Histone recognition and large-scale structural analysis of the human bromodomain family.
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-resoluti...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2012
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| _version_ | 1797105491006980096 |
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| author | Filippakopoulos, P Picaud, S Mangos, M Keates, T Lambert, J Barsyte-Lovejoy, D Felletar, I Volkmer, R Müller, S Pawson, T Gingras, A Arrowsmith, C Knapp, S |
| author_facet | Filippakopoulos, P Picaud, S Mangos, M Keates, T Lambert, J Barsyte-Lovejoy, D Felletar, I Volkmer, R Müller, S Pawson, T Gingras, A Arrowsmith, C Knapp, S |
| author_sort | Filippakopoulos, P |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T06:48:20Z |
| format | Journal article |
| id | oxford-uuid:fb9db039-772d-40d9-8e2f-6eeef76e647f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:48:20Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:fb9db039-772d-40d9-8e2f-6eeef76e647f2022-03-27T13:15:14ZHistone recognition and large-scale structural analysis of the human bromodomain family.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fb9db039-772d-40d9-8e2f-6eeef76e647fEnglishSymplectic Elements at Oxford2012Filippakopoulos, PPicaud, SMangos, MKeates, TLambert, JBarsyte-Lovejoy, DFelletar, IVolkmer, RMüller, SPawson, TGingras, AArrowsmith, CKnapp, SBromodomains (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. |
| spellingShingle | Filippakopoulos, P Picaud, S Mangos, M Keates, T Lambert, J Barsyte-Lovejoy, D Felletar, I Volkmer, R Müller, S Pawson, T Gingras, A Arrowsmith, C Knapp, S Histone recognition and large-scale structural analysis of the human bromodomain family. |
| title | Histone recognition and large-scale structural analysis of the human bromodomain family. |
| title_full | Histone recognition and large-scale structural analysis of the human bromodomain family. |
| title_fullStr | Histone recognition and large-scale structural analysis of the human bromodomain family. |
| title_full_unstemmed | Histone recognition and large-scale structural analysis of the human bromodomain family. |
| title_short | Histone recognition and large-scale structural analysis of the human bromodomain family. |
| title_sort | histone recognition and large scale structural analysis of the human bromodomain family |
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