title: Tautomerization-dependent recognition and excision of oxidation damage in base-excision DNA repair.
abstract: NEIL1 (Nei-like 1) is a DNA repair glycosylase guarding the mammalian genome against oxidized DNA bases. As the first enzymes in the base-excision repair pathway, glycosylases must recognize the cognate substrates and catalyze their excision. Here we present crystal structures of human NEIL1 bound to a range of duplex DNA. Together with computational and biochemical analyses, our results suggest that NEIL1 promotes tautomerization of thymine glycol (Tg)-a preferred substrate-for optimal binding in its active site. Moreover, this tautomerization event also facilitates NEIL1-catalyzed Tg excision. To our knowledge, the present example represents the first documented case of enzyme-promoted tautomerization for efficient substrate recognition and catalysis in an enzyme-catalyzed reaction.
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Chenxu
authors.initials: C
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Lining
authors.initials: L
authors.lastname: Lu
authors.affiliation: Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Biodynamic Optical Imaging Center, Peking University, Beijing 100871, China;
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Yue
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Jinghui
authors.initials: J
authors.lastname: Song
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Shuai
authors.initials: S
authors.lastname: Zong
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Menghao
authors.initials: M
authors.lastname: Liu
authors.affiliation: University of Chicago, Chicago, IL 60637;
authors.forename: Olivia
authors.initials: O
authors.lastname: Stovicek
authors.affiliation: Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Biodynamic Optical Imaging Center, Peking University, Beijing 100871, China; gaoyq@pku.edu.cn chengqi.yi@pku.edu.cn.
authors.forename: Yi Qin
authors.initials: YQ
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Synthetic and Functional Biomolecules Center, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China gaoyq@pku.edu.cn chengqi.yi@pku.edu.cn.
authors.forename: Chengqi
authors.initials: C
authors.lastname: Yi
mesh_terms: D003198:Computer Simulation; D003461:Crystallography; D004247:DNA / Q000378:metabolism*; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D004926:Escherichia coli; D005663:Furans; D006801:Humans; D008956:Models, Chemical; D013941:Thymine / Q000031:analogs & derivatives
chemical_list: D005663:Furans; C029389:thymine glycol; C018674:tetrahydrofuran; D004247:DNA; D045647:DNA Glycosylases; C473634:NEIL1 protein, human; D013941:Thymine
keywords: QM/MM; base-excision repair; enzyme catalysis; glycosylase; substrate recognition