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

Deganutti, G.; Liang, Y.-L.; Zhang, X.; Khoshouei, M.; Clydesdale, L.; Belousoff, M. J.; Venugopal, H.; Truong, T. T.; Glukhova, A.; Keller, A. N.; Gregory, K. J.; Leach, K.; Christopoulos, A.; Danev, R.; Reynolds, C. A.; Zhao, P.; Sexton, P. M.; Wootten, D. M.

doi:10.1101/2021.03.10.434902

bioRxiv · 10.1101/2021.03.10.434902

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

Deganutti, G.·Liang, Y.-L.·Zhang, X.·Khoshouei, M.·Clydesdale, L.·Belousoff, M. J.·Venugopal, H.·Truong, T. T.·Glukhova, A.·Keller, A. N.·Gregory, K. J.·Leach, K.·Christopoulos, A.·Danev, R.·Reynolds, C. A.·Zhao, P.·Sexton, P. M.·Wootten, D. M.

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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 have combined cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding by four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data revealed 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.

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Deganutti, G., Liang, Y.-L., Zhang, X., Khoshouei, M., Clydesdale, L., Belousoff, M. J., Venugopal, H., Truong, T. T., Glukhova, A., Keller, A. N., Gregory, K. J., Leach, K., Christopoulos, A., Danev, R., Reynolds, C. A., Zhao, P., Sexton, P. M., Wootten, D. M.. 2021-03-11. Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation. https://doi.org/10.1101/2021.03.10.434902

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