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, Denise Wootten

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    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.

    Original languageEnglish
    Article number92
    Number of pages18
    JournalNature Communications
    Volume13
    Issue number1
    Early online date10 Jan 2022
    DOIs
    Publication statusE-pub ahead of print - 10 Jan 2022

    Bibliographical note

    This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the
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    Publisher Copyright:
    © 2022, The Author(s).

    Funder

    Funding Information:
    This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (project grant 1126857, ideas grant 1184726 (D.W.), and programme grant 1150083 (P.M.S.)). P.M.S. is a Senior Principal Research Fellow (ID: 1154434) and D.W. a Senior Research Fellow of the NHMRC (ID: 1155302). R.D. was supported by Takeda Science Foundation 2019 Medical Research Grant and Japan Science and Technology Agency PRESTO (18069571). K.J.G., K.L. and P.Z. are Future Fellows of the Australian Research Council (ARC; K.J.G—FT170100392, K.L— FT160100075, P.Z—FT200100218). M.J.B. is funded by a Fellowship from the ARC Industrial Transformation Training Centre for Cryo-electron Microscopy of Membrane Proteins (IC200100052). C.A.R. is a Royal Society Industry Fellow. This work was supported by the Monash University Ramaciotti Centre for cryo-electron microscopy and the Monash University MASSIVE high-performance computing facility.

    Funding Information:
    Graphics. Molecular graphics images were produced using the UCSF Chimera (v1.14) and ChimeraX packages from the Computer Graphics Laboratory, University of California, San Francisco (supported by NIH P41 RR-01081and R01-GM129325)71,72. ShinyCircos73 was used to generate flare plots depicting the GLP-1R TM bundle contacts.

    Keywords

    • General Biochemistry
    • General Chemistry
    • General Physics and Astronomy
    • General Biochemistry, Genetics and Molecular Biology

    ASJC Scopus subject areas

    • Physics and Astronomy(all)
    • Chemistry(all)
    • Biochemistry, Genetics and Molecular Biology(all)

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