The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism
| Autor: | Laurence J. Miller, Patrick M. Sexton, John Simms, Kevin J. Smith, Juan Carlos Mobarec, Emilia Elizabeth Savage, Mengjie Liu, Philip E. Thompson, Denise Wootten, Arthur Christopoulos, Rohan Sridhar, Sebastian G.B. Furness, Christopher A. Reynolds, Cassandra Koole, Kavita Pabreja |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Agonist Models Molecular medicine.drug_class CHO Cells Biology Bioinformatics General Biochemistry Genetics and Molecular Biology Article Glucagon-Like Peptide-1 Receptor Cell Line 03 medical and health sciences Cricetulus medicine Functional selectivity Cyclic AMP Animals Humans Receptor Glucagon-like peptide 1 receptor Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Effector Venoms Biochemistry Genetics and Molecular Biology(all) Rational design 3. Good health Cell biology Rats 030104 developmental biology Oxyntomodulin Mutagenesis Site-Directed Exenatide Calcium Signal transduction Peptides Intracellular Signal Transduction |
| Zdroj: | Cell |
| ISSN: | 0092-8674 1097-4172 |
| DOI: | 10.1016/j.cell.2016.05.023 |
| Popis: | Summary 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. Graphical Abstract Highlights • Effect of mutation on affinity and efficacy of biased ligands mapped onto 3D models • Biased agonists form distinct interactions with the GLP-1R extracellular surface • Engagement of unique elements of the extracellular surface promotes biased agonism • Insights into class B GPCR activation/biased agonism can aid rational drug design Understanding how different ligands engage and activate signaling pathways downstream of the GLP-1 receptor, a key type II diabetes target, suggests strategies for shaping signaling outcomes to favor physiologically beneficial effects. |
| Databáze: | OpenAIRE |
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