Exploiting the P-1 pocket of BRCT domains toward a structure guided inhibitor design
Ziyan Yuan1, Eric A Kumar, Stephen J Campbell
1Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha NE 68022.
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.
Insights
Researchers developed a novel peptide mimic that inhibits Breast Cancer gene 1 carboxy terminus (BRCT) domains, crucial for DNA damage response. This inhibitor offers a new tool for studying DNA repair pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Breast cancer gene 1 carboxy terminus (BRCT) domains are vital for the DNA damage response (DDR) pathway.
- These domains mediate essential protein-protein interactions by binding phosphorylated proteins, playing a critical role in DNA repair.
Purpose of the Study:
- To design and synthesize high-affinity, domain-specific inhibitors for BRCT domains.
- To facilitate the dissection of protein-protein interactions within the DDR signaling pathway.
Main Methods:
- Structure-guided synthesis of peptide analogs targeting the pSXXF recognition motif of BRCT domains.
- Incorporation of hydrophobic functional groups at the P-1 position of the binding site.
- In vitro evaluation of peptide analogs to determine inhibitory constants (K(i)).
Main Results:
- Identification of a hydrophobic pocket adjacent to the pSXXF binding site in BRCA1 BRCT domains.
- A synthesized peptide mimic (peptide mimic 15) demonstrated high affinity with a K(i) of 40 nM for BRCT(BRCA1).
- The strategy shows potential for developing inhibitors for other BRCT domains, such as those in TopBP1 and MDC1.
Conclusions:
- A structure-based approach can yield potent inhibitors of BRCT domain interactions.
- Peptide mimic 15 represents a valuable chemical probe for studying BRCA1-mediated DDR.
- This methodology is applicable for designing inhibitors against other BRCT-containing proteins involved in DNA repair.
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