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

Journal article

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.

Authors: Filippakopoulos, P; Picaud, S; Mangos, M; Keates, T; Lambert, J

• Publication status: Published
• Journal: Cell
• Volume: 149
• Issue: 1
• Pages: 214-231
• Publication date: 2012-03-01
• DOI: 10.1016/j.cell.2012.02.013
• EISSN: 1097-4172
• ISSN: 0092-8674
• Language: English
• Keywords: Lysine; Animals; Histones; Amino Acid Sequence; Protein Structure, Tertiary; Protein Processing, Post-Translational; Acetylation; Humans; Proteome; Protein Interaction Domains and Motifs; Molecular Sequence Data; Models, Molecular; Genome, Human; Crystallography, X-Ray; Phylogeny