Insights into antifolate resistance from malarial DHFR-TS structures.
Article Details
- CitationCopy to clipboard
Yuvaniyama J, Chitnumsub P, Kamchonwongpaisan S, Vanichtanankul J, Sirawaraporn W, Taylor P, Walkinshaw MD, Yuthavong Y
Insights into antifolate resistance from malarial DHFR-TS structures.
Nat Struct Biol. 2003 May;10(5):357-65.
- PubMed ID
- 12704428 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Polypeptides
Name UniProt ID Bifunctional dihydrofolate reductase-thymidylate synthase P13922 Details - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Pyrimethamine Bifunctional dihydrofolate reductase-thymidylate synthase Ki (nM) 9.8 7 25 Details Pyrimethamine Bifunctional dihydrofolate reductase-thymidylate synthase IC 50 (nM) 30900 7 25 Details