2ZIA

C4S dCK variant of dCK in complex with cladribine+UDP

Summary for 2ZIA

• Entry DOI: 10.2210/pdb2zia/pdb
• Related: 1P60 2NO1 2NO7 2ZI3 2ZI4 2ZI5 2ZI6 2ZI7 2ZI9
• Descriptor: Deoxycytidine kinase, URIDINE-5'-DIPHOSPHATE, 2-chloro-2'-deoxyadenosine, ... (4 entities in total)
• Functional Keywords: dck, purine, deoxycytidine kinase, nucleoside, cladribine, 2-chloro-2'-deoxyadenosine, deoxyadenosine analog, udp, atp-binding, nucleotide-binding, nucleus, phosphoprotein, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: P27707
• Total number of polymer chains: 2
• Total formula weight: 66524.72

Authors

Sabini, E.,Lavie, A. (deposition date: 2008-02-13, release date: 2008-07-08, Last modification date: 2023-11-01)

Primary citation

Sabini, E.,Hazra, S.,Konrad, M.,Lavie, A.
Elucidation of different binding modes of purine nucleosides to human deoxycytidine kinase
J.Med.Chem., 51:4219-4225, 2008

PubMed Abstract: Purine nucleoside analogues of medicinal importance, such as cladribine, require phosphorylation by deoxycytidine kinase (dCK) for pharmacological activity. Structural studies of ternary complexes of human dCK show that the enzyme conformation adjusts to the different hydrogen-bonding properties between dA and dG and to the presence of substituent at the 2-position present in dG and cladribine. Specifically, the carbonyl group in dG elicits a previously unseen conformational adjustment of the active site residues Arg104 and Asp133. In addition, dG and cladribine adopt the anti conformation, in contrast to the syn conformation observed with dA. Kinetic analysis reveals that cladribine is phosphorylated at the highest efficiency with UTP as donor. We attribute this to the ability of cladribine to combine advantageous properties from dA (favorable hydrogen-bonding pattern) and dG (propensity to bind to the enzyme in its anti conformation), suggesting that dA analogues with a substituent at the 2-position are likely to be better activated by human dCK.

PubMed: 18570408
DOI: 10.1021/jm800134t

Experimental method

X-RAY DIFFRACTION (1.8 Å)