• Article

Structure of the human kappa-opioid receptor in complex with JDTic

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 kappa-opioid receptor (kappa-OR)-dysphoria and psychotomimesis. Here we report the crystal structure of the human kappa-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 angstrom 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 kappa-OR. Modelling of other important kappa-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 kappa-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human kappa-OR


Wu, HX., Wacker, D., Mileni, M., Katritch, V., Han, GW., Vardy, E., ... Stevens, RC. (2012). Structure of the human kappa-opioid receptor in complex with JDTic. Nature, 485(7398), 327-332. https://doi.org/10.1038/nature10939

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