2wvj

Mutation of Thr163 to Ser in Human Thymidine Kinase Shifts the Specificity from Thymidine towards the Nucleoside Analogue Azidothymidine

spinqualitylabelsall models 2wvj, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2wvj is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: MG, TTP, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KITH_HUMAN Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed The first step for the intracellular retention of several anticancer or antiviral nucleoside analogues is the addition of a phosphate group catalysed by a deoxyribonucleoside kinase such as thymidine kinase 1 (TK1). Recently, human TK1 (HuTK1) has been crystallized and characterized using different ligands. To improve our understanding of TK1 substrate specificity, we performed a detailed, mutation-based comparative structure-function study of the active sites of two thymidine kinases: HuTK1 and Caenorhabditis elegans TK1 (CeTK1). Specifically, mutations were introduced into the hydrophobic pocket surrounding the substrate base. In CeTK1, some of these mutations led to increased activity with deoxycytidine and deoxyguanosine, two unusual substrates for TK1-like kinases. In HuTK1, mutation of T163 to S resulted in a kinase with a 140-fold lower K(m) for the antiviral nucleoside analogue 3'-azido-3'-deoxythymidine (AZT) compared with the natural substrate thymidine. The crystal structure of the T163S-mutated HuTK1 reveals a less ordered conformation of the ligand thymidine triphosphate compared with the wild-type structure but the cause of the changed specificity towards AZT is not obvious. Based on its highly increased AZT activity relative to thymidine activity this TK1 mutant could be suitable for suicide gene therapy. Comparative active-site mutation study of human and Caenorhabditis elegans thymidine kinase 1.,Skovgaard T, Uhlin U, Munch-Petersen B FEBS J. 2012 May;279(10):1777-87. doi: 10.1111/j.1742-4658.2012.08554.x. Epub, 2012 Mar 21. PMID:22385435 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidine kinase 3D structures

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