Design of Potent Inhibitors of Human RAD51 Recombinase Based on BRC Motifs of BRCA2 Protein: Modeling and Experimental Validation of a Chimera Peptide
Artikel i vetenskaplig tidskrift, 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.

Författare

J. Nomme

Universite de Nantes

A. Renodon-Corniere

Universite de Nantes

Y. Asanomi

Hokkaido University

K. Sakaguchi

Hokkaido University

A. Z. Stasiak

Université de Lausanne

A. Stasiak

Université de Lausanne

Bengt Nordén

Chalmers, Kemi- och bioteknik, Fysikalisk kemi

V. Tran

Universite de Nantes

M. Takahashi

Universite de Nantes

Journal of Medicinal Chemistry

0022-2623 (ISSN) 1520-4804 (eISSN)

Vol. 53 15 5782-5791

Styrkeområden

Nanovetenskap och nanoteknik

Energi

Livsvetenskaper och teknik

Materialvetenskap

Ämneskategorier

Annan medicinsk grundvetenskap

DOI

10.1021/jm1002974