6kot: Difference between revisions
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==Quadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with B12128 and NADPH== | |||
<StructureSection load='6kot' size='340' side='right'caption='[[6kot]], [[Resolution|resolution]] 2.15Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6kot]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KOT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KOT FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DQ0:4-[3-[[2,6-bis(azanyl)-5-(3-chlorophenyl)pyrimidin-4-yl]methoxy]phenoxy]butanoic+acid'>DQ0</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> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6kot FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kot OCA], [http://pdbe.org/6kot PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kot RCSB], [http://www.ebi.ac.uk/pdbsum/6kot PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kot ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://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] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The series of des-Cl (unsubstituted) and m-Cl phenyl analogues of PYR with various flexible 6-substituents were synthesized and studied for the binding affinities with highly resistant quadruple mutant (QM) DHFR. The derivatives carrying 4 atoms linker with a terminal carboxyl substituted on the aromatic ring exhibited good inhibition to the QM enzyme and also showed effective antimalarial activities against resistant P. falciparum bearing the mutant enzymes with relatively low cytotoxicity to mammalian cells. The X-ray crystallographic analysis of the enzyme-inhibitor complexes suggested that the hydrophobic substituent at 6-position was accommodated well in the hydrophobic pocket and the optimal length of the flexible linker could effectively promote the binding of the terminal carboxyl group to the key amino acid residues, Arg59 and Arg122. | |||
6-Hydrophobic aromatic substituent pyrimethamine analogues as potential antimalarials for pyrimethamine-resistant Plasmodium falciparum.,Saepua S, Sadorn K, Vanichtanankul J, Anukunwithaya T, Rattanajak R, Vitsupakorn D, Kamchonwongpaisan S, Yuthavong Y, Thongpanchang C Bioorg Med Chem. 2019 Dec 15;27(24):115158. doi: 10.1016/j.bmc.2019.115158. Epub , 2019 Oct 28. PMID:31685330<ref>PMID:31685330</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6kot" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Vanichtanankul, J]] | |||
[[Category: Vitsupakorn, D]] | |||
[[Category: Inhibitor]] | |||
[[Category: Oxidoreductase]] | |||
[[Category: Plasmodium falciparum]] | |||
[[Category: Quadruple mutant dihydrofolate reductase]] | |||
[[Category: Transferase]] | |||
Revision as of 11:05, 4 December 2019
Quadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with B12128 and NADPHQuadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with B12128 and NADPH
Structural highlights
Function[D9N170_PLAFA] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism (By similarity).[PIRNR:PIRNR000389] Publication Abstract from PubMedThe series of des-Cl (unsubstituted) and m-Cl phenyl analogues of PYR with various flexible 6-substituents were synthesized and studied for the binding affinities with highly resistant quadruple mutant (QM) DHFR. The derivatives carrying 4 atoms linker with a terminal carboxyl substituted on the aromatic ring exhibited good inhibition to the QM enzyme and also showed effective antimalarial activities against resistant P. falciparum bearing the mutant enzymes with relatively low cytotoxicity to mammalian cells. The X-ray crystallographic analysis of the enzyme-inhibitor complexes suggested that the hydrophobic substituent at 6-position was accommodated well in the hydrophobic pocket and the optimal length of the flexible linker could effectively promote the binding of the terminal carboxyl group to the key amino acid residues, Arg59 and Arg122. 6-Hydrophobic aromatic substituent pyrimethamine analogues as potential antimalarials for pyrimethamine-resistant Plasmodium falciparum.,Saepua S, Sadorn K, Vanichtanankul J, Anukunwithaya T, Rattanajak R, Vitsupakorn D, Kamchonwongpaisan S, Yuthavong Y, Thongpanchang C Bioorg Med Chem. 2019 Dec 15;27(24):115158. doi: 10.1016/j.bmc.2019.115158. Epub , 2019 Oct 28. PMID:31685330[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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