Solution structure of the complex between the head-to-tail dimer of calicheamicin γ1I oligosaccharide and a DNA duplex containing d(ACCT) and d(TCCT) high-affinity binding sites
Solution structure of the complex between the head-to-tail dimer of calicheamicin γ1I oligosaccharide and a DNA duplex containing d(ACCT) and d(TCCT) high-affinity binding sites
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DOI：
10.1021/ja973910y
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发表时间：
1998-07-29
影响因子：
15
通讯作者：
Gomez-Paloma, L
中科院分区：
文献类型：
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作者：
Bifulco, G;Galeone, A;Gomez-Paloma, L
加利车霉素寡糖结构域的头-尾二聚体表现出比其衍生的单体显著更高的DNA结合亲和力和序列选择性以及更大的生物活性。为了确定这些功能特性的结构基础，研究了加利车霉素寡糖的头-尾二聚体和寡核苷酸双链体d（GCACCTTCCTGC）之间1：1复合物的溶液结构。d（GCAGGAAGGTGC）已解决了限制分子动力学计算使用NMR推导的距离和扭转角的约束。最终的输入数据包括562个核间距离和114个二面角约束，平均每个残基27个约束。与对DNA双链体和加利车霉素寡糖的头对头二聚体之间的复合物所做的观察相反，头对头尾二聚体在DNA小沟中表现出独特的结合模式。在两个不同的结合位点处的碳水化合物-DNA相互作用的比较分析在原子水平上解释了加利车霉素衍生物如何能够有效地识别d（ACCT）和d（TCCT）位点。这项研究带来了更深入的了解的因素，DNA结合亲和力和序列偏好的加利车霉素及其衍生物。
The head-to-tail dimer of the calicheamicin oligosaccharide domain exhibits substantially higher DNA binding affinity and sequence selectivity and greater bioactivity than the monomer from which it is derived. To determine the structural basis for these functional properties, the solution structure of the 1:1 complex between the head-to-tail dimer of the calicheamicin oligosaccharide and the oligonucleotide duplex d(GCACCTTCCTGC). d(GCAGGAAGGTGC) has been solved by restrained molecular dynamics calculations using NMR-derived distance and torsion angle constraints. The final input data consisted of 562 internuclear distance and 114 dihedral angle constraints, an average of 27 constraints per residue. In contrast to observations made for a complex between a DNA duplex and the head-to-head dimer of calicheamicin oligosaccharide, the head-to-tail dimer exhibits a unique binding mode in the DNA minor groove. A comparative analysis of the carbohydrate-DNA interactions at the two different binding sites explains at the atomic level how calicheamicin derivatives are able to effectively recognize both d(ACCT) and d(TCCT) sites. This study brings deeper insight into the factors governing DNA-binding affinity and the sequence preferences of calicheamicin and its derivatives.