Structural characterization of BRCT-tetrapeptide binding interactions

Prem Raj B. Joseph; Ziyan Yuan; Eric A. Kumar; G. L. Lokesh; Smitha Kizhake; Krishna Rajarathnam; Amarnath Natarajan

doi:10.1016/j.bbrc.2010.01.098

Structural characterization of BRCT-tetrapeptide binding interactions

Prem Raj B. Joseph, Ziyan Yuan, Eric A. Kumar, G. L. Lokesh, Smitha Kizhake, Krishna Rajarathnam, Amarnath Natarajan

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English (US)
Pages (from-to)	207-210
Number of pages	4
Journal	Biochemical and Biophysical Research Communications
Volume	393
Issue number	2
DOIs	https://doi.org/10.1016/j.bbrc.2010.01.098
State	Published - Mar 5 2010
Externally published	Yes

Keywords

BRCT(BRCA1)
NMR
Structure
Thermodynamics
pSXXF tetrapeptide

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

Access to Document

10.1016/j.bbrc.2010.01.098

Cite this

@article{b0ab4fd6dab14acb8994f4bf55d1fe81,

title = "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.",

keywords = "BRCT(BRCA1), NMR, Structure, Thermodynamics, pSXXF tetrapeptide",

author = "Joseph, {Prem Raj B.} and Ziyan Yuan and Kumar, {Eric A.} and Lokesh, {G. L.} and Smitha Kizhake and Krishna Rajarathnam and Amarnath Natarajan",

note = "Funding Information: This work was supported in part by the grants NIH R01CA127239 (A.N.), ACB G218000116 (A.N.) and John Sealy Endowment fund (K.R.). ",

year = "2010",

month = mar,

day = "5",

doi = "10.1016/j.bbrc.2010.01.098",

language = "English (US)",

volume = "393",

pages = "207--210",

journal = "Biochemical and Biophysical Research Communications",

issn = "0006-291X",

publisher = "Academic Press Inc.",

number = "2",

}

TY - JOUR

T1 - Structural characterization of BRCT-tetrapeptide binding interactions

AU - Joseph, Prem Raj B.

AU - Yuan, Ziyan

AU - Kumar, Eric A.

AU - Lokesh, G. L.

AU - Kizhake, Smitha

AU - Rajarathnam, Krishna

AU - Natarajan, Amarnath

N1 - Funding Information: This work was supported in part by the grants NIH R01CA127239 (A.N.), ACB G218000116 (A.N.) and John Sealy Endowment fund (K.R.).

PY - 2010/3/5

Y1 - 2010/3/5

N2 - 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.

AB - 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.

KW - BRCT(BRCA1)

KW - NMR

KW - Structure

KW - Thermodynamics

KW - pSXXF tetrapeptide

UR - http://www.scopus.com/inward/record.url?scp=77649186561&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77649186561&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2010.01.098

DO - 10.1016/j.bbrc.2010.01.098

M3 - Article

C2 - 20122900

AN - SCOPUS:77649186561

SN - 0006-291X

VL - 393

SP - 207

EP - 210

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

IS - 2

ER -

Structural characterization of BRCT-tetrapeptide binding interactions

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this