Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family

被引：1328

作者：

Filippakopoulos, Panagis ^{[1
]}

Picaud, Sarah ^{[1
]}

Mangos, Maria ^{[3
]}

Keates, Tracy ^{[1
]}

Lambert, Jean-Philippe ^{[6
]}

Barsyte-Lovejoy, Dalia ^{[3
]}

Felletar, Ildiko ^{[1
]}

Volkmer, Rudolf ^{[7
]}

Mueller, Susanne ^{[1
]}

Pawson, Tony ^{[6
,8
]}

Gingras, Anne-Claude ^{[6
,8
]}

Arrowsmith, Cheryl H. ^{[3
,4
,5
]}

Knapp, Stefan ^{[1
,2
,9
]}

机构：

[1] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford OX3 7LD, England

[2] Univ Oxford, Dept Oncol, Oxford OX3 7LD, England

[3] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada

[4] Univ Toronto, Ontario Canc Inst, Campbell Family Canc Res Inst, Toronto, ON M5G 1L7, Canada

[5] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada

[6] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ctr Syst Biol, Toronto, ON M5G 1X5, Canada

[7] Charite Univ Med Berlin, Inst Med Immunol, D-10115 Berlin, Germany

[8] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[9] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Washington, DC 20037 USA

来源：

CELL | 2012年 / 149卷 / 01期

基金：

加拿大自然科学与工程研究理事会; 英国惠康基金; 加拿大创新基金会;

关键词：

CHROMATIN-REMODELING COMPLEX; EMBRYONIC STEM-CELLS; GENE-EXPRESSION; PEPTIDE ARRAYS; TRANSCRIPTION ELONGATION; BET BROMODOMAINS; PHD FINGER; PROTEIN; ACETYLATION; IDENTIFICATION;

D O I：

10.1016/j.cell.2012.02.013

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：

Bromodomains (BRDs) are protein interaction modules that specifically recognize epsilon-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations of marks rather than singly acetylated sequences. We further uncovered a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4. These data provide a foundation for structure-based drug design of specific inhibitors for this emerging target family.

引用

页码：214 / 231

页数：18

共 84 条

[1] TIF1γ Controls Erythroid Cell Fate by Regulating Transcription Elongation [J].