title: Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide.
abstract: 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.
authors.affiliation: UMR 6204 U-3B, Centre National de la Recherche Scientifique & Universite de Nantes, France.
authors.forename: Julian
authors.initials: J
authors.lastname: Nomme
authors.forename: Axelle
authors.initials: A
authors.lastname: Renodon-Cornière
authors.forename: Yuya
authors.initials: Y
authors.lastname: Asanomi
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Sakaguchi
authors.forename: Alicja Z
authors.initials: AZ
authors.lastname: Stasiak
authors.forename: Andrzej
authors.initials: A
authors.lastname: Stasiak
authors.forename: Bengt
authors.initials: B
authors.lastname: Norden
authors.forename: Vinh
authors.initials: V
authors.lastname: Tran
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D024682:BRCA2 Protein / Q000737:chemistry*; D001665:Binding Sites; D002151:Calorimetry; D004247:DNA / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D024682:BRCA2 Protein; D010455:Peptides; D004247:DNA; D051135:Rad51 Recombinase