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PMID: 22437504 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature ·Vol. 485 ·No. 7398 ·2012-03-21 ·Pages 327-32

Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC

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.

MeSH Terms
Binding Sites Crystallography, X-Ray Diterpenes, Clerodane/chemistry,metabolism,pharmacology Guanidines/chemistry Humans Models, Molecular Morphinans/chemistry Mutagenesis, Site-Directed Naltrexone/analogs & derivatives,chemistry,metabolism Piperidines/chemistry,pharmacology Protein Conformation Receptors, Adrenergic, beta-2/chemistry Receptors, CXCR4/chemistry,metabolism Receptors, Opioid, kappa/antagonists & inhibitors,chemistry,genetics,metabolism Structure-Activity Relationship Tetrahydroisoquinolines/chemistry,pharmacology
Chemicals
17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan 22-thiocyanatosalvinorin A 7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide CXCR4 protein, human Diterpenes, Clerodane Guanidines Morphinans Piperidines Receptors, Adrenergic, beta-2 Receptors, CXCR4 Receptors, Opioid, kappa Tetrahydroisoquinolines norbinaltorphimine Naltrexone
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Wu Huixian
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Wacker Daniel
Mileni Mauro
Katritch Vsevolod
Han Gye Won
Vardy Eyal
Liu Wei
Thompson Aaron A
Huang Xi-Ping
Carroll F Ivy
Mascarella S Wayne
Westkaemper Richard B
Mosier Philip D
Roth Bryan L
Cherezov Vadim
Stevens Raymond C
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature10939
Published
2012-03-21
Epub
2012-00-21
Pages
327-32
Language
English
Region
England
NLM ID
0410462
PMCID
PMC3356457
Subset
IM
Grants
NIGMS NIH HHS · Y1-GM-1104 · United States
NIDA NIH HHS · R01 DA027170 · United States
NIGMS NIH HHS · U54 GM094618-02 · United States
NIDA NIH HHS · R01 DA009045 · United States
NIDA NIH HHS · R01 DA017204 · United States
NCI NIH HHS · Y1-CO-1020 · United States
NIGMS NIH HHS · P50 GM073197-08 · United States
NIDA NIH HHS · R01 DA017624 · United States
NIDA NIH HHS · R01 DA009045-17 · United States
NIGMS NIH HHS · P50 GM073197 · United States
NIGMS NIH HHS · U54 GM094618 · United States
Databases
PDB
4DJH
Corrections
CommentIn
PMID: 22596150
External Links
PubMed source DOI: 10.1038/nature10939 PMC Full Text View journal details
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