Histone recognition and large-scale structural analysis of the human bromodomain family

Cell. 2012 Mar 30;149(1):214-31. doi: 10.1016/j.cell.2012.02.013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Genome, Human
  • Histones / chemistry*
  • Histones / metabolism
  • Humans
  • Lysine / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Phylogeny
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational*
  • Protein Structure, Tertiary*
  • Proteome / analysis

Substances

  • Histones
  • Proteome
  • Lysine

Associated data

  • PDB/2NXB
  • PDB/2OO1
  • PDB/2OSS
  • PDB/2OUO
  • PDB/2RFJ
  • PDB/3D7C
  • PDB/3DAI
  • PDB/3DWY
  • PDB/3G0J
  • PDB/3G0L
  • PDB/3GG3
  • PDB/3HME
  • PDB/3HMF
  • PDB/3HMH
  • PDB/3I3J
  • PDB/3IU5
  • PDB/3IU6
  • PDB/3K2J
  • PDB/3LXJ
  • PDB/3MB3
  • PDB/3MB4
  • PDB/3MQM
  • PDB/3NXB
  • PDB/3P1C
  • PDB/3P1D
  • PDB/3Q2E
  • PDB/3RCW
  • PDB/3TLP
  • PDB/3UV2
  • PDB/3UV4
  • PDB/3UV5
  • PDB/3UVD
  • PDB/3UVW
  • PDB/3UVX
  • PDB/3UVY
  • PDB/3UW9