||Structural and Kinetic Studies of the Human Nudix Hydrolase MTH1 Reveal the Mechanism for Its Broad Substrate Specificity
玉田, 太郎 ,
Waz,, Shaimaa(熊本大学大学院薬学教育部) ,
中村, 照也(熊本大学大学院薬学教育部) ,
平田, 啓介(熊本大学大学院薬学教育部) ,
古賀-小川, 由香里(日本医療科学大学) ,
池鯉鮒, 麻美(熊本大学大学院薬学教育部) ,
有森, 貴夫(大阪大学蛋白質研究所) ,
池水, 信二(熊本大学大学院薬学教育部) ,
中別府, 雄作(九州大学生体防御医学研究所)山縣, ゆり子(熊本大学大学院薬学教育部)
The Journal of Biological Chemistry
2794 , 2017-02 , The American Society for Biochemistry and Molecular Biology, Inc.
The human MutT homolog 1 (hMTH1, human NUDT1) hydrolyzes oxidativelydamaged nucleoside triphosphates and is the main enzyme responsible for nucleotidesanitization. Here, we determined crystal structures of hMTH1 in complex with 8-oxo-dGTP or 2-oxo-dATP at neutral pH. These structures showed that the base moieties of two substrates are located on the similar but not the same position in the substrate-binding pocket and adopt a different hydrogen-bonding pattern. Analyses of bond lengths with high-resolution X-ray data and of the relation between the structure and enzymatic activity revealed that hMTH1 recognizes the different oxidized nucleotides via an exchange of the protonation state at two neighboring aspartate residues in its substrate-binding pocket. This mechanism of broad substrate recognition by enzymes has not been reported previously and may have relevance for anticancer drug development strategies targeting hMTH1.