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

被引：8

作者：

Aman, Khalid ^{[1
]}

Padroni, Giacomo ^{[1
]}

Parkinson, John A. ^{[1
]}

Welte, Thomas ^{[2
]}

Burley, Glenn A. ^{[1
]}

机构：

[1] Univ Strathclyde, Dept Pure & Appl Chem, Graham Bldg 295 Cathedral St, Glasgow G1 1XL, Lanark, Scotland

[2] Dynam Biosensors GmbH, D-82152 Planegg, Germany

来源：

CHEMISTRY-A EUROPEAN JOURNAL | 2019年 / 25卷 / 11期

基金：

英国科学技术设施理事会; 英国生物技术与生命科学研究理事会;

关键词：

allosterism; binding kinetics; minor groove binder; NMR characterisation; pyrrole-imidazole polyamide; PYRROLE-IMIDAZOLE POLYAMIDES; HIGHLY EFFICIENT SYNTHESIS; MINOR-GROOVE; BETA-ALANINE; PYRROLE/IMIDAZOLE POLYAMIDES; SEQUENCE RECOGNITION; HAIRPIN POLYAMIDES; TRANSCRIPTION; SUPPRESSION; INHIBITION;

D O I：

10.1002/chem.201805338

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：2757 / 2763

页数：7

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