Design of Potent Inhibitors of Human RAD51 Recombinase Based on BRC Motifs of BRCA2 Protein: Modeling and Experimental Validation of a Chimera Peptide
Journal article, 2010
We have previously shown that a 28-amino acid peptide derived from the BRC4 motif of BRCA2 tumor suppressor inhibits selectively human RAD51 recombinase (HsRad51). With the aim of designing better inhibitors for cancer treatment, we combined an in silico docking approach with in vitro biochemical testing to construct a highly efficient chimera peptide from eight existing human BRC motifs. We built a molecular model of all BRC motifs complexed with HsRad51 based on the crystal structure of the BRC4 motif-HsRad51 complex, computed the interaction energy of each residue in each BRC motif, and selected the best amino acid residue at each binding position. This analysis enabled us to propose four amino acid substitutions in the BRC4 motif. Three of these increased the inhibitory effect in vitro, and this effect was found to be additive. We thus obtained a peptide that is about 10 times more efficient in inhibiting HsRad51-ssDNA complex formation than the original peptide.
Renodon-Corniere
Takahashi
Andrzej] Univ Lausanne
[Stasiak
cells
Vinh
Ctr
reca protein
Dept Chem
radiosensitivity
Tran
Fac Biol & Med
Stasiak
Dept Chem & Biosci
Alicja Z.
UMR 6204 U3B
Axelle
Sweden.
Bengt] Chalmers
repair protein
Masayuki]
breast-cancer
repeats
Kazuyasu] Hokkaido Univ
Julian
F-44322 Nantes 3
stranded-dna
[Asanomi
Fac Sci
[Nomme
isothermal titration calorimetry
homologous recombination
Sakaguchi
SE-41296 Gothenburg
RS
expression
[Norden
Yuya
France.
Author
J. Nomme
Universite de Nantes
A. Renodon-Corniere
Universite de Nantes
Y. Asanomi
Hokkaido University
K. Sakaguchi
Hokkaido University
A. Z. Stasiak
Universitat Lausanne Schweiz
A. Stasiak
Universitat Lausanne Schweiz
Bengt Nordén
Chalmers, Chemical and Biological Engineering, Physical Chemistry
V. Tran
Universite de Nantes
M. Takahashi
Universite de Nantes
Journal of Medicinal Chemistry
0022-2623 (ISSN) 1520-4804 (eISSN)
Vol. 53 15 5782-5791Areas of Advance
Nanoscience and Nanotechnology
Energy
Life Science Engineering (2010-2018)
Materials Science
Subject Categories (SSIF 2011)
Other Basic Medicine
DOI
10.1021/jm1002974