2ZI9

C4S-E247A dCK variant of dCK in complex with cladribine+ADP

2ZI9 の概要

• エントリーDOI: 10.2210/pdb2zi9/pdb
• 関連するPDBエントリー: 1P60 2NO1 2NO7 2ZI3 2ZI4 2ZI5 2ZI6 2ZI7 2ZIA
• 分子名称: Deoxycytidine kinase, ADENOSINE-5'-DIPHOSPHATE, 2-chloro-2'-deoxyadenosine, ... (4 entities in total)
• 機能のキーワード: dck, purine, cladribine, deoxycytidine kinase, nucleoside, deoxyadenosine analog, atp-binding, nucleotide-binding, nucleus, phosphoprotein, 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: 2
• 化学式量合計: 66454.73

構造登録者

Sabini, E.,Lavie, A. (登録日: 2008-02-13, 公開日: 2008-07-08, 最終更新日: 2024-05-29)

主引用文献

Sabini, E.,Hazra, S.,Konrad, M.,Lavie, A.
Elucidation of different binding modes of purine nucleosides to human deoxycytidine kinase
J.Med.Chem., 51:4219-4225, 2008

PubMed Abstract: Purine nucleoside analogues of medicinal importance, such as cladribine, require phosphorylation by deoxycytidine kinase (dCK) for pharmacological activity. Structural studies of ternary complexes of human dCK show that the enzyme conformation adjusts to the different hydrogen-bonding properties between dA and dG and to the presence of substituent at the 2-position present in dG and cladribine. Specifically, the carbonyl group in dG elicits a previously unseen conformational adjustment of the active site residues Arg104 and Asp133. In addition, dG and cladribine adopt the anti conformation, in contrast to the syn conformation observed with dA. Kinetic analysis reveals that cladribine is phosphorylated at the highest efficiency with UTP as donor. We attribute this to the ability of cladribine to combine advantageous properties from dA (favorable hydrogen-bonding pattern) and dG (propensity to bind to the enzyme in its anti conformation), suggesting that dA analogues with a substituent at the 2-position are likely to be better activated by human dCK.

PubMed: 18570408
DOI: 10.1021/jm800134t

実験手法

X-RAY DIFFRACTION (2.51 Å)