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

Deganutti, G; Liang, YL; Zhang, X; Khoshouei, M; Clydesdale, L; Belousoff, MJ; Venugopal, H; Truong, TT; Glukhova, A; Keller, AN; Gregory, KJ; Leach, K; Christopoulos, A; Danev, R; Reynolds, CA; Zhao, P; Sexton, PM; Wootten, D

Author(s): Deganutti, G; Liang, YL; Zhang, X; Khoshouei, M; Clydesdale, L; Belousoff, MJ; Venugopal, H; Truong, TT; Glukhova, A; Keller, AN; Gregory, KJ; Leach, K; Christopoulos, A; Danev, R; Reynolds, CA; Zhao, P; Sexton, PM; Wootten, D;
Details: Publication Year 2022-01-10,Volume 13,Issue #1,Page 92
Journal Title: Nature Communications
Abstract: The 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.
Keywords: Allosteric Regulation; Baculoviridae/genetics/metabolism; Binding Sites; Cloning, Molecular; Cryoelectron Microscopy; Exenatide/*chemistry/genetics/metabolism; Gene Expression; Genetic Vectors/chemistry/metabolism; Glucagon-Like Peptide 1/*chemistry/genetics/metabolism; Glucagon-Like Peptide-1 Receptor/*chemistry/genetics/metabolism; HEK293 Cells; Humans; Kinetics; Ligands; Molecular Dynamics Simulation; Mutation; Oxyntomodulin/*chemistry/genetics/metabolism; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Recombinant Proteins/chemistry/genetics/metabolism; Structure-Activity Relationship
Research Division(s): Structural Biology
PubMed ID: 35013280
Publisher's Version: https://doi.org/10.1038/s41467-021-27760-0
Open Access at Publisher's Site: https://doi.org/ 10.1038/s41467-021-27760-0
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2022-02-18 11:36:35

Last Modified: 2022-02-18 01:16:02