Research Repository

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

Wootten, D and Reynolds, CA and Smith, KJ and Mobarec, JC and Koole, C and Savage, EE and Pabreja, K and Simms, J and Sridhar, R and Furness, SGB and Liu, M and Thompson, PE and Miller, LJ and Christopoulos, A and Sexton, PM (2016) 'The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.' Cell, 165 (7). 1632 - 1643. ISSN 0092-8674

[img]
Preview
Text
1-s2.0-S0092867416305712-main.pdf - Published Version
Available under License Creative Commons Attribution.

Download (3MB) | Preview
[img]
Preview
Text (Extended PDF (39 pages))
mmc5.pdf - Published Version
Available under License Creative Commons Attribution.

Download (9MB) | Preview
[img] Slideshow (Figures)
10.1016-j.cell.2016.05.023Figure.ppt - Supplemental Material

Download (15MB)
[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)
mmc3.mp4 - Supplemental Material

Download (10MB)
[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.)
mmc4.mp4 - Supplemental Material

Download (10MB)

Abstract

© 2016 The Authors. 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
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > R Medicine (General)
Divisions: Faculty of Science and Health > Biological Sciences, School of
Depositing User: Jim Jamieson
Date Deposited: 17 Jun 2016 14:08
Last Modified: 30 Jan 2019 16:20
URI: http://repository.essex.ac.uk/id/eprint/16967

Actions (login required)

View Item View Item