3w4k: Difference between revisions
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==Crystal Structure of human DAAO in complex with coumpound 13== | |||
<StructureSection load='3w4k' size='340' side='right' caption='[[3w4k]], [[Resolution|resolution]] 2.86Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3w4k]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W4K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3W4K FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3LD:3-HYDROXY-6-(2-PHENYLETHYL)PYRIDAZIN-4(1H)-ONE'>3LD</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">[[3w4i|3w4i]], [[3w4j|3w4j]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DAO, DAMOX ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/D-amino-acid_oxidase D-amino-acid oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.4.3.3 1.4.3.3] </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=3w4k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w4k OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3w4k RCSB], [http://www.ebi.ac.uk/pdbsum/3w4k PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze. | |||
4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors.,Hondo T, Warizaya M, Niimi T, Namatame I, Yamaguchi T, Nakanishi K, Hamajima T, Harada K, Sakashita H, Matsumoto Y, Orita M, Takeuchi M J Med Chem. 2013 May 9;56(9):3582-92. doi: 10.1021/jm400095b. Epub 2013 Apr 25. PMID:23566269<ref>PMID:23566269</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Amino acid oxidase|Amino acid oxidase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: D-amino-acid oxidase]] | [[Category: D-amino-acid oxidase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Hamajima, T | [[Category: Hamajima, T]] | ||
[[Category: Harada, K | [[Category: Harada, K]] | ||
[[Category: Hondo, T | [[Category: Hondo, T]] | ||
[[Category: Matsumoto, Y | [[Category: Matsumoto, Y]] | ||
[[Category: Nakanishi, K | [[Category: Nakanishi, K]] | ||
[[Category: Namatame, I | [[Category: Namatame, I]] | ||
[[Category: Niimi, T | [[Category: Niimi, T]] | ||
[[Category: Orita, M | [[Category: Orita, M]] | ||
[[Category: Sakashita, H | [[Category: Sakashita, H]] | ||
[[Category: Takeuchi, M | [[Category: Takeuchi, M]] | ||
[[Category: Warizaya, M | [[Category: Warizaya, M]] | ||
[[Category: Watanabe, T | [[Category: Watanabe, T]] | ||
[[Category: Yamaguchi, T | [[Category: Yamaguchi, T]] | ||
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | ||
Revision as of 06:41, 21 December 2014
Crystal Structure of human DAAO in complex with coumpound 13
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