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 and Raymond C. Stevens ()
Additional contact information
Huixian Wu: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Daniel Wacker: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Mauro Mileni: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Vsevolod Katritch: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Gye Won Han: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Eyal Vardy: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27599, USA
Wei Liu: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Aaron A. Thompson: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Xi-Ping Huang: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27599, USA
F. Ivy Carroll: Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, USA
S. Wayne Mascarella: Center for Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, USA
Richard B. Westkaemper: Virginia Commonwealth University, 800 E. Leigh Street, Richmond, Virginia 23298, USA
Philip D. Mosier: Virginia Commonwealth University, 800 E. Leigh Street, Richmond, Virginia 23298, USA
Bryan L. Roth: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27599, USA
Vadim Cherezov: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Raymond C. Stevens: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

Nature, 2012, vol. 485, issue 7398, 327-332

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature10939

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