3UVW

Crystal Structure of the first bromodomain of human BRD4 in complex with a diacetylated histone 4 peptide (H4K5acK8ac)

Summary for 3UVW

• Entry DOI: 10.2210/pdb3uvw/pdb
• Related: 3UV2 3UV4 3UV5 3UVD 3UVX 3UVY 3UW9
• Descriptor: Bromodomain-containing protein 4, Histone H4, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: bromodomain, bromodomain containing protein 4, cap, hunk1, mcap, mitotic chromosome associated protein, peptide complex, structural genomics consortium, sgc, protein binding, transcription, transcription-protein binding complex, transcription/protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus (By similarity): O60885; Nucleus: P62805
• Total number of polymer chains: 2
• Total formula weight: 16382.79

Authors

Filippakopoulos, P.,Felletar, I.,Picaud, S.,Keates, T.,Muniz, J.,Gileadi, O.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Weigelt, J.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2011-11-30, release date: 2012-01-18, Last modification date: 2024-10-16)

Primary citation

Filippakopoulos, P.,Picaud, S.,Mangos, M.,Keates, T.,Lambert, J.P.,Barsyte-Lovejoy, D.,Felletar, I.,Volkmer, R.,Muller, S.,Pawson, T.,Gingras, A.C.,Arrowsmith, C.H.,Knapp, S.
Histone recognition and large-scale structural analysis of the human bromodomain family.
Cell(Cambridge,Mass.), 149:214-231, 2012

PubMed 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.

PubMed: 22464331
DOI: 10.1016/j.cell.2012.02.013

Experimental method

X-RAY DIFFRACTION (1.37 Å)