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 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.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Huixian
authors.initials: H
authors.lastname: Wu
authors.forename: Daniel
authors.initials: D
authors.lastname: Wacker
authors.forename: Mauro
authors.initials: M
authors.lastname: Mileni
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.forename: Eyal
authors.initials: E
authors.lastname: Vardy
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Thompson
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.forename: S Wayne
authors.initials: SW
authors.lastname: Mascarella
authors.forename: Richard B
authors.initials: RB
authors.lastname: Westkaemper
authors.forename: Philip D
authors.initials: PD
authors.lastname: Mosier
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D045785:Diterpenes, Clerodane / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006146:Guanidines / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D009019:Morphinans / Q000737:chemistry; D016297:Mutagenesis, Site-Directed; D009271:Naltrexone / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C411465:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan; C573301:22-thiocyanatosalvinorin A; C433814:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide; C527276:CXCR4 protein, human; D045785:Diterpenes, Clerodane; D006146:Guanidines; D009019:Morphinans; D010880:Piperidines; D018343:Receptors, Adrenergic, beta-2; D019718:Receptors, CXCR4; D017473:Receptors, Opioid, kappa; D044005:Tetrahydroisoquinolines; C051844:norbinaltorphimine; D009271:Naltrexone