Structural and Kinetic Profiling of Allosteric Modulation of Duplex DNA Induced by DNA-Binding Polyamide Analogues.

Structural and Kinetic Profiling of Allosteric Modulation of Duplex DNA Induced by DNA-Binding Polyamide Analogues.
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DNA结合聚酰胺类似物诱导的双链DNA的变构调节的结构和动力学分析。

DOI:
10.1002/chem.201805338
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发表时间:
2019-02-21
期刊:
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子:
--
通讯作者:
Burley GA
Burley GA
中科院分区:
其他
文献类型:
--
作者:
Aman K;Padroni G;Parkinson JA;Welte T;Burley GA

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描述了发夹状聚酰胺类似物的DNA结合亲和力、动力学和序列选择性的结构和定量生物物理图谱。含有目标聚酰胺结合位点或错配序列的DNA双链固定在微电极表面。含有N-末端1-烷基咪唑(Im)单元的聚酰胺的DNA结合谱的定量显示出与其目标序列的皮摩尔结合亲和力,而5-烷基噻唑(NT)单元的结合强度低一个数量级(低纳摩尔)。对聚酰胺系列的比较核磁共振结构分析表明,发夹状IPR-NT聚酰胺在DNA双链结构的变构调节中起着重要的作用。这种动力学和结构相结合的研究为开发下一代发夹设计提供了基础,在这种设计中,聚酰胺的DNA结合轮廓与其物理化学性质相一致。
A combined structural and quantitative biophysical profile of the DNA binding affinity, kinetics and sequence‐selectivity of hairpin polyamide analogues is described. DNA duplexes containing either target polyamide binding sites or mismatch sequences are immobilized on a microelectrode surface. Quantitation of the DNA binding profile of polyamides containing N‐terminal 1‐alkylimidazole (Im) units exhibit picomolar binding affinities for their target sequences, whereas 5‐alkylthiazole (Nt) units are an order of magnitude lower (low nanomolar). Comparative NMR structural analyses of the polyamide series shows that the steric bulk distal to the DNA‐binding face of the hairpin iPr‐Nt polyamide plays an influential role in the allosteric modulation of the overall DNA duplex structure. This combined kinetic and structural study provides a foundation to develop next‐generation hairpin designs where the DNA‐binding profile of polyamides is reconciled with their physicochemical properties.
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