Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors
Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors
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DOI：
10.1038/43710
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发表时间：
1999-09-09
期刊：
影响因子：
64.8
通讯作者：
Pavletich, NP
中科院分区：
文献类型：
--
作者：
Finnin, MS;Donigian, JR;Pavletich, NP
组蛋白脱乙酰酶（HDAC）介导核小体构象的变化，在基因表达调控中非常重要（1）。HDAC参与细胞周期进展和分化，其失调与几种癌症相关（2，3）。HDAC抑制剂，如阿司他丁A（TSA）和辛二酰苯胺异羟肟酸（SAHA），具有抗肿瘤作用，因为它们可以抑制细胞。生长（4-6）、诱导终末分化（4，5）和防止小鼠模型中肿瘤的形成（7，8），并且它们在治疗早幼粒细胞白血病（3）中是有效的。在这里，我们描述了组蛋白脱乙酰基酶催化核心的结构，揭示了从超嗜热菌Aquifex aeolieus，共享35.2%的身份与人类HDAC 1超过375个残基，脱乙酰组蛋白在体外抑制TSA和SAHA的同源物的晶体结构。脱乙酰基酶、脱乙酰基酶-TSA和脱乙酰基酶-SAHA的结构揭示了由一个管状口袋、一个锌结合位点和两个Asp-His电荷传递系统组成的活性位点，并建立了HDAC抑制机制。构成活性位点并接触抑制剂的残基在HDAC家族中是保守的。这些结构还表明了脱乙酰化反应的机制，并为进一步开发HDAC抑制剂作为抗肿瘤药物提供了框架。
Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression(1). HDACs are involved in cell-cycle progression and differentiation, and their deregulation is associated with several cancers(2,3). HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumour effects, as they can inhibit cell. growth(4-6), induce terminal differentiation(4,5) and prevent the formation of tumours in mice models(7,8), and they are effective in the treatment of promyelocytic leukemia(3). Here we describe the structure of the histone deacetylase catalytic core, as revealed by the crystal structure of a homologue from the hyperthermophilic bacterium Aquifex aeolieus, that shares 35.2% identity with human HDACl over 375 residues, deacetylates histones in vitro and is inhibited by TSA and SAHA. The deacetylase, deacetylase-TSA and deacetylase-SAHA structures reveal an active site consisting of a tubular pocket, a zinc-binding site and two Asp-His charge-relay systems, and establish the mechanism of HDAC inhibition. The residues that make up the active site and contact the inhibitors are conserved across the HDAC family. These structures also suggest a mechanism for the deacetylation reaction and provide a framework for the further development of HDAC inhibitors as antitumour agents.