An Activity-Based Probe Targeting Non-Catalytic, Highly Conserved Amino Acid Residues within Bromodomains
An Activity-Based Probe Targeting Non-Catalytic, Highly Conserved Amino Acid Residues within Bromodomains
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DOI：
10.1002/anie.201807825
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发表时间：
2019-01-21
影响因子：
16.6
通讯作者：
Brennan, Paul E.
中科院分区：
文献类型：
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作者：
D'Ascenzio, Melissa;Pugh, Kathryn M.;Brennan, Paul E.
含溴结构域蛋白是参与广泛的细胞过程的表观遗传调节剂，从转录因子的募集到基因调控的病理性破坏和癌症发展。自从这些乙酰基-赖氨酸阅读器结构域的可药性被确定以来，人们一直在努力开发整个家族的有效且选择性的抑制剂。在这里，我们报告了一个小分子为基础的方法来共价修饰重组和内源性含溴结构域的蛋白质，通过靶向保守的赖氨酸和酪氨酸残基的可变ZA或BC环的发展。此外，报告标签的添加允许所需溴结构域的凝胶内可视化和下拉。
Bromodomain-containing proteins are epigenetic modulators involved in a wide range of cellular processes, from recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl-lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here we report the development of a small molecule-based approach to covalently modify recombinant and endogenous bromodomain-containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops. Moreover, the addition of a reporter tag allowed in-gel visualization and pull-down of the desired bromodomains.