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

Wootten, Denise and Reynolds, Christopher A and Smith, Kevin J and Mobarec, Juan C and Koole, Cassandra and Savage, Emilia E and Pabreja, Kavita and Simms, John and Sridhar, Rohan and Furness, Sebastian GB and Liu, Mengjie and Thompson, Philip E and Miller, Laurence J and Christopoulos, Arthur and Sexton, Patrick M (2016) 'The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.' Cell, 165 (7). pp. 1632-1643. ISSN 0092-8674

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[img] Video (Movie S1. Surface MD Simulation, Related to Figures 1 and 2 The N terminus of GLP-1 initially engages superficially with the GLP-1R receptor before moving deeper into the cavity driven by the E9/R190 interaction. The receptor surface is colored yellow; G)
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[img] Video (Movie S2. Deep-Pocket MD Simulation, Related to Figures 1 and 2 In the deep-pocket MD simulation, GLP1 and E9 start deep within the pocket and remain stable up to the full 500 ns. The color-coding is as above.)
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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.

Item Type: Article
Uncontrolled Keywords: Cell Line; CHO Cells; Venoms; Animals; Humans; Cricetulus; Rats; Calcium; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Peptides; Cyclic AMP; Mutagenesis, Site-Directed; Signal Transduction; Models, Molecular; Oxyntomodulin; Glucagon-Like Peptide-1 Receptor; Exenatide
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > R Medicine (General)
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 17 Jun 2016 14:08
Last Modified: 18 Aug 2022 11:17
URI: http://repository.essex.ac.uk/id/eprint/16967

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