1h69: Difference between revisions
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==Overview== | ==Overview== | ||
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 ... | 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 Structure== | ==About this Structure== | ||
1H69 is a | 1H69 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with FAD and ARH as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_1.6.5.2 Transferred entry: 1.6.5.2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.6.99.2 1.6.99.2] Structure known Active Sites: AC1, AC2, AC3, AC4, AC5, AC6, AC7 and AC8. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1H69 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: rossman fold]] | [[Category: rossman fold]] | ||
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Revision as of 14:13, 5 November 2007
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CRYSTAL STRUCTURE OF HUMAN NAD[P]H-QUINONE OXIDOREDUCTASE CO WITH 2,3,5,6,TETRAMETHYL-P-BENZOQUINONE (DUROQUINONE) AT 2.5 ANGSTROM RESOLUTION
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
1H69 is a Single protein structure of sequence from Homo sapiens with FAD and ARH 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
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