Laughlin-Toth Sarah, Carter E Kathleen, Ivanov Ivaylo, Wilson W David
Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
Nucleic Acids Res. 2017 Feb 17;45(3):1297-1306. doi: 10.1093/nar/gkw1232.
Specific targeting of protein–nucleic acid interactions is an area of current interest, for example, in the regulation of gene-expression. Most transcription factor proteins bind in the DNA major groove; however, we are interested in an approach using small molecules to target the minor groove to control expression by an allosteric mechanism. In an effort to broaden sequence recognition of DNA-targeted-small-molecules to include both A·T and G·C base pairs, we recently discovered that the heterocyclic diamidine, DB2277, forms a strong monomer complex with a DNA sequence containing 5΄-AAAGTTT-3΄. Competition mass spectrometry and surface plasmon resonance identified new monomer complexes, as well as unexpected binding of two DB2277 with certain sequences. Inherent microstructural differences within the experimental DNAs were identified through computational analyses to understand the molecular basis for recognition. These findings emphasize the critical nature of the DNA minor groove microstructure for sequence-specific recognition and offer new avenues to design synthetic small molecules for effective regulation of gene-expression.
蛋白质与核酸相互作用的特异性靶向是当前研究的一个热点领域,例如在基因表达调控方面。大多数转录因子蛋白结合在DNA的大沟中;然而,我们感兴趣的是一种利用小分子靶向小沟以通过变构机制控制表达的方法。为了拓宽对靶向DNA的小分子的序列识别范围,使其包括A·T和G·C碱基对,我们最近发现杂环二脒DB2277与包含5΄-AAAGTTT-3΄的DNA序列形成了强单体复合物。竞争质谱和表面等离子体共振鉴定出了新的单体复合物,以及两个DB2277与某些序列的意外结合。通过计算分析确定了实验DNA中固有的微观结构差异,以了解识别的分子基础。这些发现强调了DNA小沟微观结构对于序列特异性识别的关键性质,并为设计用于有效调控基因表达的合成小分子提供了新途径。