Journal article
Histone recognition and large-scale structural analysis of the human bromodomain family.
- 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.
- Publication status:
- Published
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- Publisher copy:
- 10.1016/j.cell.2012.02.013
Authors
- Journal:
- Cell More from this journal
- Volume:
- 149
- Issue:
- 1
- Pages:
- 214-231
- Publication date:
- 2012-03-01
- DOI:
- EISSN:
-
1097-4172
- ISSN:
-
0092-8674
- Language:
-
English
- Keywords:
- Pubs id:
-
pubs:322665
- UUID:
-
uuid:fb9db039-772d-40d9-8e2f-6eeef76e647f
- Local pid:
-
pubs:322665
- Source identifiers:
-
322665
- Deposit date:
-
2012-12-19
- ARK identifier:
Terms of use
- Copyright date:
- 2012
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