3jsx | pdb_00003jsx

X-ray Crystal structure of NAD(P)H: Quinone Oxidoreductase-1 (NQO1) bound to the coumarin-based inhibitor AS1

spinqualitylabelsall models 3jsx, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3jsx is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.45Å Ligands: CC2, FAD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NQO1_HUMAN The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed The synthesis is reported here of two novel series of inhibitors of human NAD(P)H quinone oxidoreductase-1 (NQO1), an enzyme overexpressed in several types of tumor cell. The first series comprises substituted symmetric dicoumarol analogues; the second series contains hybrid compounds where one 4-hydroxycoumarin system is replaced by a different aromatic moiety. Several compounds show equivalent or improved NQO1 inhibition over dicoumarol, both in the presence and in the absence of added protein. Further, correlation is demonstrated between the ability of these agents to inhibit NQO1 and computed binding affinity. We have solved the crystal structure of NQO1 complexed to a hybrid compound and find good agreement with the in silico model. For both MIA PaCa-2 pancreatic tumor cells and HCT116 colon cancer cells, dicoumarol shows the greatest toxicity of all compounds. Thus, we provide a computational, synthetic, and biological platform to generate competitive NQO1 inhibitors with superior pharmacological properties to dicoumarol. This will allow a more definitive study of NQO1 activity in cells, in particular, its drug activating/detoxifying properties and ability to modulate oncoprotein stability. Synthesis and biological evaluation of coumarin-based inhibitors of NAD(P)H: quinone oxidoreductase-1 (NQO1).,Nolan KA, Doncaster JR, Dunstan MS, Scott KA, Frenkel AD, Siegel D, Ross D, Barnes J, Levy C, Leys D, Whitehead RC, Stratford IJ, Bryce RA J Med Chem. 2009 Nov 26;52(22):7142-56. PMID:19877692 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Quinone reductase 3D structures

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