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3um6

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Current revision (08:38, 20 March 2024) (edit) (undo)
 
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<StructureSection load='3um6' size='340' side='right'caption='[[3um6]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
<StructureSection load='3um6' size='340' side='right'caption='[[3um6]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3um6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plafa Plafa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UM6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UM6 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3um6]] 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=3UM6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UM6 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1CY:1-(4-CHLOROPHENYL)-6,6-DIMETHYL-1,6-DIHYDRO-1,3,5-TRIAZINE-2,4-DIAMINE'>1CY</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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.65&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3um8|3um8]]</div></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1CY:1-(4-CHLOROPHENYL)-6,6-DIMETHYL-1,6-DIHYDRO-1,3,5-TRIAZINE-2,4-DIAMINE'>1CY</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>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dhfr-ts ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5833 PLAFA])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3um6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3um6 OCA], [https://pdbe.org/3um6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3um6 RCSB], [https://www.ebi.ac.uk/pdbsum/3um6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3um6 ProSAT]</span></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=3um6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3um6 OCA], [https://pdbe.org/3um6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3um6 RCSB], [https://www.ebi.ac.uk/pdbsum/3um6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3um6 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/A7UD81_PLAFA A7UD81_PLAFA]] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism.[PIRNR:PIRNR000389]
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[https://www.uniprot.org/uniprot/A7UD81_PLAFA A7UD81_PLAFA] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism.[PIRNR:PIRNR000389]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Natural 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.
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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<ref>PMID:22526319</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3um6" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
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== References ==
 
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<references/>
 
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Plafa]]
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[[Category: Plasmodium falciparum]]
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[[Category: Chitnumsub, P]]
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[[Category: Chitnumsub P]]
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[[Category: Kamchonwongpaisan, S]]
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[[Category: Kamchonwongpaisan S]]
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[[Category: Vanichtanankul, J]]
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[[Category: Vanichtanankul J]]
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[[Category: Yuthavong, Y]]
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[[Category: Yuthavong Y]]
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[[Category: Antifolate]]
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[[Category: Cycloguanil]]
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[[Category: Dump]]
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[[Category: Malarial dhfr-t]]
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[[Category: Napdh]]
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[[Category: Oxidoreductase]]
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[[Category: Transferase-inhibitor complex]]
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Current revision

Double mutant (A16V+S108T) Plasmodium falciparum DHFR-TS (T9/94) complexed with cycloguanil, NADPH and dUMP

PDB ID 3um6

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