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| | ==Oxidized quinone reductase 2 in complex with CK2 inhibitor TBBz== | | ==Oxidized quinone reductase 2 in complex with CK2 inhibitor TBBz== |
| - | <StructureSection load='4u7g' size='340' side='right' caption='[[4u7g]], [[Resolution|resolution]] 1.96Å' scene=''> | + | <StructureSection load='4u7g' size='340' side='right'caption='[[4u7g]], [[Resolution|resolution]] 1.96Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4u7g]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4U7G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4U7G FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4u7g]] is a 2 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=4U7G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4U7G FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=K17:4,5,6,7-TETRABROMO-BENZIMIDAZOLE'>K17</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=K17:4,5,6,7-TETRABROMO-BENZIMIDAZOLE'>K17</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4u7h|4u7h]], [[4u7f|4u7f]]</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=4u7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u7g OCA], [https://pdbe.org/4u7g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4u7g RCSB], [https://www.ebi.ac.uk/pdbsum/4u7g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4u7g ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NQO2, NMOR2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ribosyldihydronicotinamide_dehydrogenase_(quinone) Ribosyldihydronicotinamide dehydrogenase (quinone)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.10.99.2 1.10.99.2] </span></td></tr>
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4u7g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u7g OCA], [http://pdbe.org/4u7g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4u7g RCSB], [http://www.ebi.ac.uk/pdbsum/4u7g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4u7g ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NQO2_HUMAN NQO2_HUMAN]] The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.<ref>PMID:18254726</ref> | + | [https://www.uniprot.org/uniprot/NQO2_HUMAN NQO2_HUMAN] The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.<ref>PMID:18254726</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4u7g" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4u7g" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Quinone reductase|Quinone reductase]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Leung, K K]] | + | [[Category: Large Structures]] |
| - | [[Category: Shilton, B H]] | + | [[Category: Leung KK]] |
| - | [[Category: Ck2 inhibitor]] | + | [[Category: Shilton BH]] |
| - | [[Category: Oxidoreductase-inhibitor complex]]
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| - | [[Category: Quinone reductase 2]]
| + | |
| Structural highlights
Function
NQO2_HUMAN The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.[1]
Publication Abstract from PubMed
Quinone reductase 2 (NQO2) exhibits off-target interactions with two protein kinase CK2 inhibitors, 4,5,6,7-1H-tetrabromobenzimidazole (TBBz) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT). TBBz and DMAT induce apoptosis in cells expressing an inhibitor-resistant CK2, suggesting that the interaction with NQO2 may mediate some of their pharmacological effects. In this study, we have fully characterized the binding of TBBz and DMAT to NQO2. Fluorescence titrations showed that TBBz and DMAT bind oxidized NQO2 in the low nanomolar range; in the case of TBBz, the affinity for NQO2 was 40-fold greater than its affinity for CK2. A related CK2 inhibitor, 4,5,6,7-tetrabromobenzotriazole (TBB), which failed to cause apoptosis in cells expressing inhibitor-resistant CK2, binds NQO2 with an affinity 1000-fold lower than those of TBBz and DMAT. Kinetic analysis indicated that DMAT inhibits NQO2 by binding with similar affinities to the oxidized and reduced forms. Crystal structure analysis showed that DMAT binds reduced NQO2 in a manner different from that in the oxidized state. In oxidized NQO2, TBBz and DMAT are deeply buried in the active site and make direct hydrogen and halogen bonds to the enzyme. In reduced NQO2, DMAT occupies a more peripheral region and hydrogen and halogen bonds with the enzyme are mediated through three water molecules. Therefore, although TBB, TBBz, and DMAT are all potent inhibitors of CK2, they exhibit different activity profiles toward NQO2. We conclude that the active site of NQO2 is fundamentally different from the ATP binding site of CK2 and the inhibition of NQO2 by CK2 inhibitors is adventitious.
Quinone Reductase 2 Is an Adventitious Target of Protein Kinase CK2 Inhibitors TBBz (TBI) and DMAT.,Leung KK, Shilton BH Biochemistry. 2015 Jan 13;54(1):47-59. doi: 10.1021/bi500959t. Epub 2014 Nov 18. PMID:25379648[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Calamini B, Santarsiero BD, Boutin JA, Mesecar AD. Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2. Biochem J. 2008 Jul 1;413(1):81-91. PMID:18254726 doi:10.1042/BJ20071373
- ↑ Leung KK, Shilton BH. Quinone Reductase 2 Is an Adventitious Target of Protein Kinase CK2 Inhibitors TBBz (TBI) and DMAT. Biochemistry. 2015 Jan 13;54(1):47-59. doi: 10.1021/bi500959t. Epub 2014 Nov 18. PMID:25379648 doi:http://dx.doi.org/10.1021/bi500959t
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