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Updated: Sep 11, 2025
10:59
Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET
Published on: August 17, 2022
3.3K
Exploring Conformational Transitions in Biased and Balanced Ligand Binding of GLP-1R
Marc Xu1,2, Horst Vogel1,3,4, Shuguang Yuan1,5
1Research Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
Molecules (Basel, Switzerland)
|August 14, 2025
Summary
Understanding glucagon-like peptide-1 receptor (GLP-1R) activation dynamics is key for developing new metabolic disorder drugs. Molecular dynamics simulations reveal how different agonists, like small molecules and peptides, uniquely activate GLP-1R signaling pathways.
Area of Science:
- Biochemistry and structural biology
- Pharmacology
- Molecular modeling
Background:
- The glucagon-like peptide-1 receptor (GLP-1R), a class B1 G protein-coupled receptor (GPCR), is a crucial therapeutic target for metabolic disorders such as type 2 diabetes and obesity.
- GLP-1R-based therapies are gaining significant attention due to the development of diverse functional agonists and a substantial market potential.
Purpose of the Study:
- To investigate the conformational dynamics of the GLP-1R in complex with various functional agonists.
- To elucidate the atomic-level mechanisms by which different ligands induce distinct signaling pathway preferences.
Main Methods:
- All-atom molecular dynamics (MD) simulations were employed to study the receptor-ligand interactions.
- Analysis focused on conformational changes, binding modes, and induced helix packing upon agonist binding.
Main Results:
- Distinct binding modes and unique helix packing were observed for different agonists (CHU-128, danuglipron, Peptide 19).
- MD simulations revealed specific atomic features explaining how these ligands differentially modulate GLP-1R signaling pathways.
- Ligand-specific conformational dynamics were linked to signaling pathway bias.
Conclusions:
- The study provides mechanistic insights into GLP-1R activation by diverse agonists.
- Findings support the rational design of next-generation GLP-1R therapeutics with improved efficacy and specificity for metabolic diseases.
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