1gg5

From Proteopedia

(Difference between revisions)

Current revision

CRYSTAL STRUCTURE OF A COMPLEX OF HUMAN NAD[P]H-QUINONE OXIDOREDUCTASE AND A CHEMOTHERAPEUTIC DRUG (E09) AT 2.5 A RESOLUTION

Structural highlights

1gg5 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Faig M, Bianchet MA, Winski S, Hargreaves R, Moody CJ, Hudnott AR, Ross D, Amzel LM. Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones. Structure. 2001 Aug;9(8):659-67. PMID:11587640

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1gg5"

@@ Line 3: / Line 3: @@
 <StructureSection load='1gg5' size='340' side='right'caption='[[1gg5]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1gg5]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GG5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GG5 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1gg5]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GG5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GG5 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E09:3-HYDROXYMETHYL-5-AZIRIDINYL-1METHYL-2-[1H-INDOLE-4,7-DIONE]-PROPANOL'>E09</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/NAD(P)H_dehydrogenase_(quinone) NAD(P)H dehydrogenase (quinone)], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.6.5.2 1.6.5.2] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E09:3-HYDROXYMETHYL-5-AZIRIDINYL-1METHYL-2-[1H-INDOLE-4,7-DIONE]-PROPANOL'>E09</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1gg5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gg5 OCA], [https://pdbe.org/1gg5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gg5 RCSB], [https://www.ebi.ac.uk/pdbsum/1gg5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gg5 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://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.
+[https://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]]
@@ Line 31: / Line 31: @@
 ==See Also==
-*[[Quinone reductase|Quinone reductase]]
+*[[Quinone reductase 3D structures|Quinone reductase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Amzel, L M]]
+[[Category: Amzel LM]]
-[[Category: Bianchet, M A]]
+[[Category: Bianchet MA]]
-[[Category: Faig, M]]
+[[Category: Faig M]]
-[[Category: Hargreaves, R]]
+[[Category: Hargreaves R]]
-[[Category: Hudnott, A R]]
+[[Category: Hudnott AR]]
-[[Category: Moody, C J]]
+[[Category: Moody CJ]]
-[[Category: Ross, D]]
+[[Category: Ross D]]
-[[Category: Winski, S]]
+[[Category: Winski S]]
-[[Category: Flavoprotein]]
-[[Category: Oxidoreductase]]
-[[Category: Rossmann fold]]

1gg5

From Proteopedia

Current revision

CRYSTAL STRUCTURE OF A COMPLEX OF HUMAN NAD[P]H-QUINONE OXIDOREDUCTASE AND A CHEMOTHERAPEUTIC DRUG (E09) AT 2.5 A RESOLUTION

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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