1h66: Difference between revisions

Revision as of 18:29, 2 May 2008

CRYSTAL STRUCTURE OF HUMAN NAD[P]H-QUINONE OXIDOREDUCTASE CO WITH 2,5-DIAZIRIDINYL-3-HYDROXYL-6-METHYL-1,4-BENZOQUINONE

OverviewOverview

BACKGROUND: NAD(P)H:quinone acceptor oxidoreductase (QR1) protects animal cells from the deleterious and carcinogenic effects of quinones and other electrophiles. Remarkably, the same enzyme activates cancer prodrugs that become cytotoxic only after two-electron reduction. QR1's ability to bioactivate quinones and its elevated expression in many human solid tumors makes this protein an excellent target for enzyme-directed drug development. Until now, structural analysis of the mode of binding of chemotherapeutic compounds to QR1 was based on model building using the structures of complexes with simple substrates; no structure of complexes of QR1 with chemotherapeutic prodrugs had been reported. RESULTS: Here we report the high-resolution crystal structures of complexes of QR1 with three chemotherapeutic prodrugs: RH1, a water-soluble homolog of dimethylaziridinylbenzoquinone; EO9, an aziridinylindolequinone; and ARH019, another aziridinylindolequinone. The structures, determined to resolutions of 2.0 A, 2.5 A, and 1.86 A, respectively, were refined to R values below 21% with excellent geometry. CONCLUSIONS: The structures show that compounds can bind to QR1 in more than one orientation. Surprisingly, the two aziridinylindolequinones bind to the enzyme in different orientations. The results presented here reveal two new factors that must be taken into account in the design of prodrugs targeted for activation by QR1: the enzyme binding site is highly plastic and changes to accommodate binding of different substrates, and homologous drugs with different substituents may bind to QR1 in different orientations. These structural insights provide important clues for the optimization of chemotherapeutic compounds that utilize this reductive bioactivation pathway.

About this StructureAbout this Structure

1H66 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones., Faig M, Bianchet MA, Winski S, Hargreaves R, Moody CJ, Hudnott AR, Ross D, Amzel LM, Structure. 2001 Aug;9(8):659-67. PMID:11587640 Page seeded by OCA on Fri May 2 18:29:02 2008

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OCA

@@ Line 1: / Line 1: @@
 [[Image:1h66.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 1h66 |SIZE=350|CAPTION= <scene name='initialview01'>1h66</scene>, resolution 2.00&Aring;
+The line below this paragraph, containing "STRUCTURE_1h66", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=AC1:Rh1+Binding+Site+For+Chain+A'>AC1</scene>, <scene name='pdbsite=AC2:Rh1+Binding+Site+For+Chain+D'>AC2</scene>, <scene name='pdbsite=AC3:Rh1+Binding+Site+For+Chain+C'>AC3</scene>, <scene name='pdbsite=AC4:Rh1+Binding+Site+For+Chain+B'>AC4</scene>, <scene name='pdbsite=AC5:Fad+Binding+Site+For+Chain+A'>AC5</scene>, <scene name='pdbsite=AC6:Fad+Binding+Site+For+Chain+B'>AC6</scene>, <scene name='pdbsite=AC7:Fad+Binding+Site+For+Chain+C'>AC7</scene> and <scene name='pdbsite=AC8:Fad+Binding+Site+For+Chain+D'>AC8</scene>
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=RH1:2,5-DIAZIRIDIN-1-YL-3-(HYDROXYMETHYL)-6-METHYLCYCLOHEXA-2,5-DIENE-1,4-DIONE'>RH1</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <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>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_1h66|  PDB=1h66  |  SCENE=  }}
-|RELATEDENTRY=
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1h66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h66 OCA], [http://www.ebi.ac.uk/pdbsum/1h66 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1h66 RCSB]</span>
-}}
 '''CRYSTAL STRUCTURE OF HUMAN NAD[P]H-QUINONE OXIDOREDUCTASE CO WITH 2,5-DIAZIRIDINYL-3-HYDROXYL-6-METHYL-1,4-BENZOQUINONE'''
@@ Line 24: / Line 21: @@
 Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones., Faig M, Bianchet MA, Winski S, Hargreaves R, Moody CJ, Hudnott AR, Ross D, Amzel LM, Structure. 2001 Aug;9(8):659-67. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11587640 11587640]
 [[Category: Homo sapiens]]
-[[Category: NAD(P)H dehydrogenase (quinone)]]
 [[Category: Single protein]]
 [[Category: Amzel, L M.]]
@@ Line 31: / Line 27: @@
 [[Category: Ross, D.]]
 [[Category: Winski, S.]]
-[[Category: flavoprotein]]
+[[Category: Flavoprotein]]
-[[Category: oxidoreductase]]
+[[Category: Oxidoreductase]]
-[[Category: rossman fold]]
+[[Category: Rossman fold]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May  2 18:29:02 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 20:58:32 2008''