title: Structure of a type II thymidine kinase with bound dTTP.
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.
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Wolfgang-Pauli Strasse 10, 8093 Zurich, Switzerland.
authors.forename: Markus S
authors.initials: MS
authors.lastname: Birringer
authors.forename: Michael T
authors.initials: MT
authors.lastname: Claus
authors.forename: Gerd
authors.initials: G
authors.lastname: Folkers
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kloer
authors.forename: Georg E
authors.initials: GE
authors.lastname: Schulz
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013937:Thymidine Kinase / Q000737:chemistry* / Q000378:metabolism*; D013942:Thymine Nucleotides / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D021122:Protein Subunits; D013942:Thymine Nucleotides; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C024157:thymidine 5'-triphosphate