Journal article
Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation
G Deganutti, YL Liang, X Zhang, M Khoshouei, L Clydesdale, MJ Belousoff, H Venugopal, TT Truong, A Glukhova, AN Keller, KJ Gregory, K Leach, A Christopoulos, R Danev, CA Reynolds, P Zhao, PM Sexton, D Wootten
Nature Communications | NATURE PORTFOLIO | Published : 2022
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 dynamic..
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Grants
Awarded by National Institutes of Health
Funding Acknowledgements
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.