2A7Q

Crystal structure of human dCK complexed with clofarabine and ADP

2A7Q の概要

• エントリーDOI: 10.2210/pdb2a7q/pdb
• 関連するPDBエントリー: 1P5Z 1p60 1p61 1p62
• 分子名称: Deoxycytidine kinase, MAGNESIUM ION, ADENOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: alpha/beta parallel beta-sheet of 5 strands, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P27707
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31589.96

構造登録者

Zhang, Y.,Secrist III, J.A.,Ealick, S.E. (登録日: 2005-07-05, 公開日: 2006-01-24, 最終更新日: 2023-08-23)

主引用文献

Zhang, Y.,Secrist, J.A.,Ealick, S.E.
The structure of human deoxycytidine kinase in complex with clofarabine reveals key interactions for prodrug activation.
Acta Crystallogr.,Sect.D, 62:133-139, 2006

PubMed Abstract: Clofarabine [2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purin-6-amine] is a hybrid of the widely used anticancer drugs cladribine and fludarabine. It is the precursor of an effective chemotherapeutic agent for leukemias and other hematological malignancies and received accelerated approval by the FDA for the treatment of pediatric patients with relapsed or refractory acute lymphoblastic leukemia. Clofarabine is phosphorylated intracellularly by human deoxycytidine kinase (dCK) to the 5'-monophosphate, which is the rate-limiting step in activation of the prodrug. dCK has a broad substrate specificity, with a much higher activity to deoxycytidine than to deoxyadenosine and deoxyguanosine. As a purine-nucleoside analog, clofarabine is a better substrate of dCK than deoxycytidine. The crystal structure of dCK has been solved previously in complex with pyrimidine nucleosides and ADP [Sabini et al. (2003), Nature Struct. Biol. 10, 513-519]. In the current study, the crystal structure of clofarabine- and ADP-bound dCK was solved to 2.55 angstroms by molecular replacement. It appears that the enzyme takes the same conformation as in the structures of the pyrimidine nucleoside-bound complexes. The interactions between 2-Cl and its surrounding hydrophobic residues contribute to the high catalytic efficiency of dCK for clofarabine.

PubMed: 16421443
DOI: 10.1107/S0907444905034293

実験手法

X-RAY DIFFRACTION (2.55 Å)