Histone deacetylase 6 structure and molecular basis of catalysis and inhibition.
Histone deacetylase 6 structure and molecular basis of catalysis and inhibition.
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DOI：
10.1038/nchembio.2134
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发表时间：
2016-09
影响因子：
14.8
通讯作者：
Christianson DW
中科院分区：
文献类型：
--
作者：
Hai Y;Christianson DW
组蛋白去乙酰化酶6（HDAC 6）由于其在致癌转化和癌症转移中的作用而成为药物设计的关键靶标，并且在所有组蛋白去乙酰化酶中是独特的，因为它包含称为CD 1和CD 2的串联催化结构域。我们现在报告了来自智人的CD 2和来自斑马鱼HDAC 6的CD 1和CD 2的晶体结构，并且我们使用13种不同底物的面板将这些结构与活性测量相关联。来自两种物种的CD 2的催化活性表现出广泛的底物特异性，而CD 1的催化活性对具有C-末端乙酰赖氨酸残基的底物具有高度特异性。基质复合物的晶体结构产生了前所未有的催化机制的快照。此外，具有8种不同抑制剂的复合物的晶体结构，包括贝利司他和帕比司他（目前用于癌症化疗）、大环四肽HC毒素和HDAC 6特异性抑制剂N-羟基-4-（2-[（2-羟乙基）（苯基）氨基]-2-氧代乙基）苯甲酰胺，揭示了关于Zn 2+配位和同工酶特异性抑制的变化的令人惊讶的新见解。
Histone deacetylase 6 (HDAC6) is a critical target for drug design due to its role in oncogenic transformation and cancer metastasis, and is unique among all histone deacetylases in that it contains tandem catalytic domains designated CD1 and CD2. We now report the crystal structures of CD2 from Homo sapiens and CD1 and CD2 from Danio rerio HDAC6, and we correlate these structures with activity measurements using a panel of 13 different substrates. The catalytic activity of CD2 from both species exhibits broad substrate specificity, whereas that of CD1 is highly specific for substrates bearing C-terminal acetyllysine residues. Crystal structures of substrate complexes yield unprecedented snapshots of the catalytic mechanism. Additionally, crystal structures of complexes with 8 different inhibitors, including Belinostat and Panobinostat (currently used in cancer chemotherapy), the macrocyclic tetrapeptide HC toxin, and the HDAC6-specific inhibitor N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide, reveal surprising new insight regarding changes in Zn2+ coordination and isozyme-specific inhibition.