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PIP–HoGu, an Artificial Assembly with Cooperative DNA Recognition

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Part of the Springer Theses book series (Springer Theses)

Abstract

Cooperation between pairs of transcription factors (TFs) has been widely demonstrated to play a pivotal role in the spatiotemporal regulation of gene expression, but blocking cooperative TF pair–DNA interactions synergistically has been challenging. To achieve this, we designed programmable DNA binder pyrrole-imidazole polyamides conjugated to host–guest assemblies (PIP–HoGu) to mimic the cooperation between natural TF pairs. By incorporating cyclodextrin (Cyd)–adamantane (Ada), we synthesized Ada1 (PIP1-Ada) and Cyd1 (PIP2-Cyd), which were evaluated using Tm, EMSA, competitive, and SPR assays and molecular dynamics studies. The results consistently demonstrated that the PIP–HoGu system formed stable noncovalent cooperative complexes, thereby meeting key criteria for mimicking a TF pair. The system also had a longer recognition sequence (two-PIP binding length plus gap distance), favorable sequence selectivity, higher binding affinity, and in particular, a flexible gap distance (0–5 base pairs [bp]). For example, Ada1Cyd1 showed thermal stability of 7.2 °C and a minimum free energy of interaction of −2.32 kcal mol−1 with a targeting length of 14 bp. Furthermore, cell-based evaluation validated the capability of PIP–HoGu to exhibit potent cooperative inhibitory effects on gene expression under physiological conditions by disrupting TF pair–DNA function. In conclusion, the modular design of PIP–HoGu defines a general framework for mimicking naturally occurring cooperative TF pair–DNA interactions that offers a promising strategy for applications in the precise manipulation of cell fate.

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Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Department of Chemistry, Graduate School of ScienceKyoto UniversityKyotoJapan

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