利用溴配体-1 选择性配体招募 BET 蛋白的 "黄金地带"。

IF 3.5 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
ACS Chemical Biology Pub Date : 2024-11-15 Epub Date: 2024-10-14 DOI:10.1021/acschembio.4c00505
Ashraf Mohammed, Kelly Churion, Adithi Danda, Steven J Philips, Aseem Z Ansari
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引用次数: 0

摘要

合成基因组阅读器/调控器(SynGRs)是一种双功能分子,经过合理设计可与特定基因组序列结合,并与调控目标基因表达的细胞机制结合。原型 SynGR1 以 GAA 三核苷酸重复序列为靶标,并通过一种灵活的系链配体 JQ1 招募转录调控蛋白 BET 家族。这种泛 BET 配体能与 BET 蛋白(BD1 和 BD2)的两个串联溴域结合。第二代 SynGRs 用溴域选择性配体取代了 JQ1,结果意外地发现,尽管 BD1 选择性配体在体外显示出结合 BD1 的能力,但在活细胞中却无法在功能上与 BET 蛋白结合。从机理上讲,通过 BD1 或 BD2 选择性 SynGRs 招募 BET 蛋白本应产生无差别的功能结果。在这里,我们报告了通过对连接 DNA 结合分子与高选择性 BD1 配体 GSK778 的化学连接体进行结构指导下的重新设计,将非活性 BD1 靶向 SynGRs 转化为功能性基因调控因子。研究结果表明,BD1 选择性配体的最佳定位区与 BD1 结构域与组蛋白尾部远端乙酰基赖氨酸残基的优先结合相一致,从而实现了 BET 蛋白在染色质上的功能性啮合。这些结果不仅解决了机理上的难题,还为结构域选择性靶向以及化学探针和疗法的精细设计提供了启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A "Goldilocks Zone" for Recruiting BET Proteins with Bromodomain-1-Selective Ligands.

Synthetic genome readers/regulators (SynGRs) are bifunctional molecules that are rationally designed to bind specific genomic sequences and engage cellular machinery that regulates the expression of targeted genes. The prototypical SynGR1 targets GAA trinucleotide repeats and recruits the BET family of transcriptional regulatory proteins via a flexibly tethered ligand, JQ1. This pan-BET ligand binds both tandem bromodomains of BET proteins (BD1 and BD2). Second-generation SynGRs, which substituted JQ1 with bromodomain-selective ligands, unexpectedly revealed that BD1-selective ligands failed to functionally engage BET proteins in living cells despite displaying the ability to bind BD1 in vitro. Mechanistically, recruiting a BET protein via BD1- or BD2-selective SynGRs should have resulted in indistinguishable functional outcomes. Here we report the conversion of inactive BD1-targeting SynGRs into functional gene regulators by a structure-guided redesign of the chemical linker that bridges the DNA-binding molecule to the highly selective BD1 ligand GSK778. The results point to an optimal zone for positioning the BD1-selective ligand for functional engagement of BET proteins on chromatin, consistent with the preferred binding of BD1 domains to distal acetyllysine residues on histone tails. The results not only resolve the mechanistic conundrum but also provide insight into domain-selective targeting and nuanced design of chemo probes and therapeutics.

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来源期刊
ACS Chemical Biology
ACS Chemical Biology 生物-生化与分子生物学
CiteScore
7.50
自引率
5.00%
发文量
353
审稿时长
3.3 months
期刊介绍: ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.
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