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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.

Original publication

DOI

10.1016/j.cell.2012.02.013

Type

Journal article

Journal

Cell

Publication Date

30/03/2012

Volume

149

Pages

214 - 231

Keywords

Acetylation, Amino Acid Sequence, Animals, Crystallography, X-Ray, Genome, Human, Histones, Humans, Lysine, Models, Molecular, Molecular Sequence Data, Phylogeny, Protein Interaction Domains and Motifs, Protein Processing, Post-Translational, Protein Structure, Tertiary, Proteome