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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. © 2022. The Author(s).

Citation

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 Reynolds, Peishen Zhao, Patrick M Sexton, Denise Wootten. Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation. Nature communications. 2022 Jan 10;13(1):92

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PMID: 35013280

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