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PMID: 22464331 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Histone recognition and large-scale structural analysis of the human bromodomain family.

Cell ·Vol. 149 ·No. 1 ·2012-03-30 ·Pages 214-31

Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Müller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S

Abstract

Bromodomains (BRDs) are protein interaction modules that specifically recognize ε-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.

MeSH Terms
Acetylation Amino Acid Sequence Animals Crystallography, X-Ray Genome, Human Histones/chemistry,metabolism Humans Lysine/metabolism Models, Molecular Molecular Sequence Data Phylogeny Protein Interaction Domains and Motifs Protein Processing, Post-Translational Protein Structure, Tertiary Proteome/analysis
Chemicals
Histones Proteome Lysine
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Filippakopoulos Panagis
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7LD, UK. panagis.filippakopoulos@sgc.ox.ac.uk
Picaud Sarah
Mangos Maria
Keates Tracy
Lambert Jean-Philippe
Barsyte-Lovejoy Dalia
Felletar Ildiko
Volkmer Rudolf
Müller Susanne
Pawson Tony
Gingras Anne-Claude
Arrowsmith Cheryl H
Knapp Stefan
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2012.02.013
Email
panagis.filippakopoulos@sgc.ox.ac.uk
Published
2012-03-30
Pages
214-31
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3326523
Subset
IM
Grants
Wellcome Trust · 092809 · United Kingdom
Wellcome Trust · 095751/Z/11/Z · United Kingdom
CIHR · Canada
Databases
PDB
2NXB, 2OO1, 2OSS, 2OUO, 2RFJ, 3D7C, 3DAI, 3DWY, 3G0J, 3G0L, 3GG3, 3HME, 3HMF, 3HMH, 3I3J, 3IU5, 3IU6, 3K2J, 3LXJ, 3MB3, 3MB4, 3MQM, 3NXB, 3P1C, 3P1D, 3Q2E, 3RCW, 3TLP, 3UV2, 3UV4, 3UV5, 3UVD, 3UVW, 3UVX, 3UVY, 3UW9
External Links
PubMed source DOI: 10.1016/j.cell.2012.02.013 PMC Full Text View journal details
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