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3f1q
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Human dihydroorotate dehydrogenase in complex with a leflunomide derivative inhibitor 1== | |
| + | <StructureSection load='3f1q' size='340' side='right'caption='[[3f1q]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[3f1q]] 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=3F1Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3F1Q 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]] 2Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=BCE:(2Z)-N-BIPHENYL-4-YL-2-CYANO-3-HYDROXYBUT-2-ENAMIDE'>BCE</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</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=3f1q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3f1q OCA], [https://pdbe.org/3f1q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3f1q RCSB], [https://www.ebi.ac.uk/pdbsum/3f1q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3f1q 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. | ||
| + | == Evolutionary Conservation == | ||
| + | [[Image:Consurf_key_small.gif|200px|right]] | ||
| + | Check<jmol> | ||
| + | <jmolCheckbox> | ||
| + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f1/3f1q_consurf.spt"</scriptWhenChecked> | ||
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
| + | <text>to colour the structure by Evolutionary Conservation</text> | ||
| + | </jmolCheckbox> | ||
| + | </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/main_output.php?pdb_ID=3f1q ConSurf]. | ||
| + | <div style="clear:both"></div> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | 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. | ||
| - | + | 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> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| + | </div> | ||
| + | <div class="pdbe-citations 3f1q" 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: Davies M]] | ||
| + | [[Category: Fishwick CWG]] | ||
| + | [[Category: Heikkila T]] | ||
| + | [[Category: Johnson AP]] | ||
| + | [[Category: McConkey GA]] | ||
| + | [[Category: Parsons MR]] | ||
Current revision
Human dihydroorotate dehydrogenase in complex with a leflunomide derivative inhibitor 1
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