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Activation Dynamics of the Neurotensin G Protein-Coupled Receptor 1

Title
Activation Dynamics of the Neurotensin G Protein-Coupled Receptor 1
Authors
Cong, XiaojingGolebiowski, JeromeFiorucci, Sebastien
DGIST Authors
Cong, Xiaojing; Golebiowski, Jerome; Fiorucci, Sebastien
Issue Date
2018-08
Citation
Journal of Chemical Theory and Computation, 14(8), 4467-4473
Type
Article
Article Type
Article
Keywords
MU-OPIOID RECEPTORCONFORMATIONAL ENSEMBLEODORANT RECEPTORSFORCE-FIELDAGONISTIDENTIFICATIONMECHANISM
ISSN
1549-9618
Abstract
A replica-exchange protocol remarkably enhances the sampling of the activation dynamics of the neurotensin receptor type 1, a G protein-coupled receptor (GPCR) and important drug target. Our work highlights the dynamic communication between conformational changes of the agonist and the G protein-binding site, via contraction-oscillation of the orthosteric pocket. It also gives insights into the mechanism by which certain mutations diminish or stimulate activation. The replica-exchange protocol effectively enhances barrier crossing where standard brute-force molecular dynamics simulations fail. It is readily applicable to other GPCRs and represents a promising approach for virtual ligand screening, using the typical features of receptor activation as a benchmark. © 2018 American Chemical Society.
URI
http://hdl.handle.net/20.500.11750/9297
DOI
10.1021/acs.jctc.8b00216
Publisher
American Chemical Society
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