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 journalArticlepeer-review

114 Citations (Scopus)
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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
Pages (from-to)1632-1643
Number of pages12
Issue number7
Early online date16 Jun 2016
Publication statusPublished - 16 Jun 2016
Externally publishedYes

Bibliographical note

This is an open access article under the CC BY license (


  • Animals
  • CHO Cells
  • Calcium
  • Cell Line
  • Cricetulus
  • Cyclic AMP
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Oxyntomodulin
  • Peptides
  • Rats
  • Signal Transduction
  • Venoms
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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