1P62: Structure Of Human Dck Complexed With Gemcitabine And Adp-Mg

Citation:
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.
PDB ID: 1P62Download
MMDB ID: 23603
PDB Deposition Date: 2003/4/28
Updated in MMDB: 2012/12
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Similar Structures:
Biological Unit for 1P62: dimeric; determined by author and by software (PISA,PQS)
Molecular Components in 1P62
Label Count Molecule
Proteins (2 molecules)
2
Deoxycytidine Kinase(Gene symbol: DCK)
Molecule annotation
Chemicals (6 molecules)
1
2
2
2
3
2
* Click molecule labels to explore molecular sequence information.

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