Discovery of Chemical Inhibitors of Human Bromodomains.
Discovery of Chemical Inhibitors of Human Bromodomains.
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DOI：
10.1021/acs.chemrev.5b00205
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发表时间：
2015-10
期刊：
影响因子：
62.1
通讯作者：
Guangtao Zhang;Steven G. Smith;Ming-Ming Zhou-Ming
中科院分区：
文献类型：
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作者：
Guangtao Zhang;Steven G. Smith;Ming-Ming Zhou-Ming
核小体组蛋白上赖氨酸的乙酰化一直被认为是削弱DNA-组蛋白相互作用的原因，从而影响基因转录激活。[1]然而，直到20世纪70年代末，才有证据支持组蛋白尾部赖氨酸乙酰化对染色质开放和转录激活的直接贡献。2赖氨酸乙酰化是一个可逆的过程，发生在组蛋白中位点特异性赖氨酸残基的ε-氨基上。乙酰化的组合效应，即电荷中和和空间位阻，使染色质结构松弛，并增强DNA被转录因子3识别的可及性（图1）。此外，转录辅因子的HAT（组蛋白乙酰转移酶）活性的发现直接将组蛋白乙酰化与染色质中的基因转录激活联系起来。事实上，一系列转录辅因子已被证明具有内在的组蛋白HAT活性，包括GCN 5（氨基酸合成的一般控制-5），4 CBP（p300/CREB结合蛋白），7，8 PCAF（p300/CBP相关因子），9和TAF（TBP（TATA结合蛋白）相关因子）。10赖氨酸乙酰化在基因转录激活中的作用通过鉴定在许多真核转录辅因子中发现的布罗莫结构域（bromodomain）11、12的保守结构基序而进一步突出，布罗莫结构域11、12的主要功能是识别组蛋白和转录蛋白中的乙酰化赖氨酸。13 GNAT和p300/CBP家族中的大多数核HAT（A型）含有溴结构域14，其可以充当
Acetylation of lysines on nucleosomal histones has long been perceived as being responsible for weakening DNA− histone interactions, thereby influencing gene transcriptional activation. 1 It was not until the late 1970s, however, that evidence supporting the direct contribution of histone tail lysine acetylation to the opening of chromatin and activation of transcription was presented. 2 Lysine acetylation is a reversible process, occurring at the ε-amino group of site-specific lysine residues in histones. The combined effects of acetylation, namely, charge neutralization and steric hindrance, relax chromatin structure and enhance the accessibility of DNA for recognition by transcription factors 3 (Figure 1). Additionally, the discovery of HAT (histone acetyltransferase) activity of transcriptional cofactors directly linked histone acetylation to gene transcriptional activation in chromatin. 4− 6 Indeed, a series of transcriptional cofactors has been shown to possess intrinsic histone HAT activities, including GCN5 (general control of amino acid synthesis-5), 4 CBP (p300/CREB-binding protein), 7, 8 PCAF (p300/CBP-associated factor), 9 and TAF (TBP (TATA-binding protein)-associated factor). 10 The role of lysine acetylation in gene transcriptional activation was further highlighted by the identification of the bromodomain a conserved structural motif found in many eukaryotic transcription cofactors 11, 12 whose primary function is to recognize acetylated lysine in histones and transcription proteins. 13 Most nuclear HATs (type A) in the GNAT and p300/CBP families contain a bromodomain 14 that can serve as