Structural Features Underlying the Activity of Benzimidazole Derivatives that Target Phosphopeptide Recognition by the Tandem BRCT Domain of the BRCA1 Protein
Posted: 19 Feb 2020
Date Written: july 23, 2019
The tandem BRCT (tBRCT) domains of BRCA1 propagates intracellular signals initiated by DNA damage thereby controlling cell cycle arrest and DNA damage repair. BRCA1 tBRCT recognizes specific phosphorylated binding motif (pSer-X-X-Phe) on target proteins and makes protein-protein interactions (PPI). Our group has recently identified Bractoppin, a benzimidazole derivative as a first selective small-molecule PPI inhibitor of the BRCA1 tBRCT domain. Understanding the structural features that underlie the biochemical and cellular activities of Bractoppin will play a major role in lead optimization and in the realization of future potential for disease therapy. In this study, we first establish the Bractoppin binding pocket on BRCA1 tBRCT by mutations of residues that engage phospho-peptide and sub pockets abutting phospho-peptide binding site. We further showcase the significance of combining multiple structure-guided strategies like GIST analysis and dimer interface analysis in proposing testable hypothesis that lead to the development of wide range of inhibitors with Structure activity relationships. Finally, we show that Bractoppin derivatives engage its cellular target, BRCA1 and abrogate G2 checkpoint, thus interrupting BRCA1 tBRCT-dependent signals evoked by DNA breakage. Overall, we show successful application of complementary computational methodologies to define the structural features at a molecular level for optimization of biochemical and cellular activities of Bractoppin.
Keywords: BRCA1 tBRCT, Protein-Protein Interaction, DNA Damage, GIST
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