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Computational insight into conformational states of glucagon-like peptide-1 receptor (GLP-1R) and its binding mode with GLP-1
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-9035-7086
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2016 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, no 16, 13490-13497 p.Article in journal (Refereed) PublishedText
Abstract [en]

The glucagon-like peptide-1 receptor (GLP-1R) has captivated researchers because of its tremendous therapeutic effects for the treatment of type 2 diabetes mellitus (T2DM). However, since the full-length crystal structure of GLP-1R has not been revealed yet, the molecular binding mode and the activation mechanism remain unclear, which will be the obstacle for the discovery of novel potent GLP-1R agonists. In the present study, we constructed the model of GLP-1R in its full length and explored the binding modes between GLP-1 and GLP-1R by means of a bunch of computational methods including homology modeling, protein-protein docking, and molecular dynamics simulations. Our model is in agreement with previous experiment and the results from our MD simulations that verified the binding modes between GLP-1 and GLP-1R are reasonable. What's more, we found the absence or presence of GLP-1 significantly affected the conformation of extracellular domain (ECD) of GLP-1R. The GLP-1R in the apo form stabilized in a 'closed' state which is unfavorable to the binding of GLP-1, resembling as the GCGR. By contrast, in the GLP-1/GLP-1R complex, GLP-1R maintained an 'open' state.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016. Vol. 6, no 16, 13490-13497 p.
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Chemical Sciences
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URN: urn:nbn:se:kth:diva-183222DOI: 10.1039/c5ra26102cISI: 000369546100088ScopusID: 2-s2.0-84956921127OAI: oai:DiVA.org:kth-183222DiVA: diva2:908869
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QC 20160303

Available from: 2016-03-03 Created: 2016-03-03 Last updated: 2016-03-03Bibliographically approved

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Sun, Xianqiang
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