Structure of human dCK suggests strategies to improve anticancer and antiviral therapy

@article{Sabini2003StructureOH,
  title={Structure of human dCK suggests strategies to improve anticancer and antiviral therapy},
  author={Elisabetta Sabini and Stephan Ort and Christian Monnerjahn and Manfred Konrad and Arnon Lavie},
  journal={Nature Structural Biology},
  year={2003},
  volume={10},
  pages={513-519}
}
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… 
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The crystal structure of clofarabine- and ADP-bound dCK was solved to 2.55 angstroms by molecular replacement, and it appears that the enzyme takes the same conformation as in the structures of the pyrimidine nucleoside-bound complexes.
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This is the first analysis of the structural basis for activation of l-nucleoside analogs, providing further impetus for discovery and clinical development of new agents in this molecular class.
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TLDR
Kinetic analysis reveals that cladribine is phosphorylated at the highest efficiency with UTP as donor, suggesting that dA analogues with a substituent at the 2-position are likely to be better activated by human dCK.
Kinetic Analysis of Prodrug Activation and ATP/UTP Substrate Preference of Nine Human Deoxycytidine Kinase Mutants
TLDR
The results showed that mutating the dCK residues will open up the active donor site to make it more accessible to bind ATP and UTP resulting in more phosphate donor flexibility.
Systematic exploration of active site mutations on human deoxycytidine kinase substrate specificity.
TLDR
Kinetic analysis indicates that Arg104Gln/Asp133Gly creates a "generalist" kinase with broader specificity and elevated turnover for natural and prodrug substrates, while substitutions of Arg104Met/AsP133Thr yielded a mutant with reversed substrate specificity.
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TLDR
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This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers.
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TLDR
A thorough and detailed knowledge of the molecular basis for substrate specificity will be a valuable tool for design and development of new and more efficient nucleoside analogs for cancer chemotherapy and viral diseases.
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