2NO6

C4S dCK variant of dCK in complex with FTC+ADP

Summary for 2NO6

• Entry DOI: 10.2210/pdb2no6/pdb
• Related: 1NO7 1P5Z 1P60 1P61 1P62 2A2Z 2A30 2NO0 2NO1 2NO9 2NOA
• Descriptor: deoxycytidine kinase, ADENOSINE-5'-DIPHOSPHATE, 4-AMINO-5-FLUORO-1-[(2R,5S)-2-(HYDROXYMETHYL)-1,3-OXATHIOLAN-5-YL]PYRIMIDIN-2(1H)-ONE, ... (4 entities in total)
• Functional Keywords: dck, emtricitabine, human deoxycytidine kinase, ftc, enantiomer, antiviral, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 66668.07

Authors

Sabini, E.,Hazra, S.,Konrad, M.,Burley, S.K.,Lavie, A. (deposition date: 2006-10-25, release date: 2007-07-03, Last modification date: 2023-08-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.9 Å)