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

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  • Wu, Huixian
    • Other Affiliation: Department of Molecular Biology, The Scripps Research Institute
  • Wacker, Daniel
    • Other Affiliation: Department of Molecular Biology, The Scripps Research Institute
  • Mileni, Mauro
    • Other Affiliation: Department of Molecular Biology, The Scripps Research Institute
  • Katritch, Vsevolod
    • Other Affiliation: Department of Molecular Biology, The Scripps Research Institute
  • Han, Gye Won
    • Other Affiliation: Department of Molecular Biology, The Scripps Research Institute
  • Vardy, Eyal
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
    • Other Affiliation: National Institute of Mental Health Psychoactive Drug Screening Program
  • Liu, Wei
    • Other Affiliation: Department of Molecular Biology, The Scripps Research Institute
  • Thompson, Aaron A.
    • Other Affiliation: Department of Molecular Biology, The Scripps Research Institute
  • Huang, Xi-Ping
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
    • Other Affiliation: National Institute of Mental Health Psychoactive Drug Screening Program
  • Carroll, F. Ivy
    • Other Affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute
  • Mascarella, S. Wayne
    • Other Affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute
  • Westkaemper, Richard B.
    • Other Affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University
  • Mosier, Philip D.
    • Other Affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University
  • Roth, Bryan
    • ORCID: https://orcid.org/0000-0002-0561-6537
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
    • Other Affiliation: National Institute of Mental Health Psychoactive Drug Screening Program
  • Cherezov, Vadim
    • Other Affiliation: Department of Molecular Biology, The Scripps Research Institute
  • Stevens, Raymond C.
    • Other Affiliation: Department of Molecular Biology, The Scripps Research Institute
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 2.9 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.
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  • Article
Rights statement
  • In Copyright
Journal title
  • Nature
Journal volume
  • 485
Journal issue
  • 7398
Page start
  • 327
Page end
  • 332
Language
  • English
Version
  • Postprint
ISSN
  • 1476-4687

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