The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism

Denise Wootten, Christopher A. Reynolds, Kevin J. Smith, Juan C. Mobarec, Cassandra Koole, Emilia E. Savage, Kavita Pabreja, John Simms, Rohan Sridhar, Sebastian G.B. Furness, Mengjie Liu, Philip E. Thompson, Laurence J. Miller, Arthur Christopoulos, Patrick M. Sexton

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists.

Original languageEnglish (US)
Pages (from-to)1632-1643
Number of pages12
JournalCell
Volume165
Issue number7
DOIs
StatePublished - Jun 16 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wootten, D., Reynolds, C. A., Smith, K. J., Mobarec, J. C., Koole, C., Savage, E. E., Pabreja, K., Simms, J., Sridhar, R., Furness, S. G. B., Liu, M., Thompson, P. E., Miller, L. J., Christopoulos, A., & Sexton, P. M. (2016). The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism. Cell, 165(7), 1632-1643. https://doi.org/10.1016/j.cell.2016.05.023