2Y8C

Plasmodium falciparum dUTPase in complex with a trityl ligand

2Y8C の概要

• エントリーDOI: 10.2210/pdb2y8c/pdb
• 関連するPDBエントリー: 1VYQ
• 分子名称: DEOXYURIDINE 5'-TRIPHOSPHATE NUCLEOTIDOHYDROLASE, (2S)-2-[(2,4-dioxopyrimidin-1-yl)methyl]-N-(2-hydroxyethyl)-4-trityloxy-butanamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: hydrolase, malaria
• 由来する生物種: PLASMODIUM FALCIPARUM
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 60542.40

構造登録者

Baragana, B.,McCarthy, O.,Sanchez, P.,Bosch, C.,Kaiser, M.,Brun, R.,Whittingham, J.L.,Roberts, S.,Zhou, X.-X.,Wilson, K.S.,Johansson, N.G.,Gonzalez-Pacanowska, D.,Gilbert, I.H. (登録日: 2011-02-04, 公開日: 2012-03-07, 最終更新日: 2023-12-20)

主引用文献

Baragana, B.,Mccarthy, O.,Sanchez, P.,Bosch, C.,Kaiser, M.,Brun, R.,Whittingham, J.L.,Roberts, S.,Zhou, X.-X.,Wilson, K.S.,Johansson, N.G.,Gonzalez-Pacanowska, D.,Gilbert, I.H.
Beta-Branched Acyclic Nucleoside Analogues as Inhibitors of Plasmodium Falciparum Dutpase
Bioorg.Med.Chem., 19:2378-, 2011

PubMed Abstract: We report a series of β-branched acyclic tritylated deoxyuridine analogues as inhibitors of Plasmodium falciparum deoxyuridine-5'-triphosphate nucleotidohydrolase (PfdUTPase), an enzyme involved in nucleotide metabolism that acts as first line of defence against uracil incorporation into DNA. Compounds were assayed against both PfdUTPase and intact parasites showing a correlation between enzyme inhibition and cellular assays. β-Branched acyclic uridine analogues described here showed equal or slightly better potency and selectivity compared with previously reported analogues. The best inhibitor gave a K(i) of 0.5 μM against PfdUTPase with selectivity greater than 200-fold compared to the corresponding human enzyme and sub-micromolar growth inhibition of P. falciparum (EC(50) 0.6 μM). A crystal structure of the complex of PfdUTPase with one of the inhibitors shows that this acyclic derivative binds to the active site in a similar manner to that previously reported for a tritylated cyclic deoxyuridine derivative.

PubMed: 21411327
DOI: 10.1016/J.BMC.2011.02.012

実験手法

X-RAY DIFFRACTION (2.1 Å)