Bractoppin is a potent, small-molecule chemical inhibitor that specific selectively blocks phosphopeptide recognition by the BRCA1 tBRCT domain with binding IC50 of 74 nM; shows no inhibition for recognition of cognate biotinylated phosphopeptides to the TOPBP1 tBRCT 7/8, or GRB2 SH2 proteins; engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket; inhibits substrate recognition detected by Förster resonance energy transfer, and diminishes BRCA1 recruitment to DNA breaks, in turn suppressing damage-induced G2 arrest and assembly of the recombinase, RAD51; selectively interrupts BRCA1 tBRCT-dependent signals evoked by DNA damage.
