Terbrueggen R H, Barton J K
Division of Chemistry, California Institute of Technology, Pasadena 91125, USA.
Biochemistry. 1995 Jul 4;34(26):8227-34. doi: 10.1021/bi00026a003.
The chemical construction of small molecules targeted to DNA depends upon the sequence-dependent structure of the double helix. Here we describe a new structural element to be considered in the sequence-specific recognition of DNA, sequence-dependent DNA twistability. The importance of sequence-dependent DNA twistability is demonstrated in the DNA recognition properties of a novel synthetic rhodium intercalator, lambda-1-Rh(MGP)2phi5+. This metallointercalator, containing pendant guanidinium groups, binds in the major groove of DNA at subnanomolar concentrations to the 6 base pair sequence 5'-CATATG-3' with enantiospecificity. An essential feature of this recognition is the sequence-specific unwinding of the DNA helix, which permits direct contacts between guanidinium functionalities on the metal complex and guanine residues. Through an assay developed to test for sequence-specific DNA unwinding, a 70 +/- 10 degrees unwinding of the sequence 5'-CATATG-3' is established with specific binding by the metal complex. This sequence-dependent twistability may be an essential feature of the recognition of sequences by DNA-binding proteins and may be exploited in future design.
靶向DNA的小分子化学结构取决于双螺旋的序列依赖性结构。在此，我们描述了一种在DNA序列特异性识别中需考虑的新结构元件——序列依赖性DNA可扭曲性。新型合成铑嵌入剂lambda-1-Rh(MGP)2phi5+的DNA识别特性证明了序列依赖性DNA可扭曲性的重要性。这种含有侧链胍基的金属嵌入剂，在亚纳摩尔浓度下以对映体特异性结合于DNA大沟中的6碱基对序列5'-CATATG-3'。这种识别的一个基本特征是DNA螺旋的序列特异性解旋，这使得金属配合物上的胍基官能团与鸟嘌呤残基之间能够直接接触。通过开发的一种用于测试序列特异性DNA解旋的测定方法，确定了金属配合物特异性结合时5'-CATATG-3'序列有70±10度的解旋。这种序列依赖性可扭曲性可能是DNA结合蛋白识别序列的一个基本特征，并且可能在未来的设计中得到利用。
