Structural Mechanism of Transcriptional Regulator NSD3 Recognition by the ET Domain of BRD4

Structure. 2016 Jul 6;24(7):1201-8. doi: 10.1016/j.str.2016.04.019. Epub 2016 Jun 9.


The bromodomains and extra-terminal domain (BET) proteins direct gene transcription in chromatin, and represent new drug targets for cancer and inflammation. Here we report that the ET domain of the BET protein BRD4 recognizes an amphipathic protein sequence motif through establishing a two-strand antiparallel β sheet anchored on a hydrophobic cleft of the three-helix bundle. This structural mechanism likely explains BRD4 interactions with numerous cellular and viral proteins such as Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen, and NSD3 whose interaction with BRD4 via this ET domain mechanism is essential for acute myeloid leukemia maintenance.

MeSH terms

  • Binding Sites
  • Cell Cycle Proteins
  • Histone-Lysine N-Methyltransferase / chemistry*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Molecular Docking Simulation
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism


  • BRD4 protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Histone-Lysine N-Methyltransferase
  • NSD3 protein, human