Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling.
Nijaguna, Mamatha B
Hurakadli, Manjunath A
Kurup, Lokavya Meenakshi
Cell chemical biology
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Periasamy, J., Kurdekar, V., Jasti, S., Nijaguna, M. B., Boggaram, S., Hurakadli, M. A., Raina, D., et al. (2018). Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling.. Cell chemical biology, 25 (6), 677-690.e12. https://doi.org/10.1016/j.chembiol.2018.02.012
Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 carboxyl-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the human BRCA1 tandem (t)BRCT domain, which selectively inhibits substrate binding with nanomolar potency in vitro. Structure-activity exploration suggests that Bractoppin engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket that is distinct in structurally related BRCT domains, conferring selectivity. In cells, Bractoppin 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. But damage-induced MDC1 recruitment, singlestranded (ss)DNA generation, and TOPBP1 recruitment remain unaffected. Thus, an inhibitor of phosphopeptide recognition selectively interrupts BRCA1 tBRCT-dependent signals evoked by DNA damage.
Cells, Cultured, Humans, Phosphopeptides, BRCA1 Protein, Fluorescence Resonance Energy Transfer, Signal Transduction, Cell Survival, Molecular Structure, Structure-Activity Relationship, Molecular Dynamics Simulation, HEK293 Cells, Protein Domains
External DOI: https://doi.org/10.1016/j.chembiol.2018.02.012
This record's URL: https://www.repository.cam.ac.uk/handle/1810/278984
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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