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

• Published in: Nature communications Vol. 13; no. 1; p. 92
• Main Authors: Deganutti, Giuseppe, Liang, Yi-Lynn, Zhang, Xin, Khoshouei, Maryam, Clydesdale, Lachlan, Belousoff, Matthew J., Venugopal, Hari, Truong, Tin T., Glukhova, Alisa, Keller, Andrew N., Gregory, Karen J., Leach, Katie, Christopoulos, Arthur, Danev, Radostin, Reynolds, Christopher A., Zhao, Peishen, Sexton, Patrick M., Wootten, Denise
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-01-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 13/106; 13/109; 631/154/436/2387; 631/45/535/1258; 631/45/612/194; 82/1; 82/83; 96; 96/95; Agonists; Allosteric properties; Allosteric Regulation; Baculoviridae - genetics; Baculoviridae - metabolism; Binding; Binding Sites; Cloning, Molecular; Coupling (molecular); Cryoelectron Microscopy; Diabetes mellitus; Electron microscopy; Exenatide - chemistry; Exenatide - genetics; Exenatide - metabolism; Gene Expression; Genetic Vectors - chemistry; Genetic Vectors - metabolism; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - chemistry; Glucagon-Like Peptide 1 - genetics; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor - chemistry; Glucagon-Like Peptide-1 Receptor - genetics; Glucagon-Like Peptide-1 Receptor - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Kinetics; Ligands; Metabolic disorders; Molecular dynamics; Molecular Dynamics Simulation; Molecular modelling; multidisciplinary; Mutagenesis; Mutation; Oxyntomodulin - chemistry; Oxyntomodulin - genetics; Oxyntomodulin - metabolism; Peptides; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Proteins; Receptors; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Signaling; Structure-Activity Relationship
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27760-0

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.
The glucagon-like peptide-1 receptor (GLP-1R) can be targeted in the treatment of diabetes, obesity and other metabolic disorders. Here, the authors assess the molecular mechanisms of peptide agonists binding to GLP-1R and the responses elucidated by these ligands, including distinct kinetics of G protein activation.