2noa

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spinqualitylabelsall models 2noa, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

The structure of deoxycytidine kinase complexed with lamivudine and ADP.

Overview

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.

About this Structure

2NOA is a Single protein structure of sequence from Homo sapiens with ADP and 3TC as ligands. Active as Deoxycytidine kinase, with EC number 2.7.1.74 Full crystallographic information is available from OCA.

Reference

Structural basis for activation of the therapeutic L-nucleoside analogs 3TC and troxacitabine by human deoxycytidine kinase., Sabini E, Hazra S, Konrad M, Burley SK, Lavie A, Nucleic Acids Res. 2007;35(1):186-92. Epub 2006 Dec 7. PMID:17158155

Page seeded by OCA on Mon Nov 12 23:00:43 2007