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

被引：0

作者：

Xin Liu

Ling Wang

Kehao Zhao

Paul R. Thompson

Yousang Hwang

Ronen Marmorstein

Philip A. Cole

机构：

[1] Program in Gene Expression and Regulation,Department of Chemistry

[2] The Wistar Institute,Department of Pharmacology and Molecular Sciences

[3] 3601 Spruce Street,undefined

[4] Philadelphia,undefined

[5] Pennsylvania 19104,undefined

[6] USA ,undefined

[7] University of Pennsylvania,undefined

[8] Philadelphia,undefined

[9] Pennsylvania 19104,undefined

[10] USA,undefined

[11] Johns Hopkins University School of Medicine,undefined

[12] 725 North Wolfe Street,undefined

[13] Baltimore,undefined

[14] Maryland 21205,undefined

[15] USA,undefined

[16] Present addresses: Novartis Institute for Biomedical Research,undefined

[17] Cambridge,undefined

[18] Massachusetts 02139,undefined

[19] USA (K.Z.); Department of Chemistry and Biochemistry,undefined

[20] University of South Carolina,undefined

[21] 631 Sumter Street,undefined

[22] Columbia,undefined

[23] South Carolina 29208,undefined

[24] USA (P.R.T.),undefined

来源：

Nature | 2008年 / 451卷

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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 cancer1,2,3,4. 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 HATs5,6,7,8,9. 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 ‘hit-and-run’ (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

页码：846 / 850

页数：4

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