Structure of an oligodeoxynucleotide containing a butadiene oxide-derived N1 beta-hydroxyalkyl deoxyinosine adduct in the human N-ras codon 61 sequence.
Structure of an oligodeoxynucleotide containing a butadiene oxide-derived N1 beta-hydroxyalkyl deoxyinosine adduct in the human N-ras codon 61 sequence.
复制标题
含有人 N-ras 密码子 61 序列中丁二烯氧化物衍生的 N1 β-羟烷基脱氧肌苷加合物的寡脱氧核苷酸的结构。
DOI：
10.1021/bi0482452
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发表时间：
2005
期刊：
影响因子：
2.9
通讯作者：
Stone,MichaelP
中科院分区：
文献类型：
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作者：
Scholdberg,TandaceA;Merritt,WKeither;Dean,StephenM;Kowalcyzk,Agnieska;Harris,ConstanceM;Harris,ThomasM;Rizzo,CarmeloJ;Lloyd,RStephen;Stone,MichaelP
确定了寡脱氧核苷酸中 N1-(1-羟基-3-丁烯-2(S)-基)-2'-脱氧肌苷加合物的溶液结构，该加合物是由环氧化丁二烯 (BDO) 将腺嘌呤 N1 烷基化，然后脱氨基为脱氧肌苷而产生的。 d(CGGACXAGAAG)·d(CTTCTCGTCCG)。该寡脱氧核苷酸在人N-ras原癌基因密码子61的第二个位置含有BDO加合物，并被命名为theras61S-N1−BDO-(61,2)加合物。1H NMR显示弱C5H1'至X6H8 NOE，随后是强X6H8至X6H1'NOE。同时，X6H8至X6H3的NOE较弱。没有观察到由 T17 亚氨基质子产生的共振。丁二烯部分和 DNA 之间的 1 H NOE 将加合物定位在主沟中。基于总共 364 个 NOE 衍生的距离限制的结构精修产生了一种结构，其中修饰的脱氧肌苷处于糖基键的高顺式构象，并且互补核苷酸 T17 堆叠到螺旋中，但不与加合的肌苷形成氢键。精炼的结构提供了一个合理的假设，解释为什么这种 N1 脱氧肌苷加合物在大肠杆菌的跨损伤 DNA 复制过程中强烈编码 dCTP 的掺入[Rodriguez, D. A., Kowalczyk, A., Ward, J. B. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2001)Environ。摩尔。诱变剂。 38, 292−296]，以及在哺乳动物细胞中[Kanuri, M.、Nechev, L. N.、Tamura, P. J.、Harris, C. M.、Harris, T. M. 和 Lloyd, R. S. (2002)Chem. 38, 292−296]。资源。毒性。 15, 1572−1580]。 N1 脱氧肌苷加合物旋转成高顺式构象可能有助于通过 Hoogsteen 型模板与脱氧肌苷掺入 dCTP，从而产生 A 至 G 突变。
The solution structure of the N1-(1-hydroxy-3-buten-2(S)-yl)-2‘-deoxyinosine adduct arising from the alkylation of adenine N1 by butadiene epoxide (BDO), followed by deamination to deoxyinosine, was determined, in the oligodeoxynucleotide d(CGGACXAGAAG)·d(CTTCTCGTCCG). This oligodeoxynucleotide contained the BDO adduct at the second position of codon 61 of the humanN-rasprotooncogene, and was named theras61S-N1−BDO-(61,2) adduct.1H NMR revealed a weak C5H1‘ to X6H8 NOE, followed by an intense X6H8 to X6H1‘ NOE. Simultaneously, the X6H8 to X6H3‘ NOE was weak. The resonance arising from the T17imino proton was not observed.1H NOEs between the butadiene moiety and the DNA positioned the adduct in the major groove. Structural refinement based upon a total of 364 NOE-derived distance restraints yielded a structure in which the modified deoxyinosine was in the high syn conformation about the glycosyl bond, and T17, the complementary nucleotide, was stacked into the helix, but not hydrogen bonded with the adducted inosine. The refined structure provided a plausible hypothesis as to why this N1 deoxyinosine adduct strongly coded for the incorporation of dCTP during trans lesion DNA replication, both inEscherichia coli[Rodriguez, D. A., Kowalczyk, A., Ward, J. B. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2001)Environ. Mol. Mutagen. 38, 292−296], and in mammalian cells [Kanuri, M., Nechev, L. N., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002)Chem. Res. Toxicol. 15, 1572−1580]. Rotation of the N1 deoxyinosine adduct into the high syn conformation may facilitate incorporation of dCTP via Hoogsteen-type templating with deoxyinosine, thus generating A-to-G mutations.