View source for 3jsx


==X-ray Crystal structure of NAD(P)H: Quinone Oxidoreductase-1 (NQO1) bound to the coumarin-based inhibitor AS1==
<StructureSection load='3jsx' size='340' side='right' caption='[[3jsx]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3jsx]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3JSX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3JSX FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CC2:4-HYDROXY-6,7-DIMETHYL-3-(NAPHTHALEN-1-YLMETHYL)-2H-CHROMEN-2-ONE'>CC2</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DIA4, NMOR1, NQO1, NQO1 cDNA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/NAD(P)H_dehydrogenase_(quinone) NAD(P)H dehydrogenase (quinone)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.6.5.2 1.6.5.2] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3jsx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jsx OCA], [http://pdbe.org/3jsx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3jsx RCSB], [http://www.ebi.ac.uk/pdbsum/3jsx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3jsx ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/NQO1_HUMAN 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 ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/js/3jsx_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3jsx ConSurf].
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== 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<ref>PMID:19877692</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Quinone reductase|Quinone reductase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Dunstan, M S]]
[[Category: Levy, C]]
[[Category: Leys, D]]
[[Category: Coumarin-based inhibitor]]
[[Category: Fad]]
[[Category: Flavoprotein]]
[[Category: Nad]]
[[Category: Nadp]]
[[Category: Nq01]]
[[Category: Oxidoreductase]]