Document Type
Journal Article
Publication Date
3-30-2012
Journal
Cell
Volume
Volume 149, Issue 1
Inclusive Pages
Volume 149, Issue 1
Keywords
Histones--chemistry--metabolism; Protein Processing; Post-Translational; Protein Structure; Tertiary
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
APA Citation
Filippakopoulos, P., Picaud, S., Mangos, M., Keates, T., Lambert, J., Barsyte-Lovejoy, D., Felletar, I., Volkmer, R, M¸ ller, S., Pawson, T., Gingras, A., Arrowsmith, C.H., Knapp, S. (2012). Histone recognition and large-scale structural analysis of the human bromodomain family. Cell, 149(1), 214-231.
Peer Reviewed
1
Open Access
1
Comments
Reproduced with permission of Cell.