Gómez Santiago, C, Paci, E orcid.org/0000-0002-4891-2768 and Donnelly, D orcid.org/0000-0001-6048-6995 (2018) A mechanism for agonist activation of the glucagon-like peptide-1 (GLP-1) receptor through modelling & molecular dynamics. Biochemical and Biophysical Research Communications, 498 (2). pp. 359-365. ISSN 0006-291X
Abstract
The receptor for glucagon-like peptide 1 (GLP-1R) is a validated drug target for the treatment of type 2 diabetes and obesity. Recently the first three structures of GLP-1R were published – an X-ray structure of the apo transmembrane domain in the inactive conformation; an X-ray structure of the full-length receptor bound to a truncated peptide agonist; and a cryo-EM structure of the full-length receptor bound with GLP-1 and coupled to the G protein Gs. Since the inactive structure was incomplete, and the two active-state structures shared significant differences, we utilised all available knowledge to build hybrid models of the full length active and inactive state receptors. The two models were simulated using molecular dynamics and the output trajectories analysed and compared to reveal insights into the mechanism for agonist-mediated receptor activation. His-7, Glu-9 and Asp-15 of GLP-1 act together to destabilise transmembrane helix 6 and extracellular loop 3 in order to generate an active conformation of GLP-1R.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Copyright (c) 2018 Elsevier Ltd. All rights reserved. This is an author produced version of a paper published in Biochemical and Biophysical Research Communications. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | GLP-1; GPCR; Incretin; Diabetes; Molecular dynamics; Model |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 19 Jan 2018 16:37 |
Last Modified: | 12 Feb 2019 01:38 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.bbrc.2018.01.110 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:126395 |