Structure of a type II thymidine kinase with bound dTTP |
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Authors: | Birringer Markus S Claus Michael T Folkers Gerd Kloer Daniel P Schulz Georg E Scapozza Leonardo |
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Institution: | Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Wolfgang-Pauli Strasse 10, 8093 Zurich, Switzerland. |
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Abstract: | The structure of human cytosolic thymidine kinase in complex with its feedback inhibitor 2'-deoxythymidine-5'-triphosphate was determined. This structure is the first representative of the type II thymidine kinases found in several pathogens. The structure deviates strongly from the known structures of type I thymidine kinases such as the Herpes simplex enzyme. It contains a zinc-binding domain with four cysteines complexing a structural zinc ion. Interestingly, the backbone atoms of the type II enzyme bind thymine via hydrogen-bonds, in contrast to type I, where side chains are involved. This results in a specificity difference exploited for antiviral therapy. The presented structure will foster the development of new drugs and prodrugs for numerous therapeutic applications. |
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Keywords: | hTK1 human cytosolic thymidine kinase dT 2′-deoxythymidine dTTP 2′-deoxythymidine-5′-triphosphate MAD multi-wavelength anomalous diffraction |
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