Mechanism of activation of GLP-1R agonist on GLP-1R based on Markov model constructed by enhanced sampling
LIU Yibu
TANG Lei
FAN Judi
Abstract：Objective To investigate the mechanism of activation of glucagon-like peptide 1(GLP-1R)by GLP-1R agonist PF-06882961 based on the hidden Markov state model constructed by enhanced sampling.Methods The bind-ing structure of GLP-1R and PF-06882961(PDBID:6X1A)was downloaded from the PDB database,and the Gaussian ac-celerated molecular dynamics(GaMD)system of it was constructed based on the structure to simulate its dynamic trajecto-ry of the binding of PF06882961 to GLP-1R.The GaMD dynamics trajectory of PF06882961 and GLP-1R was read by the toolkit Pyemma to construct a hidden Markov model(HMM).Then,a cluster analysis was performed on several conforma-tions of PF-06882961 and GLP-1R complex in the constructed Markov model from the primary structure[αC spacing be-tween key amino acid residues(Glu247-His180;Glu364-Arg190)]and the secondary structure[torsion angle between key α helices(Val365-Pro358-Ala350;Arg380-Phe390-Met397)],and five macroscopic conformations(S1,2,3,4,5)of PF-06882961 and GLP-1R complex with different structures were obtained.After visualization,the structural differenc-es between each macroscopic conformation were analyzed to clarify the structural basis of PF-06882961 activating GLP-1R.Results Cluster analysis at the secondary structure level showed that the distance between the extracellular domain and the transmembrane domain of GLP-1R decreased after PF06882961 binding to GLP-1R,and the downstream(G protein)of GLP-1R underwent important conformational changes.Cluster analysis at the primary structure and secondary structure lev-els showed that the key amino acid residues in the transmembrane domain of GLP-1R were rearranged into a new polar net-work(Glu364-Tyr241-His180-Glu247),and the extracellular domain was composed of π-π stacking network by Phe385-Tyr203-Tyr148 after PF06882961 binding to GLP-1R.Conclusion After PF-06882961 binding to GLP-1R,the extracel-lular domain and transmembrane domain of GLP-1R were stabilized by π-π stacking network composed of Phe385-Tyr203-Tyr148 and a new polar network rearranged by Glu364-Tyr241-His180-Glu247,thereby activating GLP-1R.
Keywords：glucagon-like peptide-1 receptor agonistPF-06882961glucagon-like peptide-1 receptorMarkov state modelGaussian accelerated molecular dynamicsmolecular dynamics simulation
Publication Date：2024-01-25
Online Publishing Date：2025-08-15(First online date of this platform, not the publication date of the document)
Pages：7( 44-50 )