Structural characterization of BRCT-tetrapeptide binding interactions.

Biochemical and Biophysical Research Communications
Prem Raj B JosephAmarnath Natarajan

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.

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Citations

Nov 17, 2011·Journal of Computer-aided Molecular Design·Victor M AnisimovClaudio N Cavasotto
Jan 5, 2016·Journal of Biomolecular Structure & Dynamics·Lumbini R YadavAshok K Varma
Apr 15, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Nagsen GautamYazen Alnouti
Apr 11, 2013·Scientific Reports·Eric A KumarAmarnath Natarajan
Nov 3, 2011·ACS Medicinal Chemistry Letters·Ziyan YuanAmarnath Natarajan
Aug 15, 2014·Journal of Medicinal Chemistry·Sandeep RanaAmarnath Natarajan

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