Differential GLP-1R binding and activation by peptide and non-peptide agonists

Zhang, X.; Belousoff, M. J.; Zhao, P.; Kooistra, A. J.; Truong, T. T.; Ang, S. Y.; Underwood, C. R.; Egebjerg, T.; Senel, P.; Stewart, G. D.; Liang, Y.-L.; Glukhova, A.; Venugopal, H.; Christopoulos, A.; Furness, S. G.; Miller, L. J.; Reedtz-Runge, S.; Langmead, C. J.; Gloriam, D. E.; Danev, R.; Sexton, P. M.; Wootten, D.

doi:10.1101/2020.08.16.252585

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bioRxiv · 10.1101/2020.08.16.252585

Differential GLP-1R binding and activation by peptide and non-peptide agonists

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Abstract

Peptide drugs targeting class B1 GPCRs can treat multiple diseases, however there remains substantial interest in the development of orally delivered non-peptide drugs. Here we reveal unexpected overlap between signalling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist, PF 06882961, and GLP-1 that was not observed for another compound, OWL-833. Both compounds are currently in clinical trials for treatment of type 2 diabetes. High resolution cryo-EM structures reveal the binding sites for PF-06882961 and GLP-1 substantially overlap, whereas OWL-833 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not OWL-833, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.

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Zhang, X., Belousoff, M. J., Zhao, P., Kooistra, A. J., Truong, T. T., Ang, S. Y., Underwood, C. R., Egebjerg, T., Senel, P., Stewart, G. D., Liang, Y.-L., Glukhova, A., Venugopal, H., Christopoulos, A., Furness, S. G., Miller, L. J., Reedtz-Runge, S., Langmead, C. J., Gloriam, D. E., Danev, R., Sexton, P. M., Wootten, D.. 2020-08-16. Differential GLP-1R binding and activation by peptide and non-peptide agonists. https://doi.org/10.1101/2020.08.16.252585

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