6A2O

Crystal structure of wild type Plasmodium falciparum DHFR-TS complexed with BT3, NADPH, and dUMP

6A2O の概要

• エントリーDOI: 10.2210/pdb6a2o/pdb
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, 5,5'-[propane-1,3-diylbis(oxy-4,1-phenylene)]bis(6-ethylpyrimidine-2,4-diamine), NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• 機能のキーワード: rossmann fold, dual-binding inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Plasmodium falciparum (malaria parasite P. falciparum)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 146760.36

構造登録者

Chitnumsub, P.,Jaruwat, A.,Tarnchampoo, B.,Yuthavong, Y. (登録日: 2018-06-12, 公開日: 2019-04-24, 最終更新日: 2023-11-22)

主引用文献

Tarnchompoo, B.,Chitnumsub, P.,Jaruwat, A.,Shaw, P.J.,Vanichtanankul, J.,Poen, S.,Rattanajak, R.,Wongsombat, C.,Tonsomboon, A.,Decharuangsilp, S.,Anukunwithaya, T.,Arwon, U.,Kamchonwongpaisan, S.,Yuthavong, Y.
Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance.
ACS Med Chem Lett, 9:1235-1240, 2018

PubMed Abstract: The S108N mutation of dihydrofolate reductase (DHFR) renders malaria parasites resistant to pyrimethamine through steric clash with the rigid side chain of the inhibitor. Inhibitors with flexible side chains can avoid this clash and retain effectiveness against the mutant. However, other mutations such as N108S reversion confer resistance to flexible inhibitors. We designed and synthesized hybrid inhibitors with two structural types in a single molecule, which are effective against both wild-type and multiple mutants of through their selective target binding, as demonstrated by X-ray crystallography. Furthermore, the hybrid inhibitors can forestall the emergence of new resistant mutants, as shown by selection of mutants resistant to hybrid compound from a diverse PfDHFR random mutant library expressed in a surrogate bacterial system. These results show that it is possible to develop effective antifolate antimalarials to which the range of parasite resistance mutations is greatly reduced.

PubMed: 30613332
DOI: 10.1021/acsmedchemlett.8b00389

実験手法

X-RAY DIFFRACTION (2.35 Å)