title: The mechanism of ligand-induced activation or inhibition of μ- and κ-opioid receptors.
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.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL), Institute of Chemical Sciences and Engineering, Lausanne (Switzerland). shuguang.yuan@gmail.com.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland (USA).
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.affiliation: Department of Chemistry, University of Oxford (UK).
authors.forename: Qian
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Bioinformatics Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw (Poland).
authors.forename: Michal
authors.initials: M
authors.lastname: Kolinski
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL), Institute of Chemical Sciences and Engineering, Lausanne (Switzerland). horst.vogel@epfl.ch.
authors.forename: Horst
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Laboratory of Biomodeling, Faculty of Chemistry & Biological and Chemical Research Centre, University of Warsaw, Warsaw (Poland). sfilipek@chem.uw.edu.pl.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Filipek
mesh_terms: D008024:Ligands; D011485:Protein Binding; D011487:Protein Conformation; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu
keywords: GPCRs; molecular dynamics; protein models; receptors; signal transduction