2a7q
From Proteopedia
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Crystal structure of human dCK complexed with clofarabine and ADP
Overview
Clofarabine, [2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purin-6-amine], is a hybrid of the widely used anticancer drugs cladribine and, fludarabine. It is the precursor of an effective chemotherapeutic agent, for leukemias and other hematological malignancies and received, accelerated approval by the FDA for the treatment of pediatric patients, with relapsed or refractory acute lymphoblastic leukemia. Clofarabine is, phosphorylated intracellularly by human deoxycytidine kinase (dCK) to the, 5'-monophosphate, which is the rate-limiting step in activation of the, prodrug. dCK has a broad substrate specificity, with a much higher, activity to deoxycytidine than to deoxyadenosine and deoxyguanosine. As a, purine-nucleoside analog, clofarabine is a better substrate of dCK than, deoxycytidine. The crystal structure of dCK has been solved previously in, complex with pyrimidine nucleosides and ADP [Sabini et al. (2003), Nature, Struct. Biol. 10, 513-519]. In the current study, the crystal structure of, clofarabine- and ADP-bound dCK was solved to 2.55 angstroms by molecular, replacement. It appears that the enzyme takes the same conformation as in, the structures of the pyrimidine nucleoside-bound complexes. The, interactions between 2-Cl and its surrounding hydrophobic residues, contribute to the high catalytic efficiency of dCK for clofarabine.
About this Structure
2A7Q is a Single protein structure of sequence from Homo sapiens with MG, ADP and CFB as ligands. Active as Deoxycytidine kinase, with EC number 2.7.1.74 Full crystallographic information is available from OCA.
Reference
The structure of human deoxycytidine kinase in complex with clofarabine reveals key interactions for prodrug activation., Zhang Y, Secrist JA 3rd, Ealick SE, Acta Crystallogr D Biol Crystallogr. 2006 Feb;62(Pt 2):133-9. Epub 2006, Jan 18. PMID:16421443
Page seeded by OCA on Mon Nov 12 20:47:04 2007
