The Mechanism of Ligand-Induced Activation or Inhibition of μ- and κ-Opioid Receptors

• Published in: Angewandte Chemie International Edition 2015-06, Vol.54 (26), p.7560-7563
• Main Authors: Yuan, Shuguang, Palczewski, Krzysztof, Peng, Qian, Kolinski, Michal, Vogel, Horst, Filipek, Slawomir
• Format: Article
• Language: English
• Subjects: GPCRs; Ligands; molecular dynamics; Protein Binding; Protein Conformation; protein models; receptors; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - metabolism; Signal Transduction
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201501742

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. One rule to link them all: The same ligand can act as an agonist for the κ‐opioid receptor (κOR) and as an antagonist for the μ‐opioid receptor (μOR). Long‐time‐scale MD simulations reveal that antagonist binding diminishes the solvent‐accessible surface area (SASA) of the binding pocket, which consequently blocks the entrance of water into the receptor, whereas agonist binding leads to comparatively larger SASA values.