An unprecedented nucleic acid capture mechanism for excision of DNA damage.
An unprecedented nucleic acid capture mechanism for excision of DNA damage.
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去除烷基化和脱氨基嘌呤核碱基的DNA糖基化酶是保护基因组的必需DNA修复酶，同时通过切除由DNA靶向抗癌化合物形成的细胞毒性N3-甲基腺嘌呤碱基来混淆癌症烷基化治疗。糖基化酶对N3-和N7-烷基嘌呤特异性的基础被认为是由修饰碱基的内在不稳定性而不是由直接的酶官能团化学引起的。在这里，我们提出了最近发现的蜡状芽孢杆菌AlkD糖基化酶的晶体结构与DNA含有烷基化，错配，脱碱基核苷酸的复杂。与其他糖基化酶不同，AlkD在溶剂暴露的方向上捕获螺旋外损伤，为N3-和N7-烷基化碱基的水解如何通过增加DNA螺旋的寿命来促进提供了第一个例证。碱基翻转和催化的结构和支持生物化学分析揭示了AlkD的HEAT重复序列如何扭曲DNA骨架以检测非沃森-克里克碱基对而不插入双链体。
DNA glycosylases that remove alkylated and deaminated purine nucleobases are essential DNA repair enzymes that protect the genome, and at the same time confound cancer alkylation therapy, by excising cytotoxic N3-methyladenine bases formed by DNA targeting anticancer compounds. The basis for glycosylase specificity toward N3- and N7-alkylpurines is believed to result from intrinsic instability of the modified bases and not from direct enzyme functional group chemistry. Here, we present crystal structures of the recently discovered Bacillus cereus AlkD glycosylase in complex with DNAs containing alkylated, mismatched, and abasic nucleotides. Unlike other glycosylases, AlkD captures the extrahelical lesion in a solvent-exposed orientation, providing the first illustration for how hydrolysis of N3- and N7-alkylated bases may be facilitated by increased lifetime out of the DNA helix. The structures and supporting biochemical analysis of base flipping and catalysis reveal how AlkD’s HEAT-repeats distort the DNA backbone to detect non-Watson-Crick base pairs without duplex intercalation.
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影响因子：
64.8
作者：
Dinner, AR;Blackburn, GM;Karplus, M
通讯作者：
Karplus, M
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
2.9
作者：
Jiang, YL;Ichikawa, Y;Stivers, JT
通讯作者：
Stivers, JT
影响因子：
11.4
作者：
Eichman, BF;O'Rourke, EJ;Ellenberger, T
通讯作者：
Ellenberger, T
影响因子：
14.9
作者：
ABOULELA, F;KOH, D;MARTIN, FH
通讯作者：
MARTIN, FH