3o73: Difference between revisions
No edit summary |
No edit summary |
||
| (8 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
< | ==Crystal structure of quinone reductase 2 in complex with the indolequinone MAC627== | ||
<StructureSection load='3o73' size='340' side='right'caption='[[3o73]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3o73]] 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=3O73 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3O73 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</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=O73:5-[(4-AMINOBUTYL)AMINO]-1,2-DIMETHYL-3-[(4-NITROPHENOXY)METHYL]-1H-INDOLE-4,7-DIONE'>O73</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=3o73 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o73 OCA], [https://pdbe.org/3o73 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3o73 RCSB], [https://www.ebi.ac.uk/pdbsum/3o73 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3o73 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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;"> | |||
== Publication Abstract from PubMed == | |||
A role for the flavoprotein NRH:quinone oxidoreductase 2 (NQO2, QR2) in human diseases such as malaria, leukemia and neurodegeneration has been proposed. In order to explore the potential of NQO2 as a therapeutic target, we have developed potent and selective mechanism-based inhibitors centered on the indolequinone pharmacophore. The compounds show remarkable selectivity for NQO2 over the closely related flavoprotein NQO1, with small structural changes defining selectivity. Biochemical studies confirmed the mechanism-based inhibition, whereas X-ray crystallography and mass spectrometry revealed the nature of the inhibitor interaction with the protein. These indolequinones represent the first mechanism-based inhibitors of NQO2, and their novel mode of action involving alkylation of the flavin cofactor, provides significant advantages over existing competitive inhibitors in terms of potency and irreversibility, and will open new opportunities to define the role of NQO2 in disease. | |||
Mechanism-Based Inhibition of Quinone Reductase 2 (NQO2): Selectivity for NQO2 over NQO1 and Structural Basis for Flavoprotein Inhibition.,Dufour M, Yan C, Siegel D, Colucci MA, Jenner M, Oldham NJ, Gomez J, Reigan P, Li Y, De Matteis CI, Ross D, Moody CJ Chembiochem. 2011 Apr 19. doi: 10.1002/cbic.201100085. PMID:21506232<ref>PMID:21506232</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3o73" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Quinone reductase|Quinone reductase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
[[ | |||
== | |||
< | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Colucci | [[Category: Large Structures]] | ||
[[Category: | [[Category: Colucci MA]] | ||
[[Category: | [[Category: De Matteis CI]] | ||
[[Category: | [[Category: Dufour M]] | ||
[[Category: Moody | [[Category: Li Y]] | ||
[[Category: Ross | [[Category: Moody CJ]] | ||
[[Category: Siegel | [[Category: Ross D]] | ||
[[Category: Yan | [[Category: Siegel D]] | ||
[[Category: Yan C]] | |||
Latest revision as of 12:29, 6 September 2023
Crystal structure of quinone reductase 2 in complex with the indolequinone MAC627Crystal structure of quinone reductase 2 in complex with the indolequinone MAC627
Structural highlights
FunctionNQO2_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 PubMedA role for the flavoprotein NRH:quinone oxidoreductase 2 (NQO2, QR2) in human diseases such as malaria, leukemia and neurodegeneration has been proposed. In order to explore the potential of NQO2 as a therapeutic target, we have developed potent and selective mechanism-based inhibitors centered on the indolequinone pharmacophore. The compounds show remarkable selectivity for NQO2 over the closely related flavoprotein NQO1, with small structural changes defining selectivity. Biochemical studies confirmed the mechanism-based inhibition, whereas X-ray crystallography and mass spectrometry revealed the nature of the inhibitor interaction with the protein. These indolequinones represent the first mechanism-based inhibitors of NQO2, and their novel mode of action involving alkylation of the flavin cofactor, provides significant advantages over existing competitive inhibitors in terms of potency and irreversibility, and will open new opportunities to define the role of NQO2 in disease. Mechanism-Based Inhibition of Quinone Reductase 2 (NQO2): Selectivity for NQO2 over NQO1 and Structural Basis for Flavoprotein Inhibition.,Dufour M, Yan C, Siegel D, Colucci MA, Jenner M, Oldham NJ, Gomez J, Reigan P, Li Y, De Matteis CI, Ross D, Moody CJ Chembiochem. 2011 Apr 19. doi: 10.1002/cbic.201100085. PMID:21506232[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||