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  • 1
    Publication Date: 2012-03-23
    Description: 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 kappa-opioid receptor (kappa-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human kappa-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 A 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 kappa-OR. Modelling of other important kappa-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 kappa-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human kappa-OR.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Huixian -- 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 -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073197-08/GM/NIGMS NIH HHS/ -- R01 DA009045/DA/NIDA NIH HHS/ -- R01 DA009045-17/DA/NIDA NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA017624/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54 GM094618-02/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Mar 21;485(7398):327-32. doi: 10.1038/nature10939.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: 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
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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