View source for 6oc0


==Crystal structure of human DHODH with OSU-03012==
<StructureSection load='6oc0' size='340' side='right'caption='[[6oc0]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6oc0]] 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=6OC0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OC0 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]] 1.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=M4J:N-{4-[5-(phenanthren-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}glycinamide'>M4J</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6oc0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oc0 OCA], [https://pdbe.org/6oc0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6oc0 RCSB], [https://www.ebi.ac.uk/pdbsum/6oc0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6oc0 ProSAT]</span></td></tr>
</table>
== Disease ==
[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> 
== Function ==
[https://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 ==
Biosynthesis of the pyrimidine nucleotide uridine monophosphate (UMP) is essential for cell proliferation and is achieved by the activity of convergent de novo and salvage metabolic pathways. Here we report the development and application of a cell-based metabolic modifier screening platform that leverages the redundancy in pyrimidine metabolism for the discovery of selective UMP biosynthesis modulators. In evaluating a library of protein kinase inhibitors, we identified multiple compounds that possess nucleotide metabolism modifying activity. The JNK inhibitor JNK-IN-8 was found to potently inhibit nucleoside transport and engage ENT1. The PDK1 inhibitor OSU-03012 (also known as AR-12) and the RAF inhibitor TAK-632 were shown to inhibit the therapeutically relevant de novo pathway enzyme DHODH and their affinities were unambiguously confirmed through in vitro assays and co-crystallization with human DHODH.

Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.,Abt ER, Rosser EW, Durst MA, Lok V, Poddar S, Le TM, Cho A, Kim W, Wei L, Song J, Capri JR, Xu S, Wu N, Slavik R, Jung ME, Damoiseaux R, Czernin J, Donahue TR, Lavie A, Radu CG Cell Chem Biol. 2019 Nov 12. pii: S2451-9456(19)30357-5. doi:, 10.1016/j.chembiol.2019.10.012. PMID:31734178<ref>PMID:31734178</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6oc0" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Durst MA]]
[[Category: Lavie A]]