4DJH

Structure of the human kappa opioid receptor in complex with JDTic

Summary for 4DJH

• Entry DOI: 10.2210/pdb4djh/pdb
• Descriptor: Kappa-type opioid receptor, Lysozyme, (3R)-7-hydroxy-N-{(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, CITRIC ACID, ... (6 entities in total)
• Functional Keywords: jdtic, gpcr newtork, psi-biology, kor, hkor, kop, structural genomics, protein structure initiative, gpcr network, g-protein coupled receptor, gpcr, 7tm, kappa opioid receptor, dynorphin, membrane protein, transmembrane, hormone receptor, hydrolase, hormone receptor-antagonist complex, hormone receptor/antagonist
• Biological source: Homo Sapiens (human, Bacteriophage T4); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : P41145
• Total number of polymer chains: 2
• Total formula weight: 110629.66

Authors

Wu, H.,Wacker, D.,Katritch, V.,Mileni, M.,Han, G.W.,Vardy, E.,Liu, W.,Thompson, A.A.,Huang, X.P.,Carroll, F.I.,Mascarella, S.W.,Westkaemper, R.B.,Mosier, P.D.,Roth, B.L.,Cherezov, V.,Stevens, R.C.,GPCR Network (GPCR) (deposition date: 2012-02-01, release date: 2012-03-21, Last modification date: 2023-09-13)

Primary citation

Wu, H.,Wacker, D.,Mileni, M.,Katritch, V.,Han, G.W.,Vardy, E.,Liu, W.,Thompson, A.A.,Huang, X.P.,Carroll, F.I.,Mascarella, S.W.,Westkaemper, R.B.,Mosier, P.D.,Roth, B.L.,Cherezov, V.,Stevens, R.C.
tructure of the human kappa-opioid receptor in complex with JDTic
Nature, 485:327-332, 2012

PubMed 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.

PubMed: 22437504
DOI: 10.1038/nature10939

Experimental method

X-RAY DIFFRACTION (2.9 Å)