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首页> 外文期刊>Biochemistry >Structural alignment of the (+)-trans-anti-benzo[a]pyrene-dG adduct positioned opposite dC at a DNA template-primer junction
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Structural alignment of the (+)-trans-anti-benzo[a]pyrene-dG adduct positioned opposite dC at a DNA template-primer junction

机译：（+）-反-苯并[a] py-dG加合物在DNA模板-引物连接处与dC相对的结构比对

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This study reports on the solution conformation of the covalent (+)-trans-anti-[BP]dG adduct (derived from the binding of the highly mutagenic and tumorigenic (+)-anti-benzo[a]pyrene diol epoxide to the N2 of deoxyguanosine) positioned opposite dC at a junctional site in the d(A1-A2-C3-[BP]G4-C5- T6-A7-C8-C9-A10-T11-C12-C13).d(G14-G15-A16-T17-+ ++G18-G19-T20-A21-G22-C23) 13/10-mer DNA sequence. The 13-mer represents the template strand containing the junction [BP]dG4 lesion while the complementary 10-mer models a primer strand which extends upto and is complementary to the modified dG4 residue. The solution conformation has been determined by initially incorporating intramolecular and intermolecular proton-proton distances defined by lower and upper bounds deduced from NOESY spectra as restraints in molecular mechanics computations in torsion angle space and subsequently through restrained molecular dynamics calculations based on a NOE distance and intensity refinement protocol. The duplex segment retains a minimally perturbed B-DNA conformation with all base pairs, including the junctional [BP]dG4.dC23 pair, in Watson-Crick hydrogen-bonded alignments. The pyrenyl ring is not stacked over the adjacent dC5.dG22 base pair but is positioned on the minor groove-side of the [BP]dG moiety and directed toward the 5'-end of the template strand. The pyrenyl ring stacks over the base of the non-adjacent dA2 residue in one direction and the sugar ring of dC23 in the other direction. The solution structure of the (+)-trans-anti-[BP]dG adduct opposite dC in the 13/10-mer in which the modified deoxyguanosine adopts an anti glycosidic torsion angle (this study) is in striking contrast to the structure of the same (+)-trans-anti-[BP]dG moiety in a 13/9-mer of the same sequence but without the dC23 residue positioned opposite the adduct site [Cosman, M., et al. (1995) Biochemistry 34, 15334-15350]. For the latter case, the aromatic portion of the BP residue stacks over the adjacent dC5.dG22 base pair, the modified deoxyguanosine adopts a syn glycosidic torsion angle and is displaced toward the major groove direction. Insights into the factors that affect the sequence and context dependent conformations of stereoisomeric [BP]dG lesions have emerged following comparison of these two structures with the minor groove conformations of the same (+)-trans-anti-[BP]dG lesion in the fully complementary 11-mer duplex [Cosman, M., et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918] and in the base displaced-intercalative conformation of the 11/10-mer deletion duplex containing a -1 deletion site opposite the lesion [Cosman, M., et al. (1994) Biochemistry 33, 11507-11517]. The contributing factors where applicable include Watson-Crick base pairing at the site of the lesion, positioning of the carcinogen within the floor of the minor groove, and the tendency of the bulky hydrophobic aromatic BP residue to assume stacked or intercalative conformations.
机译：这项研究报告了共价（+）-反-[BP] dG加合物的溶液构象（源自高度诱变和致瘤性（+）-反-苯并[a] py二醇环氧化合物与N2的结合d（G14-G15-）位于dC对面，位于d（A1-A2-C3- [BP] G4-C5- T6-A7-C8-C9-A10-T11-C12-C13）的连接位点。 A16-T17-+++ G18-G19-T20-A21-G22-C23）13 / 10-mer DNA序列。 13聚体代表含有连接[BP] dG4损伤的模板链，而互补的10聚体模拟引物链，该引物链延伸至并与修饰的dG4残基互补。通过首先结合由NOESY谱得出的上下限定义的分子内和分子间质子-质子距离作为扭转角空间中分子力学计算的约束，然后通过基于NOE距离和强度的受约束的分子动力学计算来确定溶液构象优化协议。在沃森-克里克氢键比对中，双链体片段与所有碱基对（包括连接的[BP] dG4.dC23对）都保留了最小干扰的B-DNA构象。 enyl环不堆叠在相邻的dC5.dG22碱基对上，而是位于[BP] dG部分的次要凹槽侧，并指向模板链的5'端。 enyl环在一个方向上堆叠在不相邻的dA2残基的碱基上，在另一个方向上堆叠dC23的糖环。在13 / 10-mer中，与dC相对的（+）-反-[-]-[BP] dG加合物的溶液结构，其中修饰的脱氧鸟苷采用抗糖苷扭转角（本研究）与DC的结构形成鲜明对比。具有相同序列的13 / 9-mer中的相同（+）-反-抗-[BP] dG部分，但没有dC23残基位于加合物位点对面[Cosman，M。等人。 （1995）Biochemistry 34，15334-15350]。对于后一种情况，BP残基的芳族部分堆叠在相邻的dC5.dG22碱基对上，修饰的脱氧鸟苷采用顺糖苷扭转角，并朝着主凹槽方向移动。在将这两种结构与相同（+）-反-反-[BP] dG病变的小沟构型进行比较之后，对影响立体异构[BP] dG病变的序列和上下文依赖性构象的因素有了深入的了解。完全互补的11-mer双链体[Cosman，M.，et al。 （1992）美国国家科学院院刊。 Natl。学院科学U.S.A. 89，1914-1918]，并在11 / 10-mer缺失双链体的碱基置换-插入构象中，该双链体含有与病灶相对的-1缺失位点[Cosman，M.，et al。 （1994）Biochemistry 33，11507-11517]。适用的影响因素包括病变部位的Watson-Crick碱基配对，小沟底内致癌物的位置以及庞大的疏水性芳香族BP残基呈堆积或插层构象的趋势。

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