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

Huixian Wu, Daniel Wacker, Mauro Mileni, Vsevolod Katritch, Gye Won Han, Eyal Vardy, Wei Liu, Aaron A. Thompson, Xi Ping Huang, F. Ivy Carroll, S. Wayne Mascarella, Richard B. Westkaemper, Philip D. Mosier, Bryan L. Roth, Vadim Cherezov, Raymond C. Stevens

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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 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 2.9Å 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 5-2-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.

Original languageEnglish (US)
Pages (from-to)327-332
Number of pages6
JournalNature
Volume485
Issue number7398
DOIs
StatePublished - May 17 2012

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    Wu, H., Wacker, D., Mileni, M., Katritch, V., Han, G. W., Vardy, E., Liu, W., Thompson, A. A., Huang, X. P., Carroll, F. I., Mascarella, S. W., Westkaemper, R. B., Mosier, P. D., Roth, B. L., Cherezov, V., & Stevens, R. C. (2012). Structure of the human κ-opioid receptor in complex with JDTic. Nature, 485(7398), 327-332. https://doi.org/10.1038/nature10939