2NO7

C4S dCK variant of dCK in complex with L-dC+ADP

2NO7 の概要

• エントリーDOI: 10.2210/pdb2no7/pdb
• 関連するPDBエントリー: 1NO6 1P5Z 1P60 1P61 1P62 2A2Z 2A30 2NO0 2NO1 2NO9 2NOA
• 分子名称: deoxycytidine kinase, ADENOSINE-5'-DIPHOSPHATE, 4-AMINO-1-(2-DEOXY-BETA-L-ERYTHRO-PENTOFURANOSYL)PYRIMIDIN-2(1H)-ONE, ... (4 entities in total)
• 機能のキーワード: dck, human deoxycytidine kinase, l-dc, enantiomer, enantioselectivity, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66628.01

構造登録者

Sabini, E.,Hazra, S.,Konrad, M.,Burley, S.K.,Lavie, A. (登録日: 2006-10-25, 公開日: 2007-07-03, 最終更新日: 2023-08-30)

主引用文献

Sabini, E.,Hazra, S.,Konrad, M.,Lavie, A.
Nonenantioselectivity Property of Human Deoxycytidine Kinase Explained by Structures of the Enzyme in Complex with l- and d-Nucleosides.
J.Med.Chem., 50:3004-3014, 2007

PubMed Abstract: Biological molecules are predominantly enantioselective. Yet currently two nucleoside analogue prodrugs (3TC and FTC) with opposite chirality compared to physiological nucleosides are clinically approved for the treatment of HIV infections. These prodrugs require conversion to their triphosphorylated forms to achieve pharmacological activity. The first step in the activation of these agents is catalyzed by human deoxycytidine kinase (dCK). This enzyme possesses the ability to phosphorylate nucleosides of the unnatural L-chirality. To understand the molecular basis for the nonenantioselectivity of dCK, we solved the crystal structures of the enzyme in complex with the L-enantiomer and of its physiological substrate deoxycytidine and with the L-nucleoside analogue FTC. These were compared to a structure solved with D-dC. Our results highlight structural adjustments imposed on the L-nucleosides and properties of the enzyme endowing it with the ability to phosphorylate substrates with nonphysiological chirality. This work reveals the molecular basis for the activation of L-nucleosides by dCK.

PubMed: 17530837
DOI: 10.1021/jm0700215

実験手法

X-RAY DIFFRACTION (1.7 Å)