Allosteric inhibition of protein-DNA complexes by polyamide-intercalator conjugates
Allosteric inhibition of protein-DNA complexes by polyamide-intercalator conjugates
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DOI：
10.1021/ja030125e
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发表时间：
2003-07-16
影响因子：
15
通讯作者：
Dervan, PB
中科院分区：
文献类型：
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作者：
Fechter, EJ;Dervan, PB
基因启动子中必需蛋白质-DNA接触的序列特异性抑制是通过化学方法调节基因表达的中心问题。发夹聚酰胺已被证明在某些但不是所有情况下抑制蛋白质-DNA复合物。例如，在存在结合大沟的bZip蛋白的情况下，聚酰胺共占据小沟中的相同DNA序列。合成了四种发夹型聚酰胺-吖啶偶联物，并显示出以序列特异性方式以高亲和力结合DNA小沟。聚酰胺-吖啶缀合物显示出解旋DNA（phi = 14- 15度），这是吖啶部分嵌入的证据。重要的是，将联合收割机序列特异性沟结合与近端局部解旋结合的聚酰胺-嵌入剂缀合物抑制GCN 4 bZip蛋白的大沟DNA结合。这类DNA结合分子在DNA结构中产生序列特异性变构变化，并有可能成为不依赖于特定蛋白质-DNA结构的转录因子结合的一般抑制剂。
The sequence-specific inhibition of essential protein-DNA contacts in the promoter of a gene is a central issue for the regulation of gene expression by chemical methods. Hairpin polyamides have been shown to inhibit protein-DNA complexes in some but not all cases. For example, polyamides co-occupy the same DNA sequence in the minor groove in the presence of major-groove binding bZip proteins. Four hairpin polyamide-acridine conjugates were synthesized and shown to bind the minor groove of DNA with high affinity in a sequence-specific manner. The polyamide-acridine conjugates were shown to unwind DNA (phi = 14-15degrees), evidence for intercalation by the acridine moiety. Importantly, the polyamide-intercalator conjugates, which combine sequence-specific groove binding with proximal local unwinding, inhibit major-groove DNA binding by the GCN4 bZip protein. This class of DNA binding molecules creates a sequence-specific allosteric change in DNA structure and has the potential to be a general inhibitor of transcription factor binding independent of the specific protein-DNA structure.