1gg5: Difference between revisions
New page: left|200px<br /> <applet load="1gg5" size="450" color="white" frame="true" align="right" spinBox="true" caption="1gg5, resolution 2.50Å" /> '''CRYSTAL STRUCTURE O... |
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[[Image:1gg5.gif|left|200px]]<br /> | [[Image:1gg5.gif|left|200px]]<br /><applet load="1gg5" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1gg5, resolution 2.50Å" /> | caption="1gg5, resolution 2.50Å" /> | ||
'''CRYSTAL STRUCTURE OF A COMPLEX OF HUMAN NAD[P]H-QUINONE OXIDOREDUCTASE AND A CHEMOTHERAPEUTIC DRUG (E09) AT 2.5 A RESOLUTION'''<br /> | '''CRYSTAL STRUCTURE OF A COMPLEX OF HUMAN NAD[P]H-QUINONE OXIDOREDUCTASE AND A CHEMOTHERAPEUTIC DRUG (E09) AT 2.5 A RESOLUTION'''<br /> | ||
==Overview== | ==Overview== | ||
BACKGROUND: NAD(P)H:quinone acceptor oxidoreductase (QR1) protects animal | 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. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1GG5 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 E09 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http:// | 1GG5 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 <scene name='pdbligand=FAD:'>FAD</scene> and <scene name='pdbligand=E09:'>E09</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GG5 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: NAD(P)H dehydrogenase (quinone)]] | [[Category: NAD(P)H dehydrogenase (quinone)]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Amzel, L | [[Category: Amzel, L M.]] | ||
[[Category: Bianchet, M | [[Category: Bianchet, M A.]] | ||
[[Category: Faig, M.]] | [[Category: Faig, M.]] | ||
[[Category: Hargreaves, R.]] | [[Category: Hargreaves, R.]] | ||
[[Category: Hudnott, A | [[Category: Hudnott, A R.]] | ||
[[Category: Moody, C | [[Category: Moody, C J.]] | ||
[[Category: Ross, D.]] | [[Category: Ross, D.]] | ||
[[Category: Winski, S.]] | [[Category: Winski, S.]] | ||
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[[Category: rossman fold]] | [[Category: rossman fold]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:49:43 2008'' | ||
Revision as of 13:49, 21 February 2008
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CRYSTAL STRUCTURE OF A COMPLEX OF HUMAN NAD[P]H-QUINONE OXIDOREDUCTASE AND A CHEMOTHERAPEUTIC DRUG (E09) AT 2.5 A 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.
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
1GG5 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as NAD(P)H dehydrogenase (quinone), with EC number 1.6.5.2 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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