1P62

Structure of human dCK complexed with gemcitabine and ADP-MG

Summary for 1P62

• Entry DOI: 10.2210/pdb1p62/pdb
• Related: 1P5Z 1P60 1P61
• Descriptor: Deoxycytidine kinase, MAGNESIUM ION, ADENOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: nucleoside kinase, p-loop, gemcitabine, transferase
• Biological source: Mus musculus (house mouse)
• Cellular location: Nucleus: P27707
• Total number of polymer chains: 1
• Total formula weight: 31549.48

Authors

Sabini, E.,Ort, S.,Monnerjahn, C.,Konrad, M.,Lavie, A. (deposition date: 2003-04-28, release date: 2003-07-01, Last modification date: 2024-02-14)

Primary citation

Sabini, E.,Ort, S.,Monnerjahn, C.,Konrad, M.,Lavie, A.
Structure of human dCK suggests strategies to improve anticancer and antiviral therapy
Nat.Struct.Biol., 10:513-519, 2003

PubMed Abstract: Human deoxycytidine kinase (dCK) phosphorylates the natural deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA) and is an essential enzyme for the phosphorylation of numerous nucleoside analog prodrugs routinely used in cancer and antiviral chemotherapy. For many of these compounds, the phosphorylation step catalyzed by dCK is the rate-limiting step in their overall activation pathway. To determine the factors that limit the phosphorylation efficiency of the prodrug, we solved the crystal structure of dCK to a resolution of 1.6 A in complex with its physiological substrate deoxycytidine and with the prodrugs AraC and gemcitabine. The structures reveal the determinants of dCK substrate specificity. Especially relevant to new prodrug development is the interaction between Arg128 and the hydrogen-bond acceptor at the sugar 2'-arabinosyl position of AraC and gemcitabine. On the basis of the structures, we designed a catalytically superior dCK variant that could be used in suicide gene-therapy applications.

PubMed: 12808445
DOI: 10.1038/nsb942

Experimental method

X-RAY DIFFRACTION (1.9 Å)