5boo: Difference between revisions
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<StructureSection load='5boo' size='340' side='right'caption='[[5boo]], [[Resolution|resolution]] 2.80Å' scene=''> | <StructureSection load='5boo' size='340' side='right'caption='[[5boo]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5boo]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[5boo]] is a 2 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=5BOO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BOO FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D65:2-(1,1-DIFLUOROETHYL)-5-METHYL-N-[4-(PENTAFLUORO-LAMBDA~6~-SULFANYL)PHENYL][1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>D65</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D65:2-(1,1-DIFLUOROETHYL)-5-METHYL-N-[4-(PENTAFLUORO-LAMBDA~6~-SULFANYL)PHENYL][1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>D65</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</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=5boo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5boo OCA], [https://pdbe.org/5boo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5boo RCSB], [https://www.ebi.ac.uk/pdbsum/5boo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5boo ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</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. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Plasmodium falciparum 3D7]] | ||
[[Category: Deng | [[Category: Deng X]] | ||
[[Category: Phillips | [[Category: Phillips M]] | ||
[[Category: Tomchick | [[Category: Tomchick D]] | ||
Revision as of 09:02, 7 June 2023
Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM265Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM265
Structural highlights
FunctionPYRD_PLAF7 Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Publication Abstract from PubMedMalaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria.,Phillips MA, Lotharius J, Marsh K, White J, Dayan A, White KL, Njoroge JW, El Mazouni F, Lao Y, Kokkonda S, Tomchick DR, Deng X, Laird T, Bhatia SN, March S, Ng CL, Fidock DA, Wittlin S, Lafuente-Monasterio M, Benito FJ, Alonso LM, Martinez MS, Jimenez-Diaz MB, Bazaga SF, Angulo-Barturen I, Haselden JN, Louttit J, Cui Y, Sridhar A, Zeeman AM, Kocken C, Sauerwein R, Dechering K, Avery VM, Duffy S, Delves M, Sinden R, Ruecker A, Wickham KS, Rochford R, Gahagen J, Iyer L, Riccio E, Mirsalis J, Bathhurst I, Rueckle T, Ding X, Campo B, Leroy D, Rogers MJ, Rathod PK, Burrows JN, Charman SA Sci Transl Med. 2015 Jul 15;7(296):296ra111. doi: 10.1126/scitranslmed.aaa6645. PMID:26180101[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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