Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
FEBS Lett. 2011 Aug 19;585(16):2617-21. doi: 10.1016/j.febslet.2011.07.017. Epub 2011 Jul 23.
MTH1 hydrolyzes oxidized nucleotide triphosphates, thereby preventing them from being incorporated into DNA. We here present the structures of human MTH1 (1.9Å) and its complex with the product 8-oxo-dGMP (1.8Å). Unexpectedly MTH1 binds the nucleotide in the anti conformation with no direct interaction between the 8-oxo group and the protein. We suggest that the specificity depends on the stabilization of an enol tautomer of the 8-oxo form of dGTP. The binding of the product induces no major structural changes. The structures reveal the mode of nucleotide binding in MTH1 and provide the structural basis for inhibitor design.
MTH1 可水解氧化的核苷酸三磷酸，从而防止它们被掺入 DNA 中。我们在此呈现人源 MTH1（1.9Å）及其与产物 8-oxo-dGMP 的复合物结构（1.8Å）。出人意料的是，MTH1 以反式构象结合核苷酸，8-氧基团与蛋白质之间没有直接相互作用。我们推测这种特异性取决于 dGTP 的 8-氧形式的烯醇互变异构体的稳定。产物的结合不会引起结构的重大变化。这些结构揭示了 MTH1 中核苷酸结合的模式，并为抑制剂设计提供了结构基础。
