6KPR

Quadruple mutant (N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) complexed with B12155 inhibitor

6KPR の概要

• エントリーDOI: 10.2210/pdb6kpr/pdb
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• 機能のキーワード: dihydrofolate reductase, plasmodium falciparum, antimalarial, antifolate, antibiotic, oxidoreductase, transferase
• 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: 147021.50

構造登録者

Vanichtanankul, J.,Vitsupakorn, D. (登録日: 2019-08-15, 公開日: 2019-12-04, 最終更新日: 2023-11-22)

主引用文献

Saepua, S.,Sadorn, K.,Vanichtanankul, J.,Anukunwithaya, T.,Rattanajak, R.,Vitsupakorn, D.,Kamchonwongpaisan, S.,Yuthavong, Y.,Thongpanchang, C.
6-Hydrophobic aromatic substituent pyrimethamine analogues as potential antimalarials for pyrimethamine-resistant Plasmodium falciparum.
Bioorg.Med.Chem., 27:115158-115158, 2019

PubMed Abstract: The series of des-Cl (unsubstituted) and m-Cl phenyl analogues of PYR with various flexible 6-substituents were synthesized and studied for the binding affinities with highly resistant quadruple mutant (QM) DHFR. The derivatives carrying 4 atoms linker with a terminal carboxyl substituted on the aromatic ring exhibited good inhibition to the QM enzyme and also showed effective antimalarial activities against resistant P. falciparum bearing the mutant enzymes with relatively low cytotoxicity to mammalian cells. The X-ray crystallographic analysis of the enzyme-inhibitor complexes suggested that the hydrophobic substituent at 6-position was accommodated well in the hydrophobic pocket and the optimal length of the flexible linker could effectively promote the binding of the terminal carboxyl group to the key amino acid residues, Arg59 and Arg122.

PubMed: 31685330
DOI: 10.1016/j.bmc.2019.115158

実験手法

X-RAY DIFFRACTION (2.1 Å)