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Structure of the human κ-opioid receptor in complex with JDTic. Nature 2012 Mar 21;485(7398):327-32

Date

03/23/2012

Pubmed ID

22437504

Pubmed Central ID

PMC3356457

DOI

10.1038/nature10939

Scopus ID

2-s2.0-84862777742 (requires institutional sign-in at Scopus site)   742 Citations

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.

Author List

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

Authors

Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Philip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Binding Sites
Crystallography, X-Ray
Diterpenes, Clerodane
Guanidines
Humans
Models, Molecular
Morphinans
Mutagenesis, Site-Directed
Naltrexone
Piperidines
Protein Conformation
Receptors, Adrenergic, beta-2
Receptors, CXCR4
Receptors, Opioid, kappa
Structure-Activity Relationship
Tetrahydroisoquinolines