3um5: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Double mutant (A16V+S108T) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS-T9/94) complexed with pyrimethamine, NADPH, and dUMP== | ==Double mutant (A16V+S108T) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS-T9/94) complexed with pyrimethamine, NADPH, and dUMP== | ||
<StructureSection load='3um5' size='340' side='right' caption='[[3um5]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='3um5' size='340' side='right' caption='[[3um5]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3um5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[3um5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Plafa Plafa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UM5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UM5 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CP6:5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE'>CP6</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> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CP6:5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE'>CP6</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3um6|3um6]], [[3um8|3um8]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3um6|3um6]], [[3um8|3um8]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dhfr-ts ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5833 | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dhfr-ts ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5833 PLAFA])</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=3um5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3um5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3um5 RCSB], [http://www.ebi.ac.uk/pdbsum/3um5 PDBsum]</span></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=3um5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3um5 OCA], [http://pdbe.org/3um5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3um5 RCSB], [http://www.ebi.ac.uk/pdbsum/3um5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3um5 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | |||
[[http://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 16: | Line 19: | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 3um5" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
| Line 23: | Line 27: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Plafa]] | ||
[[Category: Chitnumsub, P]] | [[Category: Chitnumsub, P]] | ||
[[Category: Kamchonwongpaisan, S]] | [[Category: Kamchonwongpaisan, S]] | ||
Revision as of 17:56, 11 August 2016
Double mutant (A16V+S108T) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS-T9/94) complexed with pyrimethamine, NADPH, and dUMPDouble mutant (A16V+S108T) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS-T9/94) complexed with pyrimethamine, NADPH, and dUMP
Structural highlights
Function[A7UD81_PLAFA] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism.[PIRNR:PIRNR000389] Publication Abstract from PubMedNatural mutations of Plasmodium falciparum dihydrofolate reductase (PfDHFR) at A16V and S108T specifically confer resistance to cycloguanil (CYC) but not to pyrimethamine (PYR). In order to understand the nature of CYC resistance, the effects of various mutations at A16 on substrate and inhibitor binding were examined. Three series of mutations at A16 with or without the S108T/N mutation were generated. Only three mutants with small side chains at residue 16 (G, C, and S) were viable from bacterial complementation assay in the S108 series, whereas these three and an additional four mutants (T, V, M, and I) with slightly larger side chains were viable with simultaneous S108T mutation. Among these combinations, the A16V+S108T mutant was the most CYC resistant, and all of the S108T series ranged from being highly to moderately sensitive to PYR. In the S108N series, a strict requirement for alanine was observed at position 16. Crystal structure analyses reveal that in PfDHFR-TS variant T9/94 (A16V+S108T) complexed with CYC, the ligand has substantial steric conflicts with the side chains of both A16V and S108T, whereas in the complex with PYR, the ligand only showed mild conflict with S108T. CYC analogs designed to avoid such conflicts improved the binding affinity of the mutant enzymes. These results show that there is greater spatial limitation around the S108T/N residue when combined with the limitation imposed by A16V. The limitation of mutation of this series provides opportunities for drug design and development against antifolate-resistant malaria. Combined Spatial Limitation around Residues 16 and 108 of Plasmodium falciparum Dihydrofolate Reductase Explains Resistance to Cycloguanil.,Vanichtanankul J, Taweechai S, Uttamapinant C, Chitnumsub P, Vilaivan T, Yuthavong Y, Kamchonwongpaisan S Antimicrob Agents Chemother. 2012 Jul;56(7):3928-35. Epub 2012 Apr 23. PMID:22526319[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||