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首页> 外文期刊>Biochemistry >Structure of the 1,N~2-Etheno-2'-deoxyguanosine Lesion in the 3'-G(εdG)T-5' SequenceOpposite a One-Base Deletion
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Structure of the 1,N~2-Etheno-2'-deoxyguanosine Lesion in the 3'-G(εdG)T-5' SequenceOpposite a One-Base Deletion

机译：3'-G（εdG）T-5'序列中的1，N〜2-Etheno-2'-deoxyguanosine病变的结构与一碱基删除相对

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The structure of the 1,N~2-ethenodeoxyguanosine lesion (1,N~2-εdG) has been characterized in 5'-d(CGCATXGAATCC)-3' -5'-d(GGATTCATGCG)-3' (X = 1,N~2-εdG), in which there is no dC opposite the lesion. This duplex (named the 1-BD duplex) models the product of translesion bypass of 1,N~2-εdG by Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) [Zang, H., Goodenough, A. K., Choi, J. Y., Irimia, A., Loukachevitch, L. V., Kozekov, I. D., Angel, K. C.. Rizzo, C. J., Egli, M., and Guengerich, F. P. (2005) J. Biol. Chem. 280, 29750-29764], leading to a one-base deletion. The T_m of this duplex is 6 °C higher than that of the duplex in which dC is present opposite the 1,N~2-εdG lesion and 8 °C higher than that of the unmodified 1-BD duplex. Analysis of NOEs between the 1,N~2-εdG imidazole and deoxyribose H1' protons and between the 1,N~2-εdG etheno H6 and H7 protons and DNA protons establishes that 1,N~2-εdG adopts the anti conformation about the glycosyl bond and that the etheno moiety is accommodated within the helix. The resonances of the 1,N~2-εdG H6 and H7 etheno protons shift upfield relative to the monomer 1,N~2-εdG, attributed to ring current shielding, consistent with their intrahelical location. NMR data reveal that Watson-Crick base pairing is maintained at both the 5' and 3' neighbor base pairs. The structure of the 1-BD duplex has been refined using molecular dynamics calculations restrained by NMR-derived distance and dihedral angle restraints. The increased stability of the 1,N~2-εdG lesion in the absence of the complementary dC correlates with the one-base deletion extension product observed during the bypass of the I ,N~2-εdG lesion by the Dpo4 polymerase, suggesting that stabilization of this bulged intermediate may be significant with regard to the biological processing of the lesion.
机译：1，N〜2-乙氧基脱氧鸟苷病变（1，N〜2-εdG）的结构已通过5'-d（CGCATXGAATCC）-3'-5'-d（GGATTCATGCG）-3'（X = 1 ，N〜2-εdG），其中病变对面没有dC。该双链体（称为1-BD双链体）模拟了Sulfolobus solfataricus P2 DNA聚合酶IV（Dpo4）[Nang，H.，Goodenough，AK，Choi，JY，Irimia， A.，Loukachevitch，LV，Kozekov，ID，Angel，KC.Rizzo，CJ，Egli，M.，and Guengerich，FP（2005）J.Biol。化学280，29750-29764]，导致一碱基删除。该双链体的T_m比其中在1，N〜2-εdG病变处存在dC的双链体的T_m高6°C，并且比未修饰的1-BD双链体的双链体的T_m高8°C。 1，N〜2-εdG咪唑与脱氧核糖H1'质子之间，1，N〜2-εdG乙炔H6与H7质子和DNA质子之间的NOE分析确定1，N〜2-εdG采用约糖基键和乙炔部分被容纳在螺旋内。 1，N〜2-εdGH6和H7乙炔质子的共振相对于单体1，N〜2-εdG发生向高场移动，这归因于环电流屏蔽，与其螺旋内位置一致。 NMR数据显示Watson-Crick碱基配对在5'和3'相邻碱基对处均保持不变。 1-BD双链体的结构已通过分子动力学计算得到完善，该分子动力学计算受NMR距离和二面角约束的约束。在没有互补dC的情况下1，N〜2-εdG病变的稳定性增加与Dpo4聚合酶绕过I，N〜2-εdG病变时观察到的一碱基缺失延伸产物相关，这表明就病变的生物学处理而言，这种鼓起的中间体的稳定化可能是重要的。

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