SOLUTION CONFORMATION OF THE MAJOR ADDUCT BETWEEN THE CARCINOGEN (+)-ANTI-BENZO[A]PYRENE DIOL EPOXIDE AND DNA
SOLUTION CONFORMATION OF THE MAJOR ADDUCT BETWEEN THE CARCINOGEN (+)-ANTI-BENZO[A]PYRENE DIOL EPOXIDE AND DNA
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DOI：
10.1073/pnas.89.5.1914
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发表时间：
1992-03-01
影响因子：
11.1
通讯作者：
PATEL, DJ
中科院分区：
文献类型：
--
作者：
COSMAN, M;DELOSSANTOS, C;PATEL, DJ
我们已经合成，分离，并纯化了几乎等于10毫克的脱氧十一核苷酸双链体含有一个单一的中心定位的共价加合物之间的（+）-反-苯并[a]芘（BP）二醇环氧化物和环外氨基的鸟苷。对于位于dC对面并且在d[C1-C2-A3-T4-C5-（BP）G6-C7-T8-A9-C10-C11].d[G12-G13-T14-A15-G16-C17-G18-A19-T20-G21-G22]双链体[命名为（BP）G.C 11-mer]中侧接G. C对的（+）-反式-反式-BP二醇环氧化物-N2-dG加合物，观察到优异的质子NMR光谱。我们已经确定了解决方案的结构为中心的BP共价加合物网站（BP）G.C 11-mer双链体纳入分子内和分子间的质子-质子的距离界限推导出的NMR数据集的约束，在能量最小化计算。BP环位于小沟中并朝向修饰链的5'端。（BP）G6的BP环的一面堆叠在配偶体链上的G18和A19糖-磷酸骨架上，另一面暴露于溶剂。对于d[T4-C5-（BP）G6-C7-T8].d[A15-G16-C17-G18-A19]区段，观察到最小扰动的B-DNA螺旋，其以加合物位点为中心，对于（BP）G6.C17对和侧翼G. C对，Watson-Crick比对。检测到加合物位点处小沟的加宽，其容纳BP环，BP环的长轴与DNA螺旋轴的平均方向成几乎等于45度的角度。我们的研究为BP二醇环氧化物与DNA的其他立体异构纯加合物的表征提供了未来的希望，以阐明与突变和致癌活性的立体异构依赖谱相关的构效关系的分子基础。
We have synthesized, separated, and purified almost-equal-to 10 mg of a deoxyundecanucleotide duplex containing a single centrally positioned covalent adduct between (+)-anti-benzo[a]pyrene (BP) diol epoxide and the exocyclic amino group of guanosine. Excellent proton NMR spectra are observed for the (+)-trans-anti-BP diol epoxide-N2-dG adduct positioned opposite dC and flanked by G.C pairs in the d[C1-C2-A3-T4-C5-(BP)G6-C7-T8-A9-C1O-C11].d[G12-G13-T14-A15-G16-C17-G18-A19-T20-G21-G22] duplex [designated (BP)G.C 11-mer]. We have determined the solution structure centered about the BP covalent adduct site in the (BP)G.C 11-mer duplex by incorporating intramolecular and intermolecular proton-proton distance bounds deduced from the NMR data sets as constraints in energy minimization computations. The BP ring is positioned in the minor groove and directed toward the 5' end of the modified strand. One face of the BP ring of (BP)G6 is stacked over the G18 and A19 sugar-phosphate backbone on the partner strand and the other face is exposed to solvent. A minimally perturbed B-DNA helix is observed for the d[T4-C5-(BP)G6-C7-T8].d[A15-G16-C17-G18-A19] segment centered about the adduct site with Watson-Crick alignment for both the (BP)G6.C17 pair and flanking G.C pairs. A widening of the minor groove at the adduct site is detected that accommodates the BP ring whose long axis makes an angle of almost-equal-to 45-degrees with the average direction of the DNA helix axis. Our study holds future promise for the characterization of other stereoisomerically pure adducts of BP diol epoxides with DNA to elucidate the molecular basis of structure-activity relationships associated with the stereoisomer-dependent spectrum of mutational and carcinogenic activities.