Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases
Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases
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DOI：
10.1016/j.str.2004.04.012
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发表时间：
2004-07-01
期刊：
影响因子：
5.7
通讯作者：
Tari, LW
中科院分区：
文献类型：
--
作者：
Somoza, JR;Skene, RJ;Tari, LW
组蛋白乙酰化状态的调节在基因表达的调节中起着关键作用。组蛋白脱乙酰酶 (HDAC) 催化组蛋白 N 末端附近赖氨酸上乙酰基的去除。该反应促进染色质浓缩，导致转录抑制。 HDAC 失调与多种癌症有关，这表明 HDAC 抑制剂在肿瘤学中具有潜在用途。在这里，我们描述了人类 HDAC 的第一个晶体结构：人类 HDAC8 与四种结构不同的异羟肟酸抑制剂复合的结构。这项工作揭示了 HDAC 的催化机制以及 HDAC 家族底物特异性的差异。该结构还表明 Ser39 磷酸化如何影响 HDAC8 活性。
Modulation of the acetylation state of histones plays a pivotal role in the regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysines near the N termini of histones. This reaction promotes the condensation of chromatin, leading to repression of transcription. HDAC deregulation has been linked to several types of cancer, suggesting a potential use for HDAC inhibitors in oncology. Here we describe the first crystal structures of a human HDAC: the structures of human HDAC8 complexed with four structurally diverse hydroxamate inhibitors. This work sheds light on the catalytic mechanism of the HDACs, and on differences in substrate specificity across the HDAC family. The structure also suggests how phosphorylation of Ser39 affects HDAC8 activity.