Structural basis for the sequence-specific DNA strand cleavage by the enediyne neocarzinostatin chromophore. Structure of the post-activated chromophore-DNA complex.
Structural basis for the sequence-specific DNA strand cleavage by the enediyne neocarzinostatin chromophore. Structure of the post-activated chromophore-DNA complex.
复制标题
烯二炔新制癌菌素发色团进行序列特异性 DNA 链切割的结构基础。
DOI：
10.1021/bi00001a006
复制
发表时间：
1995
期刊：
影响因子：
2.9
通讯作者：
Goldberg,IH
中科院分区：
文献类型：
--
作者：
Gao,X;Stassinopoulos,A;Rice,JS;Goldberg,IH
1994年11月1日接收的修订版Mannipt ®摘要：新制癌素发色团（NCS chrom）属于一个高效烯二炔类抗肿瘤抗生素家族，其与特定DNA序列结合并引起单链和/或双链病变。NCS chrom-DNA复合物已经回避了结构研究，因为药物的天然形式在水性条件下极其不稳定。本文用NMR和距离几何-分子动力学模拟方法研究了谷胱甘肽后活化的NCS色素（NCSi-glu）-DNA复合物[NCSi-glu-d（GGAGCGC）* d（GCGCTCC）]的三维结构。NCSi-glu通过在5 '-CT/5'-AG步骤处的独特嵌入和小沟结合与一条链上的GCTC四核苷酸和另一条链上的AGC三核苷酸相互作用。DNA-药物复合物表现出一个扩展的，未缠绕的V形嵌入位点和更宽和更浅的凹槽比游离DNA双链体。该复合物的结构表现出特定的货车范德华相互作用和碳水化合物部分和特定的DNA糖/磷酸之间的氢键形成。其中突出的是NCSi-glu残基与小沟中的官能团的接触，这些官能团是单个DNA碱基的特征。这些结果为理解烯二炔NCS chrom在AGC和相关位点的单链和双链切割的序列特异性提供了结构模型。新制癌素发色团（NCS chrom，1图1）在自然界中以与其宿主蛋白1：1复合物的形式存在（Ishida et al.，1965;纳皮耶等人，1979; Kim等人，1993年）。已将分离的发色团作为一类高效抗肿瘤抗生素的原型化合物进行了广泛研究[Goldberg（1991）综述]。这些抗生素的作用靶标，包括kedarcidin的发色团（Lam等人，1991）和C-1027（Otani等人，1988）蛋白质，以及烯二炔化合物dyne-micin（Konishi等人，1990）、加利车霉素和埃斯佩兰霉素（Lee et al.，1987; Golik等人，1987），被认为是细胞DNA [由Dedon和Goldberg（1992）综述]。这些分子的新奇源于它们的化学结构，其由高度应变的烯二炔环和各种取代基组成（Edo等人，1985; Nicolaou & Dai，1991）。对于NCS chrom，需要在C12位置亲核加成硫醇以促进体外和体内DNA切割。在NCS色谱中，烯二炔环的活化导致形成
Revised Manuscript Received November 1, 1994® abstract: Neocarzinostatin chromophore (NCS chrom) belongsto a family of highly potent enediyne antitumor antibiotics which bind to specific DNA sequences and cause single-and/or double-strand lesions. NCS chrom—DNA complexes have eluded structural studies since the native form of the drug is extremely labile in aqueous conditions. We report the three-dimensional structure of the stable glutathione postactivated NCS chrom (NCSi-glu)—DNA complex [NCSi-glu-d (GGAGCGC)* d (GCGCTCC)] using NMR and distance geometry—molecular dynamicssimulation methods. NCSi-glu interacts with the GCTC tetranucleotide on one strand and with the AGC trinucleotide on the other strand through the unique intercalation at the 5'-CT/5'-AG step and minor groove binding. The DNA—drug complex exhibits an extended, unwound V-shaped intercalation site and wider and shallower grooves than the free DNA duplex. The structure of the complex manifests specific van der Waals interactions and H-bondformation between the carbohydrate moiety and a specific DNA sugar/phosphate. Prominent among those are the contacts of the NCSi-glu residues with the functional groups in the minor groove that are characteristic of individual DNA bases. Theseresults provide a structural model for understanding the sequence specificity of the single-and double-strand cleavage at the AGC and related sites by the enediyne NCS chrom.Neocarzinostatin chromophore (NCS chrom, 1 Figure 1) exists in nature as a 1: 1 complex with its host protein (Ishida et al., 1965; Napier et al., 1979; Kim et al., 1993). The isolated chromophore has been studied extensively as the prototype compound for a family of highly potent antitumor antibiotics [reviewed by Goldberg (1991)]. The target of action for these antibiotics, which include the chromophores of kedarcidin (Lam et al., 1991) and C-1027 (Otani et al., 1988) proteins, as well as the enediyne compounds dyne-micin (Konishi et al., 1990), calicheamicins, and esperam-icins (Lee et al., 1987; Golik et al., 1987), is thought to be cellular DNA [reviewed by Dedon and Goldberg (1992)]. The novelty of these molecules stems from their chemical structure which consists of a highly strained enediyne ring and a variety of substituent groups (Edo et al., 1985; Nicolaou & Dai, 1991). For NCS chrom, nucleophilic addition of thiol to the C12 position is required for promoting DNA cleavage in vitro and in vivo. In NCS chrom, activation of the enediyne ring results in the formation of a