Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide.
Détails
Télécharger: BIB_501909E7F3E7.P001.pdf (3476.70 [Ko])
Etat: Public
Version: de l'auteur⸱e
Etat: Public
Version: de l'auteur⸱e
ID Serval
serval:BIB_501909E7F3E7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide.
Périodique
Journal of Medicinal Chemistry
ISSN
1520-4804[electronic], 0022-2623[linking]
Statut éditorial
Publié
Date de publication
2010
Volume
53
Numéro
15
Pages
5782-5791
Langue
anglais
Résumé
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.
Mots-clé
isothermal titration calorimetry, homologous recombination, breast-cancer, repair protein, stranded-dna, reca protein, repeats, cells, radiosensitivity, expression
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/08/2010 9:02
Dernière modification de la notice
20/08/2019 14:06