title: Exploiting the P-1 pocket of BRCT domains toward a structure guided inhibitor design.
abstract: Breast cancer gene 1 carboxy terminus (BRCT) domains are found in a number of proteins that are important for DNA damage response (DDR). The BRCT domains bind phosphorylated proteins and these protein-protein interactions are essential for DDR and DNA repair. High affinity domain specific inhibitors are needed to facilitate the dissection of the protein-protein interactions in the DDR signaling. The BRCT domains of BRCA1 bind phosphorylated protein through a pSXXF consensus recognition motif. We identified a hydrophobic pocket at the P-1 position of the pSXXF binding site. Here we conducted a structure-guided synthesis of peptide analogs with hydrophobic functional groups at the P-1 position. Evaluation of these led to the identification of a peptide mimic 15 with a inhibitory constant (K(i)) of 40 nM for BRCT(BRCA1). Analysis of the TopBP1 and MDC1 BRCT domains suggests a similar approach is viable to design high affinity inhibitors.
authors: Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha NE 68022.
authors: Ziyan
authors: Z
authors: Yuan
authors: Eric A
authors: EA
authors: Kumar
authors: Stephen J
authors: SJ
authors: Campbell
authors: Nicholas Y
authors: NY
authors: Palermo
authors: Smitha
authors: S
authors: Kizhake
authors: J N
authors: JN
authors: Mark Glover
authors: Amarnath
authors: A
authors: Natarajan