4igh: Difference between revisions
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==High resolution crystal structure of human dihydroorotate dehydrogenase bound with 4-quinoline carboxylic acid analog== | |||
<StructureSection load='4igh' size='340' side='right' caption='[[4igh]], [[Resolution|resolution]] 1.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4igh]] is a 1 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=4IGH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IGH FirstGlance]. <br> | |||
==Disease== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1EA:6-FLUORO-2-[2-METHYL-4-PHENOXY-5-(PROPAN-2-YL)PHENYL]QUINOLINE-4-CARBOXYLIC+ACID'>1EA</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=ZWI:3-[DECYL(DIMETHYL)AMMONIO]PROPANE-1-SULFONATE'>ZWI</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DHODH ([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/Dihydroorotate_dehydrogenase_(quinone) Dihydroorotate dehydrogenase (quinone)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.5.2 1.3.5.2] </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=4igh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4igh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4igh RCSB], [http://www.ebi.ac.uk/pdbsum/4igh PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:[http://omim.org/entry/263750 263750]]; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.<ref>PMID:19915526</ref> | [[http://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:[http://omim.org/entry/263750 263750]]; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.<ref>PMID:19915526</ref> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM, and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogs of brequinar. | |||
SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity.,Das P, Deng X, Zhang L, Roth MG, Fontoura BM, Phillips MA, De Brabander JK ACS Med Chem Lett. 2013 Jun 13;4(6):517-521. PMID:23930152<ref>PMID:23930152</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Dihydroorotate dehydrogenase|Dihydroorotate dehydrogenase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Brabander, J K.De | [[Category: Brabander, J K.De]] | ||
[[Category: Das, P | [[Category: Das, P]] | ||
[[Category: Deng, X | [[Category: Deng, X]] | ||
[[Category: Fontoura, B M.A | [[Category: Fontoura, B M.A]] | ||
[[Category: Phillips, M A | [[Category: Phillips, M A]] | ||
[[Category: Anti-viral]] | [[Category: Anti-viral]] | ||
[[Category: Dehydrogenase]] | [[Category: Dehydrogenase]] | ||
