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.

Conformational Heterogeneity of Intracellular Loop 3 of the μ-opioid G-protein Coupled Receptor

“…Thus, extending the dimeric simulations to the 5 μs time range and carrying out additional 1 μs monomeric simulations from inactive conformations did not yield insights into larger conformational changes in the receptor leading to the active conformation, consistent with the previously reported simulation studies of the μ OR. 22, 23 However, the results are consistent with the previously observed trend for agonists to have much higher probabilities to sample shorter D147 sidechain to basic N distances than antagonists. As shown in Fig.…”

“…A further study by Yuan et al involving 3 μs simulations of μ-OR and κ-OR bound with the agonist morphine and antagonist levallorphan confirmed the disruption of water pathway by specific interactions between the antagonist and the ORs. 23 Shang and coworkers performed up to 1 μs MD simulations of several μ-OR, κ-OR and δ-OR systems, with the analysis also focused on the binding and allostery of sodium ions. 24 Fossepre et al reported a 0.5 μs MD trajectory of apo μ-OR, and analyzed the flexibility, bendability and coupling between its TM helices.…”

NMR structure and dynamics of the agonist dynorphin peptide bound to the human kappa opioid receptor

“…The width of the cone indicates the flexibility of G2 (orange), R6 (green), and L12 (red) dynorphin residues in a KOR-bound state. increased penetration of water into the receptor cavity, which has been linked to the activation mechanism upon agonist binding (49). Mutations of the sodium site in DOR shift nalfurafine, an antagonist, to an arrestin-biased ligand, establishing this sodium site as a key mediator of receptor function (43).…”

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT1A Receptor

“…The existence of such hydrophobic layers of amino acids agrees with the disruption of water-mediated hydrogen-bond networks observed in GPCR crystal structures [22,23] and in MD simulations. [6, 7, 21, 24] …”