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Angew Chem Int Ed Engl. 2015 Jun 22;54(26):7560-3. doi: 10.1002/anie.201501742. Epub 2015 May 12.

The mechanism of ligand-induced activation or inhibition of μ- and κ-opioid receptors.

Author information

1
Ecole Polytechnique Fédérale de Lausanne (EPFL), Institute of Chemical Sciences and Engineering, Lausanne (Switzerland). shuguang.yuan@gmail.com.
2
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland (USA).
3
Department of Chemistry, University of Oxford (UK).
4
Bioinformatics Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw (Poland).
5
Ecole Polytechnique Fédérale de Lausanne (EPFL), Institute of Chemical Sciences and Engineering, Lausanne (Switzerland). horst.vogel@epfl.ch.
6
Laboratory of Biomodeling, Faculty of Chemistry & Biological and Chemical Research Centre, University of Warsaw, Warsaw (Poland). sfilipek@chem.uw.edu.pl.

Abstract

G-protein-coupled receptors (GPCRs) are important targets for treating severe diseases. However why certain molecules act as activators whereas others, with similar structures, block GPCR activation, is poorly understood since the same molecule can activate one receptor subtype while blocking another closely related receptor. To shed light on these central questions, we used all-atom, long-time-scale molecular dynamics simulations on the κ-opioid and μ-opioid receptors (κOR and μOR). We found that water molecules penetrating into the receptor interior mediate the activating versus blocking effects of a particular ligand-receptor interaction. Both the size and the flexibility of the bound ligand regulated water influx into the receptor. The solvent-accessible inner surface area was found to be a parameter that can help predict the function of the bound ligand.

KEYWORDS:

GPCRs; molecular dynamics; protein models; receptors; signal transduction

PMID:
25968837
DOI:
10.1002/anie.201501742
[Indexed for MEDLINE]

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