A Common Binding Motif in the ET Domain of BRD3 Forms Polymorphic Structural Interfaces with Host and Viral Proteins

The extra-terminal (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 BRD3-ET domain with either the 79-residue murine leukemia virus integrase (IN) C-terminal domain (IN329-408), or its 22-residue IN tail peptide (TP) (IN386-407) alone, reveal similar intermolecular three-stranded β-sheet formation. 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, impacting its potential range of orientations in the IN - nucleosome complex.  The complex of the ET-binding peptide of host NSD3 protein (NSD3148-184) and BRD3-ET domain includes a similar three-stranded b-sheet interaction, but the orientation of the b-hairpin is flipped compared to 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.