The Bromodomain: A New Target in Emerging Epigenetic Medicine

Abstract

The bromodomain (BrD) is a conserved protein modular domain found in many chromatin- and transcription-associated proteins that has the ability to recognize acetylated lysine residues. This activity allows bromodomains to play a vital role in many acetylation-mediated protein-protein interactions in the cell, ranging from substrate recruitment for histone acetyltransferases (HATs) to aiding in multiple-protein complex assembly for gene transcriptional activation or suppression in chromatin. In recent years, considerable efforts have been made to develop chemical inhibitors of these bromodomains in an effort to probe their cellular functions. Potent and selective inhibitors have been extensively developed for one group of the bromodomain family termed BET proteins that consist of tandem bromodomains followed by an extra terminal domain. Drug developers are actively designing inhibitors of other bromodomains and working to move the most successful inhibitors into the clinic.

Figure 1.

Bromodomain as the acetyl-lysine reader domain. (a) NMR structure of the PCAF bromodomain (PDB: 1N72). The four helices (αZ, αA, αB, αC) are noted, as are the N and C termini of the structure and the ZA and BC loops. The conserved asparagine residue, N803, is highlighted in yellow. (b) 2D ¹H–¹⁵N-heteronuclear single quantum coherence (HSQC) spectra of the PCAF bromodomain (~0.5 mM) in its free form (red) and in complex with the acetylated H4 peptide (molar ratio 1:6; black). Figure adapted with permission from ref . Copyright 1999 Macmillan Publishers Limited. (c) Crystal structure of the GCN5 bromodomain (blue) in complex with the acetylated peptide H4K16ac (green; PDB: 1E6I). The five water molecules at the base of the bromodomain binding pocket are represented as red spheres, the conserved asparagine residue, N407, is highlighted in yellow, and the ZA and BC loops are labeled. The key hydrogen bond between the conserved asparagine residue and the acetyl-lysine is represented by a black dashed line. (d) Stick diagram of the network of interactions among the H4K16ac peptide and the residues and water molecules within the GCN5 binding pocket. Key residues are labeled. Water molecules are represented by red spheres, and the hydrogen bonding network is represented by black dashed lines.

Figure 2.

Phylogenetic tree of the human bromodomain proteins. Sequence similarity-based phylogenetic tree of the 61 human bromodomains divided into eight groups. Generated using the web knowledgebase Chepimod; modified with permission from ref . Copyright 2014 Elsevier.