2NO9

The structure of deoxycytidine kinase complexed with troxacitabine and ADP.

Summary for 2NO9

• Entry DOI: 10.2210/pdb2no9/pdb
• Related: 1NO6 1P5Z 1P60 1P61 1P62 2A2Z 2A30 2NO0 2NO1 2NO7 2NOA
• Descriptor: deoxycytidine kinase, ADENOSINE-5'-DIPHOSPHATE, 4-AMINO-1-[(2S,4S)-2-(HYDROXYMETHYL)-1,3-DIOXOLAN-4-YL]PYRIMIDIN-2(1H)-ONE, ... (4 entities in total)
• Functional Keywords: dck, troxacitabine, human deoxycytidine kinase, l-dc, enantiomer, anticancer, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 66599.96

Authors

Sabini, E.,Lavie, A. (deposition date: 2006-10-25, release date: 2007-02-13, Last modification date: 2023-08-30)

Primary citation

Sabini, E.,Hazra, S.,Konrad, M.,Burley, S.K.,Lavie, A.
Structural basis for activation of the therapeutic L-nucleoside analogs 3TC and troxacitabine by human deoxycytidine kinase.
Nucleic Acids Res., 35:186-192, 2007

PubMed Abstract: L-nucleoside analogs represent an important class of small molecules for treating both viral infections and cancers. These pro-drugs achieve pharmacological activity only after enzyme-catalyzed conversion to their tri-phosphorylated forms. Herein, we report the crystal structures of human deoxycytidine kinase (dCK) in complex with the L-nucleosides (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC)--an approved anti-human immunodeficiency virus (HIV) agent--and troxacitabine (TRO)--an experimental anti-neoplastic agent. The first step in activating these agents is catalyzed by dCK. Our studies reveal how dCK, which normally catalyzes phosphorylation of the natural D-nucleosides, can efficiently phosphorylate substrates with non-physiologic chirality. The capability of dCK to phosphorylate both D- and L-nucleosides and nucleoside analogs derives from structural properties of both the enzyme and the substrates themselves. First, the nucleoside-binding site tolerates substrates with different chiral configurations by maintaining virtually all of the protein-ligand interactions responsible for productive substrate positioning. Second, the pseudo-symmetry of nucleosides and nucleoside analogs in combination with their conformational flexibility allows the L- and D-enantiomeric forms to adopt similar shapes when bound to the enzyme. This is the first analysis of the structural basis for activation of L-nucleoside analogs, providing further impetus for discovery and clinical development of new agents in this molecular class.

PubMed: 17158155
DOI: 10.1093/nar/gkl1038

Experimental method

X-RAY DIFFRACTION (2.15 Å)