A common binding motif in the ET domain of BRD3 forms polymorphic structural interfaces with host and viral proteins

Structure. 2021 Aug 5;29(8):886-898.e6. doi: 10.1016/j.str.2021.01.010. Epub 2021 Feb 15.


The extraterminal (ET) domain of BRD3 is conserved among BET proteins (BRD2, BRD3, BRD4), interacting with multiple host and viral protein-protein networks. Solution NMR structures of complexes formed between the BRD3 ET domain and either the 79-residue murine leukemia virus integrase (IN) C-terminal domain (IN329-408) or its 22-residue IN tail peptide (IN386-407) alone reveal similar intermolecular three-stranded β-sheet formations. 15N relaxation studies reveal a 10-residue linker region (IN379-388) tethering the SH3 domain (IN329-378) to the ET-binding motif (IN389-405):ET complex. This linker has restricted flexibility, affecting its potential range of orientations in the IN:nucleosome complex. The complex of the ET-binding peptide of the host NSD3 protein (NSD3148-184) and the BRD3 ET domain includes a similar three-stranded β-sheet interaction, but the orientation of the β hairpin is flipped compared with the two IN:ET complexes. These studies expand our understanding of molecular recognition polymorphism in complexes of ET-binding motifs with viral and host proteins.

Keywords: BET proteins; BRD3; Moloney murine leukemia virus; NSD3; extraterminal domain; integrase; interdomain dynamics; isotope peptide labeling; solution NMR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Histone-Lysine N-Methyltransferase / chemistry*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Integrases / chemistry*
  • Integrases / metabolism
  • Leukemia Virus, Murine / enzymology*
  • Models, Molecular
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Protein Conformation
  • Transcription Factors / chemistry*
  • Viral Proteins / chemistry
  • Viral Proteins / metabolism


  • BRD3 protein, human
  • Nuclear Proteins
  • Transcription Factors
  • Viral Proteins
  • Histone-Lysine N-Methyltransferase
  • NSD3 protein, human
  • Integrases