1J3I

Wild-type Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with WR99210, NADPH, and dUMP

1J3I の概要

• エントリーDOI: 10.2210/pdb1j3i/pdb
• 関連するPDBエントリー: 1J3J 1J3K
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, 6,6-DIMETHYL-1-[3-(2,4,5-TRICHLOROPHENOXY)PROPOXY]-1,6-DIHYDRO-1,3,5-TRIAZINE-2,4-DIAMINE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• 機能のキーワード: bifunctional, oxidoreductase, transferase
• 由来する生物種: Plasmodium falciparum (malaria parasite P. falciparum); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 146588.83

構造登録者

Yuvaniyama, J.,Chitnumsub, P.,Kamchonwongpaisan, S.,Vanichtanankul, J.,Sirawaraporn, W.,Taylor, P.,Walkinshaw, M.,Yuthavong, Y. (登録日: 2003-02-03, 公開日: 2003-05-06, 最終更新日: 2023-12-27)

主引用文献

Yuvaniyama, J.,Chitnumsub, P.,Kamchonwongpaisan, S.,Vanichtanankul, J.,Sirawaraporn, W.,Taylor, P.,Walkinshaw, M.D.,Yuthavong, Y.
Insights into antifolate resistance from malarial DHFR-TS structures.
NAT.STRUCT.BIOL., 10:357-365, 2003

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.

PubMed: 12704428
DOI: 10.1038/nsb921

実験手法

X-RAY DIFFRACTION (2.33 Å)