3sfk

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<StructureSection load='3sfk' size='340' side='right'caption='[[3sfk]], [[Resolution|resolution]] 2.95&Aring;' scene=''>
<StructureSection load='3sfk' size='340' side='right'caption='[[3sfk]], [[Resolution|resolution]] 2.95&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3sfk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SFK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SFK FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3sfk]] 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=3SFK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SFK FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D67:2-(1,1-DIFLUOROETHYL)-5-METHYL-N-[4-(TRIFLUOROMETHYL)PHENYL][1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>D67</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene></td></tr>
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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]] 2.95&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PFF0160c ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</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=D67:2-(1,1-DIFLUOROETHYL)-5-METHYL-N-[4-(TRIFLUOROMETHYL)PHENYL][1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>D67</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dihydroorotate_dehydrogenase_(quinone) Dihydroorotate dehydrogenase (quinone)], with EC number [https://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=3sfk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sfk OCA], [https://pdbe.org/3sfk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sfk RCSB], [https://www.ebi.ac.uk/pdbsum/3sfk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sfk 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=3sfk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sfk OCA], [https://pdbe.org/3sfk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sfk RCSB], [https://www.ebi.ac.uk/pdbsum/3sfk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sfk ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
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[https://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7] 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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Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential anti-malarials we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound towards clinical candidate status.
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Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential.,Coteron JM, Marco M, Esquivias J, Deng X, White KL, White J, Koltun M, El Mazouni F, Kokkonda S, Katneni K, Bhamidipati R, Shackleford D, Barturen I, Ferrer S, Jimenez-Diaz MB, Gamo FJ, Goldsmith EJ, Charman B, Bathurst I, Floyd D, Matthews D, Burrows JN, Rathod PK, Charman SA, Phillips MA J Med Chem. 2011 Jun 22. PMID:21696174<ref>PMID:21696174</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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</div>
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<div class="pdbe-citations 3sfk" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
*[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]]
*[[Dihydroorotate dehydrogenase 3D structures|Dihydroorotate dehydrogenase 3D structures]]
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== References ==
 
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<references/>
 
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Plaf7]]
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[[Category: Plasmodium falciparum 3D7]]
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[[Category: Deng, X]]
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[[Category: Deng X]]
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[[Category: Phillips, M]]
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[[Category: Phillips M]]
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[[Category: Alpha beta barrel oxidoreductase]]
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[[Category: Alpha beta fold]]
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[[Category: Flavoprotein]]
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[[Category: Fmn]]
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[[Category: Inhibitor dsm267]]
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[[Category: Mitochondrion inner membrane]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Plasmodium falciparum membrane mitochondrion]]
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[[Category: Pyrimidine biosynthesis]]
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Current revision

Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM267

PDB ID 3sfk

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