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4oqv

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==High resolution crystal structure of human dihydroorotate dehydrogenase bound with DSM338 (N-[3,5-difluoro-4-(trifluoromethyl)phenyl]-5-methyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine)==
==High resolution crystal structure of human dihydroorotate dehydrogenase bound with DSM338 (N-[3,5-difluoro-4-(trifluoromethyl)phenyl]-5-methyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine)==
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<StructureSection load='4oqv' size='340' side='right' caption='[[4oqv]], [[Resolution|resolution]] 1.23&Aring;' scene=''>
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<StructureSection load='4oqv' size='340' side='right'caption='[[4oqv]], [[Resolution|resolution]] 1.23&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4oqv]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OQV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OQV FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4oqv]] 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=4OQV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OQV FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2V6:N-[3,5-DIFLUORO-4-(TRIFLUOROMETHYL)PHENYL]-5-METHYL-2-(TRIFLUOROMETHYL)[1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>2V6</scene>, <scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene><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]] 1.23&#8491;</td></tr>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ori|4ori]], [[4orm|4orm]]</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=2V6:N-[3,5-DIFLUORO-4-(TRIFLUOROMETHYL)PHENYL]-5-METHYL-2-(TRIFLUOROMETHYL)[1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>2V6</scene>, <scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr><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>
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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=4oqv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oqv OCA], [https://pdbe.org/4oqv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4oqv RCSB], [https://www.ebi.ac.uk/pdbsum/4oqv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4oqv ProSAT]</span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4oqv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oqv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4oqv RCSB], [http://www.ebi.ac.uk/pdbsum/4oqv PDBsum]</span></td></tr>
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</table>
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<table>
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== Disease ==
== 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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[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 ==
== 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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[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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Malaria is one of the most serious global infectious diseases. The pyrimidine biosynthetic enzyme Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is an important target for antimalarial chemotherapy. We describe a detailed analysis of protein-ligand interactions between DHODH and a triazolopyrimidine-based inhibitor series exploring effects of fluorine on affinity and species-selectivity. We show increasing fluorination dramatically increases binding to mammalian DHODHs, leading to a loss of species selectivity. Triazolopyrimidines bind Plasmodium and mammalian DHODHs in overlapping but distinct binding-sites. Key hydrogen-bond and stacking-interactions underlying strong binding to PfDHODH are absent in the mammalian enzymes. Increasing fluorine substitution leads to an increase in the entropic contribution to binding suggesting that strong binding to mammalian DHODH is a consequence of an enhanced hydrophobic effect upon binding to an apolar pocket. We conclude that hydrophobic interactions between fluorine and hydrocarbons provide significant binding energy to protein-ligand interactions. Our studies define the requirements for species selective binding to PfDHODH and show that the triazolopyrimidine scaffold can alternatively be tuned to inhibit human DHODH, an important target for autoimmune diseases.
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Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors.,Deng X, Kokkonda S, El Mazouni F, White J, Burrows JN, Kaminsky W, Charman SA, Matthews D, Rathod PK, Phillips MA J Med Chem. 2014 May 7. PMID:24801997<ref>PMID:24801997</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
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</div>
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*[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Deng, X.]]
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[[Category: Homo sapiens]]
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[[Category: Phillips, M A.]]
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[[Category: Large Structures]]
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[[Category: Alpha/beta barrel]]
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[[Category: Deng X]]
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[[Category: Dehydrogenase]]
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[[Category: Phillips MA]]
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[[Category: Fmn]]
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[[Category: Mitochondrial membrane]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Redox]]
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Current revision

High resolution crystal structure of human dihydroorotate dehydrogenase bound with DSM338 (N-[3,5-difluoro-4-(trifluoromethyl)phenyl]-5-methyl-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine)

PDB ID 4oqv

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