Structure of the human kappa opioid receptor in complex with JDTic
By Huixian Wu, Daniel Wacker, Mauro Mileni, Vsevolod Katritch, Gye Won Han, E. Vardy, Wei Liu, A. Thompson, Xi-Ping Huang, F. Carroll and 6 more. Nature, 2012
778 citations recorded by the source corpus.
Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and—in the case of κ-opioid receptor (κ-OR)—dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Å resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human κ-OR. Modelling of other important κ-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5′-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure–activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for κ-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human κ-OR.
Subfields: Cellular and Molecular Neuroscience, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/5172220842e1aa55cf0f04232ce3f4efc7201f8b
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Citations in the corpus
- Ligand–receptor interaction platforms and their applications for drug discovery (2012, background): “These include rhodopsin [124], b2-adrenergic receptor [125], b1-adrenergic receptor [126], adenosine A2A receptor [127], CXCR4 chemokine receptor [128], dopamine D3 receptor [129], histamine H1 receptor [130], sphingosine 1-phosphate S1P1 receptor [131], muscarinic M3 acetylcholine receptor [132], m”
- Regulation of µ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance (2013, background): “X-ray crystal structures of the MOR, DOR, and KOR have been recently reported (Granier et al., 2012; Manglik et al., 2012; Wu et al., 2012), as was a structure of the orphanin FQ receptor (Thompson et al.”
- Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors (2013, neutral): “This includes the following G-protein coupled receptors: rhodopsin [14], b1-adrenergic [15], b2-adrenergic [16], A2A adenosine [17], CXCR4 chemokine [18], dopamine D3 [19], histamine H1 [20], S1P1 sphingosine 1-phosphate [21], M2 muscarinc acetylcholine [22], M3 muscarinic acetylecholine [23], mu-op”
- Loss of constitutive activity is correlated with increased thermostability of the human adenosine A2A receptor (2013, background): “…fusion proteins, where a T4 lysozyme replaces the conformationally dynamic third intracellular loop (ICL3), for example (Cherezov et al., 2007; Jaakola et al., 2008; Chien et al., 2010; Wu et al., 2010; 2012; Shimamura et al., 2011; Xu et al., 2011; Granier et al., 2012; Thompson et al., 2012).”
- A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior (2015, methodology): “Therefore, we employed a rational approach to designing the KOR DREADD based on our recent crystallographic, mutagenesis, and molecular modeling studies of hKOR (Vardy et al., 2013; Wu et al., 2012).”