Birringer Markus S, Claus Michael T, Folkers Gerd, Kloer Daniel P, Schulz Georg E, Scapozza Leonardo
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Wolfgang-Pauli Strasse 10, 8093 Zurich, Switzerland.
FEBS Lett. 2005 Feb 28;579(6):1376-82. doi: 10.1016/j.febslet.2005.01.034.
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.
确定了与反馈抑制剂2'-脱氧胸苷-5'-三磷酸结合的人胞质胸苷激酶的结构。该结构是在几种病原体中发现的II型胸苷激酶的首个代表性结构。该结构与I型胸苷激酶（如单纯疱疹酶）的已知结构有很大差异。它包含一个锌结合结构域，四个半胱氨酸与一个结构锌离子络合。有趣的是，与I型胸苷激酶不同，II型胸苷激酶的主链原子通过氢键结合胸腺嘧啶，I型胸苷激酶是侧链参与结合。这导致了在抗病毒治疗中利用的特异性差异。所呈现的结构将促进用于多种治疗应用的新药和前药的开发。
