Encounter and extrusion of an intrahelical lesion by a DNA repair enzyme.
Encounter and extrusion of an intrahelical lesion by a DNA repair enzyme.
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作者：
生物系统如何检测上百万倍的未损伤DNA中基因毒性损伤的存在，是生物学中尚未解决的问题。在这里，我们捕获并从结构上阐明了碱基切除DNA修复酶MutM，它在与DNA双链中嵌套的受损核碱基8-氧鸟嘌呤（oxoG）初始相遇的阶段。三种结构的螺旋内oxoG-遭遇复合物与序列匹配的结构包含一个正常的G碱基在oxoG病变的地方进行比较。尽管匹配复合体中的蛋白质- DNA界面只相差两个原子，即区分oxoG和g的原子，但它们明显的结构差异表明，MutM甚至在接触的最初阶段就能检测到DNA的损伤。全原子计算机模拟显示了酶与损伤相遇导致DNA双链挤压的途径，并阐明了oxoG和G在挤压途径上的临界自由能差。
How living systems detect the presence of genotoxic damage embedded in a million-fold excess of undamaged DNA is an unresolved question in biology. Here we have captured and structurally elucidated a base-excision DNA repair enzyme, MutM, at the stage of initial encounter with a damaged nucleobase, 8-oxoguanine (oxoG), nested within a DNA duplex. Three structures of intrahelical oxoG-encounter complexes are compared with sequence-matched structures containing a normal G base in place of an oxoG lesion. Although the protein–DNA interfaces in the matched complexes differ by only two atoms—those that distinguish oxoG from G—their pronounced structural differences indicate that MutM can detect a lesion in DNA even at the earliest stages of encounter. All-atom computer simulations show the pathway by which encounter of the enzyme with the lesion causes extrusion from the DNA duplex, and they elucidate the critical free energy difference between oxoG and G along the extrusion pathway.
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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：
15
作者：
Cheng, XL;Kelso, C;Simmerling, C
通讯作者：
Simmerling, C
DOI：
10.1073/pnas.0708058105
发表时间：
2008-03-25
影响因子：
11.1
作者：
Hu, Jie;Ma, Ao;Dinner, Aaron R.
通讯作者：
Dinner, Aaron R.
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML