Human bromodomains were classified based on structural and binding properties.

  • Major finding: Human bromodomains are classified based on structural and binding properties.

  • Approach: Bromodomain proteins were analyzed by X-ray crystallography and histone peptide arrays.

  • Impact: Structural data may facilitate the rational design of selective bromodomain protein inhibitors.

Bromodomains (BRD) are protein modules that recognize and bind acetylated lysine residues. Many BRD-containing proteins have been linked to epigenetic regulation of gene expression through their interactions with acetylated histones and have emerged as promising drug targets. Filippakopoulos and colleagues searched human protein sequence databases for BRD homology and identified 61 unique BRDs contained in 46 diverse proteins. The authors used available nuclear magnetic resonance models and secondary structure prediction algorithms to perform a structure-guided phylogenetic analysis that clustered the human BRDs into 8 major families, which may suggest functional similarities. All human BRD proteins were subcloned into bacterial expression systems, and the crystal structures of 44 BRDs, representing each of the 8 families, in complex with acetylated peptides were determined. This comprehensive structural analysis allowed the identification of common BRD structural elements, such as a hydrophobic acetylated-lysine binding pocket formed by 4 α-helices, as well as family-specific motifs and surface properties. Representative BRDs were also screened against peptide arrays that covered all possible histone tail acetylation sites to assess the specificity of individual binding domains, which revealed that some BRDs specifically interact with particular acetylated lysines and others bind nonspecifically. The binding affinities were generally low, suggesting that additional modifications may be needed for higher-affinity target binding. Indeed, BRD screening against histone H3- and H4-specific peptide arrays with various combinations of polyacetylated and trimethylated lysines as well as phosphorylated serines and threonines revealed that the binding affinity of many BRDs increased when multiple residues were modified, suggesting that BRDs recognize more than a single acetylation mark. Together, these findings provide insight into the functions of human bromodomains and offer a framework for the rational design of competitive BRD inhibitors for epigenetic therapies.

Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 2012;149:214–31.

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