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| | ==Crystal structure of Saccharomyces cerevisiae KMO in complex with Ro 61-8048== | | ==Crystal structure of Saccharomyces cerevisiae KMO in complex with Ro 61-8048== |
| - | <StructureSection load='5x6r' size='340' side='right' caption='[[5x6r]], [[Resolution|resolution]] 1.91Å' scene=''> | + | <StructureSection load='5x6r' size='340' side='right'caption='[[5x6r]], [[Resolution|resolution]] 1.91Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5x6r]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Baker's_yeast Baker's yeast]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5X6R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5X6R FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5x6r]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5X6R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5X6R FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7ZR:3,4-dimethoxy-N-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]benzenesulfonamide'>7ZR</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]] 1.911Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5x68|5x68]], [[5x6p|5x6p]], [[5x6q|5x6q]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7ZR:3,4-dimethoxy-N-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]benzenesulfonamide'>7ZR</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BNA4, YBL098W, YBL0828 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=559292 Baker's yeast])</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=5x6r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x6r OCA], [https://pdbe.org/5x6r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5x6r RCSB], [https://www.ebi.ac.uk/pdbsum/5x6r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5x6r ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Kynurenine_3-monooxygenase Kynurenine 3-monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.9 1.14.13.9] </span></td></tr>
| + | |
| - | <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=5x6r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x6r OCA], [http://pdbe.org/5x6r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5x6r RCSB], [http://www.ebi.ac.uk/pdbsum/5x6r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5x6r ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KMO_YEAST KMO_YEAST]] Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of quinolinic acid.<ref>PMID:12062417</ref> <ref>PMID:15806102</ref> | + | [https://www.uniprot.org/uniprot/KMO_YEAST KMO_YEAST] Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of quinolinic acid.<ref>PMID:12062417</ref> <ref>PMID:15806102</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 5x6r" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5x6r" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Monooxygenase 3D structures|Monooxygenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Baker's yeast]] | + | [[Category: Large Structures]] |
| - | [[Category: Kynurenine 3-monooxygenase]] | + | [[Category: Saccharomyces cerevisiae S288C]] |
| - | [[Category: Hwang, K Y]] | + | [[Category: Hwang KY]] |
| - | [[Category: Kim, H T]] | + | [[Category: Kim HT]] |
| - | [[Category: Monooxygenase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Function
KMO_YEAST Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of quinolinic acid.[1] [2]
Publication Abstract from PubMed
Kynurenine 3-monooxygenase (KMO) inhibitors have been developed for the treatment of neurodegenerative disorders. The mechanisms of flavin reduction and hydrogen peroxide production by KMO inhibitors are unknown. Herein, we report the structure of human KMO and crystal structures of Saccharomyces cerevisiae (sc) and Pseudomonas fluorescens (pf) KMO with Ro 61-8048. Proton transfer in the hydrogen bond network triggers flavin reduction in p-hydroxybenzoate hydroxylase, but the mechanism triggering flavin reduction in KMO is different. Conformational changes via pi-pi interactions between the loop above the flavin and substrate or non-substrate effectors lead to disorder of the C-terminal alpha helix in scKMO and shifts of domain III in pfKMO, stimulating flavin reduction. Interestingly, Ro 61-8048 has two different binding modes. It acts as a competitive inhibitor in scKMO and as a non-substrate effector in pfKMO. These findings provide understanding of the catalytic cycle of KMO and insight for structure-based drug design of KMO inhibitors.
Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase.,Kim HT, Na BK, Chung J, Kim S, Kwon SK, Cha H, Son J, Cho JM, Hwang KY Cell Chem Biol. 2018 Feb 1. pii: S2451-9456(18)30030-8. doi:, 10.1016/j.chembiol.2018.01.008. PMID:29429898[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Panozzo C, Nawara M, Suski C, Kucharczyka R, Skoneczny M, Becam AM, Rytka J, Herbert CJ. Aerobic and anaerobic NAD+ metabolism in Saccharomyces cerevisiae. FEBS Lett. 2002 Apr 24;517(1-3):97-102. PMID:12062417
- ↑ Giorgini F, Guidetti P, Nguyen Q, Bennett SC, Muchowski PJ. A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nat Genet. 2005 May;37(5):526-31. Epub 2005 Apr 3. PMID:15806102 doi:ng1542
- ↑ Kim HT, Na BK, Chung J, Kim S, Kwon SK, Cha H, Son J, Cho JM, Hwang KY. Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase. Cell Chem Biol. 2018 Feb 1. pii: S2451-9456(18)30030-8. doi:, 10.1016/j.chembiol.2018.01.008. PMID:29429898 doi:http://dx.doi.org/10.1016/j.chembiol.2018.01.008
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