X-RAY CRYSTALLOGRAPHIC STUDIES OF DEOXYCYTIDINE KINASE

Cornell University, Ithaca NY

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have crystallized dCK with the substrates and several substrate analogs. Crystals of dCK complexed with the prodrug clofarabine and ADP were taken to NE-CAT beamline 24-IDC. The crystal structure was solved to 2.55 [unreadable] resolution and the result was recently published as the first example of a purine analog complexed with this important activator of nucleoside analog prodrugs. Although the prodrug was a purine-nucleoside analog, the enzyme had the same conformation as the pyrimidine nucleoside complexes. The structure reveals that both purine and pyrimidine analogs display similar active site geometries. The presence of the 2-chloro substituent in clofarabine causes a 1 [unreadable] shift of the substrate and is probably responsible for the enhanced catalytic efficiency of dCK for clofarabine. The structure also suggests modifications to dCK that might make it useful as a prodrug activator in the gene therapy approach to anticancer treatment.