3um5

Double mutant (A16V+S108T) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS-T9/94) complexed with pyrimethamine, NADPH, and dUMP

spinqualitylabelsall models 3um5, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3um5 is a 2 chain structure with sequence from Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: CP6, NDP, UMP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A7UD81_PLAFA Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism.[PIRNR:PIRNR000389] Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrofolate reductase 3D structures

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