Publication: Insights into antifolate resistance from malarial DHFR-TS structures
Issued Date
2003-05-01
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ISSN
10728368
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2-s2.0-0242501573
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Mahidol University
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SCOPUS
Bibliographic Citation
Nature Structural Biology. Vol.10, No.5 (2003), 357-365
Suggested Citation
Jirundon Yuvaniyama, Penchit Chitnumsub, Sumalee Kamchonwongpaisan, Jarunee Vanichtanankul, Worachart Sirawaraporn, Paul Taylor, Malcolm D. Walkinshaw, Yongyuth Yuthavong Insights into antifolate resistance from malarial DHFR-TS structures. Nature Structural Biology. Vol.10, No.5 (2003), 357-365. doi:10.1038/nsb921 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/20734
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Title
Insights into antifolate resistance from malarial DHFR-TS structures
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.