Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling.
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Authors
Periasamy, Jayaprakash
Kurdekar, Vadiraj
Jasti, Subbarao
Nijaguna, Mamatha B
Boggaram, Sanjana
Hurakadli, Manjunath A
Kurup, Lokavya Meenakshi
Chintha, Chetan
Goyal, Aneesh
Sadasivam, Gayathri
Bharatham, Kavitha
Padigaru, Muralidhara
Potluri, Vijay
Venkitaraman, Ashok
Publication Date
2018-06-21Journal Title
Cell Chem Biol
ISSN
2451-9456
Publisher
Elsevier BV
Volume
25
Issue
6
Pages
677-690.e12
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
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 Chem Biol, 25 (6), 677-690.e12. https://doi.org/10.1016/j.chembiol.2018.02.012
Abstract
Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-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, single-stranded DNA (ssDNA) generation, and TOPBP1 recruitment remain unaffected. Thus, an inhibitor of phosphopeptide recognition selectively interrupts BRCA1 tBRCT-dependent signals evoked by DNA damage.
Keywords
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
Sponsorship
MRC (MR/N501876/1)
Identifiers
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
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