4orm
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4orm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ORM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ORM FirstGlance]. <br> | <table><tr><td colspan='2'>[[4orm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ORM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ORM FirstGlance]. <br> | ||
| - | </td></tr><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=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.07Å</td></tr> |
| + | <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=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=4orm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4orm OCA], [https://pdbe.org/4orm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4orm RCSB], [https://www.ebi.ac.uk/pdbsum/4orm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4orm ProSAT]</span></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=4orm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4orm OCA], [https://pdbe.org/4orm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4orm RCSB], [https://www.ebi.ac.uk/pdbsum/4orm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4orm ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. | [https://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | 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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4orm" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]] | *[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]] | ||
| - | == References == | ||
| - | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor 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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