1h66
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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.
DiseaseDisease
Known diseases associated with this structure: Benzene toxicity, susceptibility to OMIM:[125860], Leukemia, post-chemotherapy, susceptibility to OMIM:[125860]
About this StructureAbout this Structure
1H66 is a Single protein structure of sequence from Homo sapiens with RH1 and FAD as ligands. Active as Transferred entry: 1.6.5.2, with EC number 1.6.99.2 Structure known Active Sites: AC1, AC2, AC3, AC4, AC5, AC6, AC7 and AC8. 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 Mon Nov 12 17:13:08 2007