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Molecular dynamics of ligand binding and concurrent activation steps in opioid receptors

Michał Koliński 1,2Sławomir Filipek 1

1. Laboratory of Biomodelling, International Institute of Molecular and Cell Biology (IIMCB), Ks. Trojdena 4, Lublin 02-109, Poland
2. Laboratory of Drug-Receptor Interaction, Medical University, Lublin 20-950, Poland

Abstract

Opioid receptors belong to large and diverse family of transmembrane receptor proteins called GPCRs (G Protein Coupled Receptors) which are responsible for transduction of a signal across the plasma membrane. Activated receptor goes through series of conformational changes that enable binding of a G protein in a cytosol. Drugs that interact with opioid receptors cause multiple effects including analgesia, sedation, euphoria and physical dependence. Therefore, the three opioid receptor subtypes: mu (MOR), delta (DOR) and kappa (KOR) are very important pharmacological targets. Discovery of new more potent and selective ligands for each of these three receptor subtypes should suppress the unwanted side effects. Drug design is mostly limited by the scarcity of structural information on receptor proteins. Up to date, structures of only four members of GPCR family have been reported: rhodopsin, β1-, β2-adrenergic receptor and adenosine receptor.

Agonist binding is the first step in ligand-induced receptor activation. During activation receptor undergoes a series of conformational rearrangements controlled by molecular switches leading to partially or fully active state of the receptor [1]. To investigate the relationship between the final movements of a ligand in a binding site and the first steps of the activation process in opioid receptors we chose a set of rigid ligands with the structural motif of tyramine (analogs of morphine). The structures of three opioid receptors were built using homology/comparative modeling techniques based on crystallographic structure of inactive rhodopsin. Additionally, N-termini and extracellular loops of KOR were built using the ab initio CABS method. Series of agonists and antagonists were docked to the receptor models using simulated annealing procedure and the complexes were simulated in water and lipid environment using GROMACS program. Based on conducted molecular dynamics simulations and on available mutagenesis data we proposed different binding modes for agonists and antagonists. They all initially bind to Y3.33 but only agonists are able to move deeper to H6.52. The movement from Y3.33 to H6.52 induces breaking of the connection between TM3 and TM7 (3-7 lock). Breaking of TM3-TM7 connection was suggested to be the first activation step in rhodopsin [2]. We also observed an action of the extended rotamer toggle switch which can suggest interdependence between those two switches [3].


1.  Nygaard, R., et al., Ligand binding and micro-switches in 7TM receptor structures. Trends Pharmacol Sci, 2009. 30(5): p. 249-59.
2.  Kim, J.M., et al., Structural origins of constitutive activation in rhodopsin: Role of the K296/E113 salt bridge. Proc Natl Acad Sci U S A, 2004. 101(34): p. 12508-13.
3.  Kolinski, M. and S. Filipek., Study of a structurally similar kappa opioid receptor agonist and antagonist pair by molecular dynamics simulations. J Mol Model, 2010 (in press).

 

 

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Related papers

Presentation: Poster at VII Multidyscyplinarna Konferencja Nauki o Leku, by Michał Koliński
See On-line Journal of VII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2010-03-12 14:48
Revised:   2010-03-12 15:12