@article{132822f8a93c491e9f79ac74473a7061,
title = "Structure of the human κ-opioid receptor in complex with JDTic",
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{\AA} 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.",
author = "Huixian Wu and Daniel Wacker and Mauro Mileni and Vsevolod Katritch and Han, {Gye Won} and Eyal Vardy and Wei Liu and Thompson, {Aaron A.} and Huang, {Xi Ping} and Carroll, {F. Ivy} and Mascarella, {S. Wayne} and Westkaemper, {Richard B.} and Mosier, {Philip D.} and Roth, {Bryan L.} and Vadim Cherezov and Stevens, {Raymond C.}",
note = "Funding Information: Acknowledgements This work was supported by PSI:Biology grant U54 GM094618 (V.K., V.C., R.C.S.) for biological studies and structure production, NIH Roadmap grant P50 GM073197 (V.C., R.C.S.) for technology development and R01 DA017624 (B.L.R., E.V., R.B.M., P.D.M.), R01 DA027170 (B.L.R.), the NIMH Psychoactive Drug Screening Program Contract (B.L.R., X.-P.H.), the Michael Hooker Distinguished Chair of Pharmacology (B.L.R.), and the NIH grant R01 DA009045 (F.I.C.). D.W. is supported by a Boehringer Ingelheim Fonds PhD Fellowship. The JDTic X-ray structure was determined by C. George at the Laboratory for the Structure of Matter, Naval Research Laboratory. We thank J. Velasquez for help on molecular biology; T. Trinh, K. Allin and M. Chu for help on baculovirus expression; V. Setola for help with functional activity assays; J. Evans for help acquiring compounds; the National Institute of Drug Abuse Drug Supply Program for supplying JDTic and other opioid ligands used in these studies; K. Kadyshevskaya for assistance with figure preparation; E. Abola for assistance with manuscript preparation; A. Walker for assistance with manuscript preparation; J. Smith, R. Fischetti and N. Sanishvili for assistance in the development and use of the minibeam and beamtime at GM/CA-CAT beamline 23-ID at the Advanced Photon Source, which is supported by National Cancer Institute grant Y1-CO-1020 and National Institute of General Medical Sciences grant Y1-GM-1104.",
year = "2012",
month = may,
day = "17",
doi = "10.1038/nature10939",
language = "English",
volume = "485",
pages = "327--332",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Research",
number = "7398",
}