Molecular Dynamics Uncovers Distinct Allosteric Communication Pathways in GLP-1R for Activation and Inhibition

The glucagon-like peptide-1 receptor (GLP-1R), a class B1 G protein-coupled receptor (GPCR), is a crucial therapeutic target for type 2 diabetes and obesity. While structural studies have identified agonist and allosteric modulator binding sites, the precise residue-level communication pathways governing receptor activation, inhibition, and allosteric regulation remain incompletely understood. Elucidating these pathways is vital for developing more effective and targeted therapeutics.

Researchers performed 3-µs molecular dynamics simulations of GLP-1R in its apo state and when independently bound to a positive allosteric modulator (PAM), a negative allosteric modulator (NAM), and to agonists such as glucagon-like peptide-1 (GLP-1) and the stimulatory G protein (Gs). The resulting trajectories were analyzed using root-mean square deviation (RMSD) analysis and protein structure network (PSN) theory to compare dynamic structural changes.