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

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 () and Denise Wootten ()
Additional contact information
Giuseppe Deganutti: Coventry University
Yi-Lynn Liang: Monash University
Xin Zhang: Monash University
Maryam Khoshouei: Max Planck Institute of Biochemistry
Lachlan Clydesdale: Monash University
Matthew J. Belousoff: Monash University
Hari Venugopal: Monash University
Tin T. Truong: Monash University
Alisa Glukhova: Monash University
Andrew N. Keller: Monash University
Karen J. Gregory: Monash University
Katie Leach: Monash University
Arthur Christopoulos: Monash University
Radostin Danev: University of Tokyo
Christopher A. Reynolds: Coventry University
Peishen Zhao: Monash University
Patrick M. Sexton: Monash University
Denise Wootten: Monash University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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Citations: View citations in EconPapers (2)

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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27760-0

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DOI: 10.1038/s41467-021-27760-0

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