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利用来自bHLH DNA结合域的模块化合成转录阻遏子靶向MYC
2022-10-30 19:56

美国芝加哥大学Raymond E. Moellering团队近期取得重要工作进展,他们研究利用来自bHLH DNA结合域的模块化合成转录阻遏子靶向MYC。相关研究成果2022年10月27日在线发表于《自然—生物技术》杂志上。

研究人员报道了一种从MAX的bHLH结构域生成模块化合成转录阻遏子(STRs)的化学策略。他们的合成方法产生了化学稳定的三级结构域模拟物,能以纳摩尔的亲和力结合MYC/MAX共同的E-box基序,表现出等同于或超过全长TFs的特异性,并直接与MYC/MAX蛋白竞争DNA结合。先导STR直接抑制MYC在细胞中的结合,在蛋白组水平上调节MYC依赖的表达程序,抑制MYC依赖的细胞增殖。STR:E-box DNA复合体的共结晶和结构测定证实了它们以与全长bHLH TFs几乎相同的方式保留了DNA的识别能力。研究人员还展示了来自替代性bHLH-TFs的结构盲设计,证实STRs还可用于开发针对其他基因调控元件的TFs高特异性模仿物。

据介绍,尽管转录因子(TFs)在疾病发生中发挥着明确的作用,但由于针对蛋白-蛋白和蛋白-DNA相互作用的挑战,TFs在很大程度上仍未被作为药理学靶标。

附:英文原文

Title: Targeting MYC with modular synthetic transcriptional repressors derived from bHLH DNA-binding domains

Author: Speltz, Thomas E., Qiao, Zeyu, Swenson, Colin S., Shangguan, Xianghang, Coukos, John S., Lee, Christopher W., Thomas, Deborah M., Santana, Jesse, Fanning, Sean W., Greene, Geoffrey L., Moellering, Raymond E.

Issue&Volume: 2022-10-27

Abstract: Despite unequivocal roles in disease, transcription factors (TFs) remain largely untapped as pharmacologic targets due to the challenges in targeting protein–protein and protein–DNA interactions. Here we report a chemical strategy to generate modular synthetic transcriptional repressors (STRs) derived from the bHLH domain of MAX. Our synthetic approach yields chemically stabilized tertiary domain mimetics that cooperatively bind the MYC/MAX consensus E-box motif with nanomolar affinity, exhibit specificity that is equivalent to or beyond that of full-length TFs and directly compete with MYC/MAX protein for DNA binding. A lead STR directly inhibits MYC binding in cells, downregulates MYC-dependent expression programs at the proteome level and inhibits MYC-dependent cell proliferation. Co-crystallization and structure determination of a STR:E-box DNA complex confirms retention of DNA recognition in a near identical manner as full-length bHLH TFs. We additionally demonstrate structure-blind design of STRs derived from alternative bHLH-TFs, confirming that STRs can be used to develop highly specific mimetics of TFs targeting other gene regulatory elements.

DOI: 10.1038/s41587-022-01504-x

Source: https://www.nature.com/articles/s41587-022-01504-x

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:68.164
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex


本期文章:《自然—生物技术》:Online/在线发表

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