View source for 5zj9


==human D-amino acid oxidase complexed with 5-chlorothiophene-3-carboxylic acid==
<StructureSection load='5zj9' size='340' side='right'caption='[[5zj9]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5zj9]] is a 4 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=5ZJ9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZJ9 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]] 2.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9E6:5-chloro+thiophene-3-carboxylic+acid'>9E6</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</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=5zj9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zj9 OCA], [https://pdbe.org/5zj9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zj9 RCSB], [https://www.ebi.ac.uk/pdbsum/5zj9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zj9 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/OXDA_HUMAN OXDA_HUMAN] Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D-amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids.<ref>PMID:17303072</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A series of thiophene-2-carboxylic acids and thiophene-3-carboxylic acids were identified as a new class of DAO inhibitors. Structure-activity relationship (SAR) studies revealed that small substituents are well-tolerated on the thiophene ring of both the 2-carboxylic acid and 3-carboxylic acid scaffolds. Crystal structures of human DAO in complex with potent thiophene carboxylic acids revealed that Tyr224 was tightly stacked with the thiophene ring of the inhibitors, resulting in the disappearance of the secondary pocket observed with other DAO inhibitors. Molecular dynamics simulations of the complex revealed that Tyr224 preferred the stacked conformation irrespective of whether Tyr224 was stacked or not in the initial state of the simulations. MM/GBSA indicated a substantial hydrophobic interaction between Tyr244 and the thiophene-based inhibitor. In addition, the active site was tightly closed with an extensive network of hydrogen bonds including those from Tyr224 in the stacked conformation. The introduction of a large branched side chain to the thiophene ring markedly decreased potency. These results are in marked contrast to other DAO inhibitors that can gain potency with a branched side chain extending to the secondary pocket due to Tyr224 repositioning. These insights should be of particular importance in future efforts to optimize DAO inhibitors with novel scaffolds.

Structural basis for potent inhibition of d-amino acid oxidase by thiophene carboxylic acids.,Kato Y, Hin N, Maita N, Thomas AG, Kurosawa S, Rojas C, Yorita K, Slusher BS, Fukui K, Tsukamoto T Eur J Med Chem. 2018 Sep 18;159:23-34. doi: 10.1016/j.ejmech.2018.09.040. PMID:30265959<ref>PMID:30265959</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5zj9" style="background-color:#fffaf0;"></div>

==See Also==
*[[Amino acid oxidase 3D structures|Amino acid oxidase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fukui K]]
[[Category: Hin N]]
[[Category: Kato Y]]
[[Category: Kurosawa S]]
[[Category: Maita N]]
[[Category: Rojas C]]
[[Category: Slusher BS]]
[[Category: Thomas AG]]
[[Category: Tsukamoto T]]
[[Category: Yorita K]]