View source for 6lhj


==Quadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with C452 (compound 16) and NADPH==
<StructureSection load='6lhj' size='340' side='right'caption='[[6lhj]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6lhj]] 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=6LHJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LHJ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EA6:1-[3-(2-chloranyl-4-fluoranyl-phenoxy)propoxy]-6,6-dimethyl-1,3,5-triazine-2,4-diamine'>EA6</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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'>[https://proteopedia.org/fgij/fg.htm?mol=6lhj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lhj OCA], [https://pdbe.org/6lhj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6lhj RCSB], [https://www.ebi.ac.uk/pdbsum/6lhj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6lhj ProSAT]</span></td></tr>
</table>
== Function ==
[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]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A series of flexible diaminodihydrotriazines or cycloguanil (Cyc) analogues are developed and shown to inhibit P. falciparum dihydrofolate reductase (PfDHFR) of the wild type or those carrying either single (S108N), double (C59R + S108N and A16V + S108T), triple (N51I + C59R + S108N and C59R + S108N + I164L) or quadruple (N51I + C59R + S108N + I164L) mutations, responsible for antifolate resistance. The flexibility of the side chain at position N(1) has been included in the design so as to avoid unfavourable steric interaction with the side chain of residue 108 of the resistant mutants. The inhibition constants of many inhibitors for the mutant enzymes are in the low nanomolar region. Regaining of drug binding efficacies was achieved with both A16V and S108N series of mutants. X-ray studies of some enzyme-inhibitor complexes designed for optimal interaction with the mutant enzymes reveal the modes of binding in line with the Ki values. A number of these compounds show excellent antimalarial activities against resistant P. falciparum bearing the mutant enzymes, and exhibit low cytotoxicity to mammalian cells, making them good candidates for further development as antimalarial drugs.

Flexible diaminodihydrotriazine inhibitors of Plasmodium falciparum dihydrofolate reductase: Binding strengths, modes of binding and their antimalarial activities.,Kamchonwongpaisan S, Charoensetakul N, Srisuwannaket C, Taweechai S, Rattanajak R, Vanichtanankul J, Vitsupakorn D, Arwon U, Thongpanchang C, Tarnchompoo B, Vilaivan T, Yuthavong Y Eur J Med Chem. 2020 Jun 1;195:112263. doi: 10.1016/j.ejmech.2020.112263. Epub, 2020 Mar 25. PMID:32294614<ref>PMID:32294614</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6lhj" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Plasmodium falciparum]]
[[Category: Vanichtanankul J]]
[[Category: Vitsupakorn D]]