4dpd: Difference between revisions
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==WILD TYPE PLASMODIUM FALCIPARUM DIHYDROFOLATE REDUCTASE-THYMIDYLATE SYNTHASE (PfDHFR-TS), DHF COMPLEX, NADP+, dUMP== | ==WILD TYPE PLASMODIUM FALCIPARUM DIHYDROFOLATE REDUCTASE-THYMIDYLATE SYNTHASE (PfDHFR-TS), DHF COMPLEX, NADP+, dUMP== | ||
<StructureSection load='4dpd' size='340' side='right' caption='[[4dpd]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='4dpd' size='340' side='right'caption='[[4dpd]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4dpd]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4dpd]] 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=4DPD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DPD FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DHF:DIHYDROFOLIC+ACID'>DHF</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=4dpd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dpd OCA], [https://pdbe.org/4dpd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dpd RCSB], [https://www.ebi.ac.uk/pdbsum/4dpd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dpd 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/A7UD81_PLAFA A7UD81_PLAFA] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism.[PIRNR:PIRNR000389] | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 23: | Line 21: | ||
==See Also== | ==See Also== | ||
*[[Dihydrofolate reductase|Dihydrofolate reductase]] | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Plasmodium falciparum]] | ||
[[Category: Arwon | [[Category: Arwon U]] | ||
[[Category: Bongard | [[Category: Bongard E]] | ||
[[Category: Charman | [[Category: Charman SA]] | ||
[[Category: Charman | [[Category: Charman WN]] | ||
[[Category: Chitnumsub | [[Category: Chitnumsub P]] | ||
[[Category: Fantauzzi | [[Category: Fantauzzi P]] | ||
[[Category: Kamchonwongpaisan | [[Category: Kamchonwongpaisan S]] | ||
[[Category: Matthews | [[Category: Matthews D]] | ||
[[Category: McLennan | [[Category: McLennan DN]] | ||
[[Category: Tarnchompoo | [[Category: Tarnchompoo B]] | ||
[[Category: Taweechai | [[Category: Taweechai S]] | ||
[[Category: Thongphanchang | [[Category: Thongphanchang C]] | ||
[[Category: Vanichtanakul | [[Category: Vanichtanakul J]] | ||
[[Category: Vilaivan | [[Category: Vilaivan T]] | ||
[[Category: Vivas | [[Category: Vivas L]] | ||
[[Category: White | [[Category: White KL]] | ||
[[Category: Yuthavong | [[Category: Yuthavong Y]] | ||
[[Category: Yuvaniyama | [[Category: Yuvaniyama J]] | ||
Latest revision as of 16:44, 8 November 2023
WILD TYPE PLASMODIUM FALCIPARUM DIHYDROFOLATE REDUCTASE-THYMIDYLATE SYNTHASE (PfDHFR-TS), DHF COMPLEX, NADP+, dUMPWILD TYPE PLASMODIUM FALCIPARUM DIHYDROFOLATE REDUCTASE-THYMIDYLATE SYNTHASE (PfDHFR-TS), DHF COMPLEX, NADP+, dUMP
Structural highlights
FunctionA7UD81_PLAFA Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism.[PIRNR:PIRNR000389] Publication Abstract from PubMedMalarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clinical efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclinical development of a selective, highly efficacious, and orally available antimalarial drug candidate that potently inhibits both wild-type and clinically relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering). An analogous interaction of P218 with human DHFR is disfavored because of three species-dependent amino acid substitutions in the vicinity of the conserved Arg. Thus, P218 binds to the active site of PfDHFR in a substantially different fashion from the human enzyme, which is the basis for its high selectivity. Unlike pyrimethamine, P218 binds both wild-type and mutant PfDHFR in a slow-on/slow-off tight-binding mode, which prolongs the target residence time. P218, when bound to PfDHFR-TS, resides almost entirely within the envelope mapped out by the dihydrofolate substrate, which may make it less susceptible to resistance mutations. The high in vivo efficacy in a SCID mouse model of P. falciparum malaria, good oral bioavailability, favorable enzyme selectivity, and good safety characteristics of P218 make it a potential candidate for further development. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target.,Yuthavong Y, Tarnchompoo B, Vilaivan T, Chitnumsub P, Kamchonwongpaisan S, Charman SA, McLennan DN, White KL, Vivas L, Bongard E, Thongphanchang C, Taweechai S, Vanichtanankul J, Rattanajak R, Arwon U, Fantauzzi P, Yuvaniyama J, Charman WN, Matthews D Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16823-8. doi:, 10.1073/pnas.1204556109. Epub 2012 Oct 3. PMID:23035243[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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