal half of the peptide agonist and progressively shifts the N-terminal head of the peptide to facilitate insertion into the orthosteric pocket. Our findings provide novel mechanistic insights into the activation and function of class B GPCRs and should provide a realistic basis for structure-based ligand design.

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Activation of the Class B Glucagon-like Peptide 1 Receptor Begins with G Protein Binding and Changes Guided by Its Front Domain

Abstract

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