Exploiting the P-1 pocket of BRCT domains toward a structure guided inhibitor design

Ziyan Yuan, Eric A. Kumar, Stephen J. Campbell, Nicholas Y. Palermo, Smitha Kizhake, J. N Mark Glover, Amarnath Natarajan

Research output: Contribution to journalArticle

17 Scopus citations

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 analogues 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.

Original languageEnglish (US)
Pages (from-to)764-767
Number of pages4
JournalACS Medicinal Chemistry Letters
Volume2
Issue number10
DOIs
StatePublished - Oct 13 2011

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Keywords

  • BRCT inhibitors and breast cancer
  • Protein-protein interface
  • peptide mimics

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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