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

Source:

Cell. 2016 Jun 16;165(7):1632-43. doi: 10.1016/j.cell.2016.05.023.

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.

Wootten D¹, Reynolds CA², Smith KJ², Mobarec JC², Koole C³, Savage EE⁴, Pabreja K⁴, Simms J⁵, Sridhar R⁴, Furness SG⁴, Liu M⁶, Thompson PE⁶, Miller LJ⁷, Christopoulos A⁴, Sexton PM⁸.

Author information

• ¹Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: denise.wootten@monash.edu.
• ²School of Biological Sciences, University of Essex, Colchester CO4 3SQ, UK.
• ³Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
• ⁴Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
• ⁵School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
• ⁶Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
• ⁷Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ 85259, USA.
• ⁸Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: patrick.sexton@monash.edu.