Structural characterization of BRCT–tetrapeptide binding interactions

BRCT(BRCA1) plays a major role in DNA repair pathway, and does so by recognizing the conserved sequence pSXXF in its target proteins. Remarkably, tetrapeptides containing pSXXF motif bind with high specificity and micromolar affinity. Here, we have characterized the binding interactions of pSXXF tet...

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Published inBiochemical and biophysical research communications Vol. 393; no. 2; pp. 207 - 210
Main Authors Joseph, Prem Raj B., Yuan, Ziyan, Kumar, Eric A., Lokesh, G.L., Kizhake, Smitha, Rajarathnam, Krishna, Natarajan, Amarnath
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 05.03.2010
Subjects
Amino Acid Motifs
BRCA1 Protein - antagonists & inhibitors
BRCA1 Protein - chemistry
BRCT(BRCA1)
Drug Design
Humans
NMR
Nuclear Magnetic Resonance, Biomolecular
Oligopeptides - chemistry
Protein Binding
Protein Conformation
pSXXF tetrapeptide
Structure
Thermodynamics
pSXXF tetrapeptide
Thermodynamics
TROSY
NMR
BRCT(BRCA1)
ITC
Structure
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Summary:BRCT(BRCA1) plays a major role in DNA repair pathway, and does so by recognizing the conserved sequence pSXXF in its target proteins. Remarkably, tetrapeptides containing pSXXF motif bind with high specificity and micromolar affinity. Here, we have characterized the binding interactions of pSXXF tetrapeptides using NMR spectroscopy and calorimetry. We show that BRCT is dynamic and becomes structured on binding, that pSer and Phe residues dictate overall binding, and that the binding affinities of the tetrapeptides are intimately linked to structural and dynamic changes both in the BRCT(BRCA1) and tetrapeptides. These results provide critical insights for designing high-affinity BRCT(BRCA1) inhibitors.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2010.01.098