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| | ==Cocrystal Structure of kynurenine 3-monooxygenase in complex with UPF 648 inhibitor(KMO-394UPF)== | | ==Cocrystal Structure of kynurenine 3-monooxygenase in complex with UPF 648 inhibitor(KMO-394UPF)== |
| - | <StructureSection load='4j36' size='340' side='right' caption='[[4j36]], [[Resolution|resolution]] 2.13Å' scene=''> | + | <StructureSection load='4j36' size='340' side='right'caption='[[4j36]], [[Resolution|resolution]] 2.13Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4j36]] 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=4J36 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4J36 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4j36]] 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=4J36 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J36 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1HR:(1S,2S)-2-(3,4-DICHLOROBENZOYL)CYCLOPROPANECARBOXYLIC+ACID'>1HR</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1HR:(1S,2S)-2-(3,4-DICHLOROBENZOYL)CYCLOPROPANECARBOXYLIC+ACID'>1HR</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4j2w|4j2w]], [[4j31|4j31]], [[4j33|4j33]], [[4j34|4j34]]</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=4j36 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j36 OCA], [https://pdbe.org/4j36 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j36 RCSB], [https://www.ebi.ac.uk/pdbsum/4j36 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j36 ProSAT]</span></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='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>
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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=4j36 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j36 OCA], [http://pdbe.org/4j36 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4j36 RCSB], [http://www.ebi.ac.uk/pdbsum/4j36 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4j36 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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| | ==See Also== | | ==See Also== |
| - | *[[Monooxygenase|Monooxygenase]] | + | *[[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: Amaral, M]] | + | [[Category: Amaral M]] |
| - | [[Category: Giorgini, F]] | + | [[Category: Giorgini F]] |
| - | [[Category: Heyes, D J]] | + | [[Category: Heyes DJ]] |
| - | [[Category: Lafite, P]] | + | [[Category: Lafite P]] |
| - | [[Category: Levy, C]] | + | [[Category: Levy C]] |
| - | [[Category: Leys, D]] | + | [[Category: Leys D]] |
| - | [[Category: Outeiro, T F]] | + | [[Category: Outeiro TF]] |
| - | [[Category: Scrutton, N S]] | + | [[Category: Scrutton NS]] |
| - | [[Category: Monooxygenase kynurenine upf 648]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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| 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
Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (that is, kynurenine pathway), leads to amelioration of Huntington's-disease-relevant phenotypes in yeast, fruitfly and mouse models, as well as in a mouse model of Alzheimer's disease. KMO is a flavin adenine dinucleotide (FAD)-dependent monooxygenase and is located in the outer mitochondrial membrane where it converts l-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders, as well as cancer and several peripheral inflammatory conditions. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained unknown. Here we report the first crystal structure of Saccharomyces cerevisiae KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active-site structure, preventing productive binding of the substrate l-kynurenine. Functional assays and targeted mutagenesis reveal that the active-site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO-UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington's, Alzheimer's and Parkinson's diseases.
Structural basis of kynurenine 3-monooxygenase inhibition.,Amaral M, Levy C, Heyes DJ, Lafite P, Outeiro TF, Giorgini F, Leys D, Scrutton NS Nature. 2013 Apr 18;496(7445):382-5. doi: 10.1038/nature12039. Epub 2013 Apr 10. PMID:23575632[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
- ↑ Amaral M, Levy C, Heyes DJ, Lafite P, Outeiro TF, Giorgini F, Leys D, Scrutton NS. Structural basis of kynurenine 3-monooxygenase inhibition. Nature. 2013 Apr 18;496(7445):382-5. doi: 10.1038/nature12039. Epub 2013 Apr 10. PMID:23575632 doi:http://dx.doi.org/10.1038/nature12039
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