4igh

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{{STRUCTURE_4igh| PDB=4igh | SCENE= }}
 
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===High resolution crystal structure of human dihydroorotate dehydrogenase bound with 4-quinoline carboxylic acid analog===
 
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{{ABSTRACT_PUBMED_23930152}}
 
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==Disease==
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==High resolution crystal structure of human dihydroorotate dehydrogenase bound with 4-quinoline carboxylic acid analog==
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[[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>
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<StructureSection load='4igh' size='340' side='right'caption='[[4igh]], [[Resolution|resolution]] 1.30&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4igh]] is a 1 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=4IGH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IGH FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.3&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4igh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4igh OCA], [https://pdbe.org/4igh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4igh RCSB], [https://www.ebi.ac.uk/pdbsum/4igh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4igh ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:[https://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>
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== Function ==
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[https://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==Function==
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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>
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[[http://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[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].
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</div>
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<div class="pdbe-citations 4igh" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:023930152</ref><references group="xtra"/><references/>
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*[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Brabander, J K.De.]]
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[[Category: Large Structures]]
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[[Category: Das, P.]]
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[[Category: Das P]]
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[[Category: Deng, X.]]
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[[Category: De Brabander JK]]
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[[Category: Fontoura, B M.A.]]
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[[Category: Deng X]]
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[[Category: Phillips, M A.]]
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[[Category: Fontoura BMA]]
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[[Category: Anti-viral]]
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[[Category: Phillips MA]]
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[[Category: Dehydrogenase]]
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[[Category: Fmn]]
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[[Category: Membrane]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Quinoline-4-carboxylic acid]]
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[[Category: Redox]]
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Current revision

High resolution crystal structure of human dihydroorotate dehydrogenase bound with 4-quinoline carboxylic acid analog

PDB ID 4igh

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