Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation

• DOI: 10.1038/s41467-021-27760-0
• Publication Date: 2022-01-10T11:02:59Z
• Authors: Giuseppe Deganutti; Yi-Lynn Liang; Xin Zhang; Maryam Khoshouei; Lachlan Clydesdale; Matthew J. Belousoff; Hari Venugopal; Tin T. Truong; Alisa Glukhova; Andrew N. Keller; Karen J. Gregory; Katie Leach; Arthur Christopoulos; Radostin Danev; Christopher A. Re...; Peishen Zhao; Patrick M. Sexton; Denise Wootten
• Keywords: Protein Conformation, alpha-Helical; 0301 basic medicine; 570; Science; Genetic Vectors; 610; Gene Expression; Molecular Dynamics Simulation; Ligands; Article; Glucagon-Like Peptide-1 Receptor; 03 medical and health sciences; Allosteric Regulation; Glucagon-Like Peptide 1; Humans; Cloning, Molecular; 0303 health sciences; Binding Sites; Q; Cryoelectron Microscopy; Kinetics; HEK293 Cells; Oxyntomodulin; Mutation; Exenatide; Protein Conformation, beta-Strand; Baculoviridae; Protein Binding

AbstractThe glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists.