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 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.
Joseph
Prem Raj B
PR
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, 77555, USA.
Yuan
Ziyan
Z
Kumar
Eric A
EA
Lokesh
G L
GL
Kizhake
Smitha
S
Rajarathnam
Krishna
K
Natarajan
Amarnath
A
D020816:Amino Acid Motifs; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D009842:Oligopeptides