Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family
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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.
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The record
- Venue
- Cell
- Topic
- Protein Degradation and Inhibitors
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- Canada Research ChairsOntario Institute for Cancer ResearchUniversity of TorontoLunenfeld-Tanenbaum Research InstituteStructural Genomics Consortium
- Funders
- Canada Research ChairsCanadian Institutes of Health ResearchGenome CanadaWellcome TrustGlaxoSmithKlineOntario Ministry of Research and InnovationNatural Sciences and Engineering Research Council of CanadaPfizerEli Lilly and Company
- Keywords
- BromodomainAcetylationBiologyBRD4HistoneComputational biologyGeneticsStructural similarityBET inhibitorEpigeneticsBiochemistryDNAGene
- Has abstract in OpenAlex
- yes