3g0x

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{{STRUCTURE_3g0x| PDB=3g0x | SCENE= }}
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==Human dihydroorotate dehydrogenase in complex with a leflunomide derivative inhibitor 5==
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===Human dihydroorotate dehydrogenase in complex with a leflunomide derivative inhibitor 5===
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<StructureSection load='3g0x' size='340' side='right' caption='[[3g0x]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
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{{ABSTRACT_PUBMED_19351152}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3g0x]] 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=3G0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3G0X FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=MD7:(2Z)-N-BIPHENYL-4-YL-2-CYANO-3-CYCLOPROPYL-3-HYDROXYPROP-2-ENAMIDE'>MD7</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3f1q|3f1q]], [[3fj6|3fj6]], [[3fjl|3fjl]], [[3g0u|3g0u]]</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydroorotate_oxidase Dihydroorotate oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.3.1 1.3.3.1] </span></td></tr>
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<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=3g0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g0x OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3g0x RCSB], [http://www.ebi.ac.uk/pdbsum/3g0x PDBsum]</span></td></tr>
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</table>
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== Disease ==
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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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== Function ==
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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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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g0/3g0x_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate dehydrogenase, an enzyme catalyzing the only redox reaction of the pyrimidine biosynthesis pathway, is a well-characterized target for chemotherapeutical intervention. In this study, we have applied SPROUT-LeadOpt, a software package for structure-based drug discovery and lead optimization, to improve the binding of the active metabolite of the anti-inflammatory drug leflunomide to the target cavities of the P. falciparum and human dihydroorotate dehydrogenases. Following synthesis of a library of compounds based upon the SPROUT-optimized molecular scaffolds, a series of inhibitors generally showing good inhibitory activity was obtained, in keeping with the SPROUT-LeadOpt predictions. Furthermore, cocrystal structures of five of these SPROUT-designed inhibitors bound in the ubiquinone binding cavity of the human dihydroorotate dehydrogenase are also analyzed.
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==Disease==
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Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases.,Davies M, Heikkila T, McConkey GA, Fishwick CW, Parsons MR, Johnson AP J Med Chem. 2009 May 14;52(9):2683-93. PMID:19351152<ref>PMID:19351152</ref>
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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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==Function==
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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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[[3g0x]] 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=3G0X OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:019351152</ref><references group="xtra"/><references/>
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*[[Dihydroorotate dehydrogenase|Dihydroorotate dehydrogenase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Dihydroorotate oxidase]]
[[Category: Dihydroorotate oxidase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Davies, M.]]
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[[Category: Davies, M]]
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[[Category: Fishwick, C W.G.]]
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[[Category: Fishwick, C W.G]]
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[[Category: Heikkila, T.]]
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[[Category: Heikkila, T]]
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[[Category: Johnson, A P.]]
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[[Category: Johnson, A P]]
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[[Category: McConkey, G A.]]
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[[Category: McConkey, G A]]
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[[Category: Parsons, M R.]]
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[[Category: Parsons, M R]]
[[Category: Beta barrel]]
[[Category: Beta barrel]]
[[Category: Fad]]
[[Category: Fad]]

Revision as of 13:20, 18 December 2014

Human dihydroorotate dehydrogenase in complex with a leflunomide derivative inhibitor 5

3g0x, resolution 1.80Å

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