• Journal Article

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

Citation

Wu, H. X., Wacker, D., Mileni, M., Katritch, V., Han, G. W., Vardy, E., ... Stevens, R. C. (2012). Structure of the human kappa-opioid receptor in complex with JDTic. Nature, 485(7398), 327-332. DOI: 10.1038/nature10939

Abstract

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