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Structural characterization of BRCT-tetrapeptide binding interactions.

ABSTRACT: 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.

SUBMITTER: Joseph PR

PROVIDER: S-EPMC2834807 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Structural characterization of BRCT-tetrapeptide binding interactions.

Joseph Prem Raj B PR Yuan Ziyan Z Kumar Eric A EA Lokesh G L GL Kizhake Smitha S Rajarathnam Krishna K Natarajan Amarnath A

Biochemical and biophysical research communications 20100201 2

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 o ...[more]

PMID: 20122900

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