4DJH : Structure of the human kappa opioid receptor in complex with JDTic

  • Raymond C. Stevens (Contributor)
  • Philip D. Mosier (Contributor)
  • Bryan L. Roth (Contributor)
  • Eyal Vardy (Contributor)
  • Aaron A. Thompson (Contributor)
  • Wei Liu (Scripps Research Institute) (Contributor)
  • Vsevolod Katritch (Contributor)
  • Huixian Wu (Contributor)
  • Xi Ping Huang (Contributor)
  • Vadim Cherezov (Contributor)
  • Gye Won Han (Contributor)
  • S. Wayne Mascarella (Contributor)
  • F. Ivy Carroll (Contributor)
  • Xi Ping Huang (Contributor)
  • F. Ivy Carroll (Contributor)
  • Daniel Wacker (Contributor)
  • Mauro Mileni (Contributor)
  • Richard B. Westkaemper (Contributor)



Experimental Technique/Method:X-RAY DIFFRACTION
Classification:Hormone receptor/antagonist
Release Date:2012-03-21
Deposition Date:2012-02-01
Revision Date:2012-05-30#2012-08-08#2017-07-26
Molecular Weight:110629.66
Macromolecule Type:Protein
Residue Count:960
Atom Site Count:7064

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.
Date made available2012

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