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Updated: Oct 3, 2026

Mechanisms Underlying Gut Hormone Secretion Using the Isolated Perfused Rat Small Intestine
Published on: February 26, 2019
Interactions of Glucagon-Like Peptide-1 Receptor Agonists With GLP-1R-Gs Complex: Insights From Gaussian-Accelerated
Xue Zhou1, Minghao Liu1, Yunlai Shi2
1Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, Changchun, China.
Abstract:
The glucagon-like peptide-1 receptor (GLP-1R) is a critical therapeutic target for metabolic diseases. GLP-1 receptor agonists (GLP-1RAs) have been developed to treat type 2 diabetes and promote weight loss. In this study, Gaussian accelerated molecular dynamics (GaMD) simulations, MM-PBSA calculations, and conformational dynamic analyses were systematically employed to elucidate the binding mechanisms and dynamic stability of three representative agonists-native GLP-1, semaglutide, and tirzepatide-bound to the GLP-1R-Gs membrane protein complex. Molecular docking and trajectory analyses revealed that ligand binding significantly stabilizes the overall receptor structure, triggering conformational shifts in the extracellular domain (ECD) and transmembrane domain (TMD), particularly inducing long-range allosteric cross-talk with the intracellular Gs protein to downstream signal transduction. Compared to GLP-1 and semaglutide, tirzepatide demonstrated distinct conformational shifts, superior structural compactness, and the higher binding affinity with a significantly more negative binding free energy. Furthermore, micro-interfacial localization demonstrated that lipid bilayer interaction with basic and aromatic residues at the Zp interface synergistically stabilizes the active transmembrane conformation. These atomic-level insights highlight the unique structural advantages of tirzepatide and provide a solid theoretical foundation for the novel rational design of next-generation multi-target peptide therapeutics.
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