3jsu

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{{Seed}}
 
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[[Image:3jsu.jpg|left|200px]]
 
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==Quadruple mutant(N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase(PFDHFR-TS) complexed with QN254, NADPH, and dUMP==
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The line below this paragraph, containing "STRUCTURE_3jsu", creates the "Structure Box" on the page.
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<StructureSection load='3jsu' size='340' side='right'caption='[[3jsu]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[3jsu]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3JSU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3JSU FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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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]] 2.7&#8491;</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=KA5:5-CHLORO-N~6~-(2,5-DIMETHOXYBENZYL)QUINAZOLINE-2,4,6-TRIAMINE'>KA5</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr>
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{{STRUCTURE_3jsu| PDB=3jsu | SCENE= }}
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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=3jsu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jsu OCA], [https://pdbe.org/3jsu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3jsu RCSB], [https://www.ebi.ac.uk/pdbsum/3jsu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3jsu ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/D9N170_PLAFA D9N170_PLAFA] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism (By similarity).[PIRNR:PIRNR000389]
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/js/3jsu_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=3jsu ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Drug resistance against dihydrofolate reductase (DHFR) inhibitors-such as pyrimethamine (PM)-has now spread to almost all regions where malaria is endemic, rendering antifolate-based malaria treatments highly ineffective. We have previously shown that the di-amino quinazoline QN254 [5-chloro-N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine] is active against the highly PM-resistant Plasmodium falciparum V1S strain, suggesting that QN254 could be used to treat malaria in regions with a high prevalence of antifolate resistance. Here, we further demonstrate that QN254 is highly active against Plasmodium falciparum clinical isolates, displaying various levels of antifolate drug resistance, and we provide biochemical and structural evidence that QN254 binds and inhibits the function of both the wild-type and the quadruple-mutant (V1S) forms of the DHFR enzyme. In addition, we have assessed QN254 oral bioavailability, efficacy, and safety in vivo. The compound displays favorable pharmacokinetic properties after oral administration in rodents. The drug was remarkably efficacious against Plasmodium berghei and could fully cure infected mice with three daily oral doses of 30 mg/kg. In the course of these efficacy studies, we have uncovered some dose limiting toxicity at higher doses that was confirmed in rats. Thus, despite its relative in vitro selectivity toward the Plasmodium DHFR enzyme, QN254 does not show the adequate therapeutic index to justify its further development as a single agent.
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===Quadruple mutant(N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase(PFDHFR-TS) complexed with QN254, NADPH, and dUMP===
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Preclinical evaluation of the antifolate QN254, 5-chloro- N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine, as an antimalarial drug candidate.,Nzila A, Rottmann M, Chitnumsub P, Kiara SM, Kamchonwongpaisan S, Maneeruttanarungroj C, Taweechai S, Yeung BK, Goh A, Lakshminarayana SB, Zou B, Wong J, Ma NL, Weaver M, Keller TH, Dartois V, Wittlin S, Brun R, Yuthavong Y, Diagana TT Antimicrob Agents Chemother. 2010 Jun;54(6):2603-10. Epub 2010 Mar 29. PMID:20350951<ref>PMID:20350951</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 3jsu" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_20350951}}, adds the Publication Abstract to the page
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*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 20350951 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_20350951}}
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__TOC__
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</StructureSection>
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==About this Structure==
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[[Category: Large Structures]]
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3JSU is a 2 chains structure with sequences from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3JSU OCA].
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==Reference==
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<ref group="xtra">PMID:20350951</ref><references group="xtra"/>
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[[Category: Plasmodium falciparum]]
[[Category: Plasmodium falciparum]]
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[[Category: Chitnumsub, P.]]
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[[Category: Chitnumsub P]]
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[[Category: Diagana, T T.]]
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[[Category: Diagana TT]]
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[[Category: Kamchonwongpaisan, S.]]
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[[Category: Kamchonwongpaisan S]]
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[[Category: Maneeruttanarungroj, C.]]
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[[Category: Maneeruttanarungroj C]]
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[[Category: Yuthavong, Y.]]
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[[Category: Yuthavong Y]]
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[[Category: Oxidoreductase]]
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[[Category: Rossmann fold]]
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[[Category: Transferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jul 28 12:36:36 2010''
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Current revision

Quadruple mutant(N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase(PFDHFR-TS) complexed with QN254, NADPH, and dUMP

PDB ID 3jsu

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