1p60

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Structure of human dCK complexed with 2'-Deoxycytidine and ADP, Space group C 2 2 21

Structural highlights

1p60 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:ADP, DCZ
Gene:DCK (HUMAN)
Activity:Deoxycytidine kinase, with EC number 2.7.1.74
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[DCK_HUMAN] Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents.[1] [2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

Structure of human dCK suggests strategies to improve anticancer and antiviral therapy.,Sabini E, Ort S, Monnerjahn C, Konrad M, Lavie A Nat Struct Biol. 2003 Jul;10(7):513-9. PMID:12808445[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
10 reviews cite this structure
Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer.
Parker et al. (2009)
9 more
80 other articles
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See Also

References

  1. ↑ Sabini E, Hazra S, Ort S, Konrad M, Lavie A. Structural basis for substrate promiscuity of dCK. J Mol Biol. 2008 May 2;378(3):607-21. Epub 2008 Mar 3. PMID:18377927 doi:http://dx.doi.org/10.1016/j.jmb.2008.02.061
  2. ↑ Hazra S, Ort S, Konrad M, Lavie A. Structural and kinetic characterization of human deoxycytidine kinase variants able to phosphorylate 5-substituted deoxycytidine and thymidine analogues . Biochemistry. 2010 Aug 10;49(31):6784-90. PMID:20614893 doi:10.1021/bi100839e
  3. ↑ 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. 2003 Jul;10(7):513-9. PMID:12808445 doi:http://dx.doi.org/10.1038/nsb942

Contents


1p60, resolution 1.96Å

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