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G-protein-coupled receptor dynamics: Dimerization and activation models compared with experiment

Taddese, B and Simpson, LM and Wall, ID and Blaney, FE and Kidley, NJ and Clark, HSX and Smith, RE and Upton, GJG and Gouldson, PR and Psaroudakis, G and Bywater, RP and Reynolds, CA (2012) 'G-protein-coupled receptor dynamics: Dimerization and activation models compared with experiment.' Biochemical Society Transactions, 40 (2). 394 - 399. ISSN 0300-5127

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Abstract

Our previously derived models of the active state of the β 2-adrenergic receptor are compared with recently published X-ray crystallographic structures of activated GPCRs (G-protein-coupled receptors). Thesemolecular dynamics-based models using experimental data derived from biophysical experiments on activation were used to restrain the receptor to an active state that gave high enrichment for agonists in virtual screening. The β 2-adrenergic receptor active model and X-ray structures are in good agreement over both the transmembrane region and the orthosteric binding site, although in some regions the active model is more similar to the active rhodopsin X-ray structures. The general features of the microswitches were well reproduced, but with minor differences, partly because of the unexpected X-ray results for the rotamer toggle switch. In addition, most of the interacting residues between the receptor and the G-protein were identified. This analysis of the modelling has also given important additional insight into GPCR dimerization: re-analysis of results on photoaffinity analogues of rhodopsin provided additional evidence that TM4 (transmembrane helix 4) resides at the dimer interface and that ligands such as bivalent ligands may pass between the mobile helices. A comparison, and discussion, is also carried out between the use of implicit and explicit solvent for active-state modelling. ©The Authors Journal compilation ©2012 Biochemical Society.

Item Type: Article
Subjects: Q Science > Q Science (General)
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Christopher Reynolds
Date Deposited: 02 Feb 2013 16:41
Last Modified: 16 Sep 2019 18:15
URI: http://repository.essex.ac.uk/id/eprint/5415

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