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タイトル: | Pip-HoGu: An Artificial Assembly with Cooperative DNA Recognition Capable of Mimicking Transcription Factor Pairs |
著者: | Yu, Zutao Guo, Chuanxin Wei, Yulei Hashiya, Kaori Bando, Toshikazu Sugiyama, Hiroshi https://orcid.org/0000-0001-8923-5946 (unconfirmed) |
著者名の別形: | 板東, 俊和 杉山, 弘 |
発行日: | 21-Feb-2018 |
出版者: | American Chemical Society |
誌名: | Journal of the American Chemical Society |
巻: | 140 |
開始ページ: | 2426 |
終了ページ: | 2429 |
抄録: | 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 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 bp). For example, Ada1–Cyd1 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. |
著作権等: | This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/jacs.7b13275. The full-text file will be made open to the public on February 2, 2019 in accordance with publisher's 'Terms and Conditions for Self-Archiving'. This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 |
URI: | http://hdl.handle.net/2433/230818 |
DOI(出版社版): | 10.1021/jacs.7b13275 |
PubMed ID: | 29393635 |
出現コレクション: | 学術雑誌掲載論文等 |
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