Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family

TLDR

Bromodomains are protein modules that recognize lysine acetylation motifs and the 61 human BRDs cluster into eight families based on structural and sequence similarity. The study aims to present 29 high‑resolution crystal structures covering all human BRD families. The authors determined 29 crystal structures and performed systematic screening of over 30 BRDs on histone‑peptide arrays, revealing a structural mechanism for simultaneous binding of diacetyl peptides by BRD4. Cross‑family structural analysis uncovered conserved and family‑specific features essential for acetylation‑dependent recognition, identified new BRD substrates influenced by flanking post‑translational modifications, revealed a mechanism for diacetyl peptide binding by BRD4, and laid the groundwork for structure‑based inhibitor design.

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.