4dp3: Difference between revisions
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[[ | ==Quadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with P218 and NADPH== | ||
<StructureSection load='4dp3' size='340' side='right' caption='[[4dp3]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4dp3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum_vs/1 Plasmodium falciparum vs/1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DP3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DP3 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MMV:3-(2-{3-[(2,4-DIAMINO-6-ETHYLPYRIMIDIN-5-YL)OXY]PROPOXY}PHENYL)PROPANOIC+ACID'>MMV</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1j3k|1j3k]], [[2jsu|2jsu]], [[3qg2|3qg2]], [[4dpd|4dpd]], [[4dph|4dph]], [[4ddr|4ddr]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DHFR-TS, V1/S ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=478864 Plasmodium falciparum VS/1])</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=4dp3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dp3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dp3 RCSB], [http://www.ebi.ac.uk/pdbsum/4dp3 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Malarial 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<ref>PMID:23035243</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | |||
== | *[[Dihydrofolate reductase|Dihydrofolate reductase]] | ||
[[ | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Plasmodium falciparum vs/1]] | [[Category: Plasmodium falciparum vs/1]] | ||
[[Category: Arwon, U | [[Category: Arwon, U]] | ||
[[Category: Bongard, E | [[Category: Bongard, E]] | ||
[[Category: Charman, S A | [[Category: Charman, S A]] | ||
[[Category: Charman, W N | [[Category: Charman, W N]] | ||
[[Category: Chitnumsub, P | [[Category: Chitnumsub, P]] | ||
[[Category: Fantauzzi, P | [[Category: Fantauzzi, P]] | ||
[[Category: Kamchonwongpaisan, S | [[Category: Kamchonwongpaisan, S]] | ||
[[Category: Matthews, D | [[Category: Matthews, D]] | ||
[[Category: McLennan, D N | [[Category: McLennan, D N]] | ||
[[Category: Tarnchompoo, B | [[Category: Tarnchompoo, B]] | ||
[[Category: Taweechai, S | [[Category: Taweechai, S]] | ||
[[Category: Thongphanchang, C | [[Category: Thongphanchang, C]] | ||
[[Category: Vanichtanakul, J | [[Category: Vanichtanakul, J]] | ||
[[Category: Vilaivan, T | [[Category: Vilaivan, T]] | ||
[[Category: Vivas, L | [[Category: Vivas, L]] | ||
[[Category: White, K L | [[Category: White, K L]] | ||
[[Category: Yuthavong, Y | [[Category: Yuthavong, Y]] | ||
[[Category: Yuvaniyama, J | [[Category: Yuvaniyama, J]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
[[Category: Reductase]] | [[Category: Reductase]] | ||
[[Category: Rossmann fold]] | [[Category: Rossmann fold]] | ||
[[Category: Transferase-inhibitor complex]] | [[Category: Transferase-inhibitor complex]] | ||
Revision as of 19:22, 9 December 2014
Quadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with P218 and NADPHQuadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with P218 and NADPH
Structural highlights
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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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Plasmodium falciparum vs/1
- Arwon, U
- Bongard, E
- Charman, S A
- Charman, W N
- Chitnumsub, P
- Fantauzzi, P
- Kamchonwongpaisan, S
- Matthews, D
- McLennan, D N
- Tarnchompoo, B
- Taweechai, S
- Thongphanchang, C
- Vanichtanakul, J
- Vilaivan, T
- Vivas, L
- White, K L
- Yuthavong, Y
- Yuvaniyama, J
- Oxidoreductase
- Reductase
- Rossmann fold
- Transferase-inhibitor complex