The structural basis of protein acetylation by the p300/CBP transcriptional coactivator

被引:330
作者
Liu, Xin [1 ,2 ]
Wang, Ling [3 ]
Zhao, Kehao [1 ]
Thompson, Paul R. [3 ]
Hwang, Yousang [3 ]
Marmorstein, Ronen [1 ,2 ]
Cole, Philip A. [3 ]
机构
[1] Wistar Inst Anat & Biol, Program Gene Express & Regulat, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA
[3] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1038/nature06546
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The transcriptional coactivator p300/ CBP ( CREBBP) is a histone acetyltransferase ( HAT) that regulates gene expression by acetylating histones and other transcription factors. Dysregulation of p300/ CBP HAT activity contributes to various diseases including cancer(1-4). Sequence alignments, enzymology experiments and inhibitor studies on p300/ CBP have led to contradictory results about its catalytic mechanism and its structural relation to the Gcn5/ PCAF and MYST HATs(5-9). Here we describe a high- resolution X- ray crystal structure of a semi- synthetic heterodimeric p300 HAT domain in complex with a bi- substrate inhibitor, Lys- CoA. This structure shows that p300/ CBP is a distant cousin of other structurally characterized HATs, but reveals several novel features that explain the broad substrate specificity and preference for nearby basic residues. Based on this structure and accompanying biochemical data, we propose that p300/ CBP uses an unusual 'hitandrun' ( Theorell - Chance) catalytic mechanism that is distinct from other characterized HATs. Several disease- associated mutations can also be readily accounted for by the p300 HAT structure. These studies pave the way for new epigenetic therapies involving modulation of p300/ CBP HAT activity.
引用
收藏
页码:846 / 850
页数:5
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