Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases

被引:634
作者
Somoza, JR
Skene, RJ
Katz, BA
Mol, C
Ho, JD
Jennings, AJ
Luong, C
Arvai, A
Buggy, JJ
Chi, E
Tang, J
Sang, BC
Verner, E
Wynands, R
Leahy, EM
Dougan, DR
Snell, G
Navre, M
Knuth, MW
Swanson, RV
McRee, DE
Tari, LW
机构
[1] Celera, San Francisco, CA 94080 USA
[2] Syrrx Inc, San Diego, CA 92121 USA
关键词
D O I
10.1016/j.str.2004.04.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1325 / 1334
页数:10
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