PMID:12704428

Citation	Yuvaniyama, J, Chitnumsub, P, Kamchonwongpaisan, S, Vanichtanankul, J, Sirawaraporn, W, Taylor, P, Walkinshaw, MD and Yuthavong, Y (2003) Insights into antifolate resistance from malarial DHFR-TS structures. Nat. Struct. Biol. 10:357-65
Abstract	Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is an important target of antimalarial drugs. The efficacy of this class of DHFR-inhibitor drugs is now compromised because of mutations that prevent drug binding yet retain enzyme activity. The crystal structures of PfDHFR-TS from the wild type (TM4/8.2) and the quadruple drug-resistant mutant (V1/S) strains, in complex with a potent inhibitor WR99210, as well as the resistant double mutant (K1 CB1) with the antimalarial pyrimethamine, reveal features for overcoming resistance. In contrast to pyrimethamine, the flexible side chain of WR99210 can adopt a conformation that fits well in the active site, thereby contributing to binding. The single-chain bifunctional PfDHFR-TS has a helical insert between the DHFR and TS domains that is involved in dimerization and domain organization. Moreover, positively charged grooves on the surface of the dimer suggest a function in channeling of substrate from TS to DHFR active sites. These features provide possible approaches for the design of new drugs to overcome antifolate resistance.
Links	PubMed Online version:10.1038/nsb921
Keywords	Amino Acid Sequence; Animals; Conserved Sequence; Drug Resistance; Folic Acid Antagonists/pharmacology; Models, Molecular; Molecular Sequence Data; Multienzyme Complexes/antagonists & inhibitors; Multienzyme Complexes/chemistry; Plasmodium/enzymology; Plasmodium falciparum/enzymology; Protein Conformation; Sequence Alignment; Sequence Homology, Amino Acid; Tetrahydrofolate Dehydrogenase/chemistry; Thymidylate Synthase/antagonists & inhibitors; Thymidylate Synthase/chemistry
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
PLAFK:DRTS		GO:0004799: thymidylate synthase activity	ECO:0000314:		F		Panel B in Figure 2 establishes the activity of Thymidylate Synthase in Plasmodium falciparium dihydrofolate reductase-thymidylate synthase. Figure 2 shows the junction region of alpha helix as a docking element onto the DHFR-TS domain interface. The long-range electrostatic interactions are among the major forces attracting the negatively charged alpha helix of a TS domain to the surface groove lined with positively charged amino acids from the helices of the DHFR domain.	complete CACAO 11982

References

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