Panagis Filippakopoulos 1 , ∗ , Sarah Picaud 1 , Maria Mangos 3 , Tracy Keates 1 , Jean-Philippe Lambert 5 , Dalia Barsyte-Lovejoy 3 , Ildiko Felletar 1 , Rudolf Volkmer 6 , Susanne Müller 1 , Tony Pawson 5 , 7 , Anne-Claude Gingras 5 , 7 , Cheryl H. Arrowsmith 3 , 4 , Stefan Knapp 1 , 2 , 8 , ∗∗
30 March 2012
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.
► Human bromodomain family characterized with 29 high-resolution crystal structures ► Peptide arrays establish core histone binding preferences of BRD ► Interactions with histone-acetylated lysine sites are quantified ► Flanking posttranslational modifications greatly impact acetylated lysine recognition
Bromodomains bind acetylated lysines in histones, a key event in the “reading” of epigenetic marks. A foundation for designing inhibitors for this emerging class of drug targets is provided by a systematic biochemical analysis of their binding preferences and a compendium of 29 crystal structures of human bromodomains.