Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide.

Handle URI:
http://hdl.handle.net/10754/596780
Title:
Design of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide.
Authors:
Nomme, Julian; Renodon-Cornière, Axelle; Asanomi, Yuya; Sakaguchi, Kazuyasu; Stasiak, Alicja Z; Stasiak, Andrzej; Norden, Bengt; Tran, Vinh; Takahashi, Masayuki
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.
Citation:
Nomme J, Renodon-Cornière A, Asanomi Y, Sakaguchi K, Stasiak AZ, et al. (2010) Design of Potent Inhibitors of Human RAD51 Recombinase Based on BRC Motifs of BRCA2 Protein: Modeling and Experimental Validation of a Chimera Peptide. Journal of Medicinal Chemistry 53: 5782–5791. Available: http://dx.doi.org/10.1021/jm1002974.
Publisher:
American Chemical Society (ACS)
Journal:
Journal of Medicinal Chemistry
KAUST Grant Number:
KUK-11-008-23
Issue Date:
1-Aug-2010
DOI:
10.1021/jm1002974
PubMed ID:
20684611
PubMed Central ID:
PMC2917172
Type:
Article
ISSN:
0022-2623; 1520-4804
Sponsors:
We thank Drs. Fabrice Fleury and Pierre Weigel for discussions and Dr. Kyoko Iwasaki-Yoshikane for CD measurements. This work was supported by grants from the Association pour la Recherche sur le Cancer [no. 3862], the Région de Pays de la Loire [MIAPS] and [CIMATH], the King Abdullah University of Science and Technology [KUK-11-008-23 to B.N.], and Swiss National Science Foundation [31003A-116275 to A.S.]. J.N. is a recipient of a Ph.D. fellowship from the Ligue Contre le Cancer Comité Loire Atlantique.
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Full metadata record

DC FieldValue Language
dc.contributor.authorNomme, Julianen
dc.contributor.authorRenodon-Cornière, Axelleen
dc.contributor.authorAsanomi, Yuyaen
dc.contributor.authorSakaguchi, Kazuyasuen
dc.contributor.authorStasiak, Alicja Zen
dc.contributor.authorStasiak, Andrzejen
dc.contributor.authorNorden, Bengten
dc.contributor.authorTran, Vinhen
dc.contributor.authorTakahashi, Masayukien
dc.date.accessioned2016-02-21T08:50:32Zen
dc.date.available2016-02-21T08:50:32Zen
dc.date.issued2010-08-01en
dc.identifier.citationNomme J, Renodon-Cornière A, Asanomi Y, Sakaguchi K, Stasiak AZ, et al. (2010) Design of Potent Inhibitors of Human RAD51 Recombinase Based on BRC Motifs of BRCA2 Protein: Modeling and Experimental Validation of a Chimera Peptide. Journal of Medicinal Chemistry 53: 5782–5791. Available: http://dx.doi.org/10.1021/jm1002974.en
dc.identifier.issn0022-2623en
dc.identifier.issn1520-4804en
dc.identifier.pmid20684611en
dc.identifier.doi10.1021/jm1002974en
dc.identifier.urihttp://hdl.handle.net/10754/596780en
dc.description.abstractWe 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.en
dc.description.sponsorshipWe thank Drs. Fabrice Fleury and Pierre Weigel for discussions and Dr. Kyoko Iwasaki-Yoshikane for CD measurements. This work was supported by grants from the Association pour la Recherche sur le Cancer [no. 3862], the Région de Pays de la Loire [MIAPS] and [CIMATH], the King Abdullah University of Science and Technology [KUK-11-008-23 to B.N.], and Swiss National Science Foundation [31003A-116275 to A.S.]. J.N. is a recipient of a Ph.D. fellowship from the Ligue Contre le Cancer Comité Loire Atlantique.en
dc.publisherAmerican Chemical Society (ACS)en
dc.rightsThis is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at .en
dc.rights.urihttp://pubs.acs.orgen
dc.subject.meshModels, Molecularen
dc.titleDesign of potent inhibitors of human RAD51 recombinase based on BRC motifs of BRCA2 protein: modeling and experimental validation of a chimera peptide.en
dc.typeArticleen
dc.identifier.journalJournal of Medicinal Chemistryen
dc.identifier.pmcidPMC2917172en
dc.contributor.institutionUniversite de Nantes, Nantes, Franceen
dc.contributor.institutionHokkaido University, Sapporo, Japanen
dc.contributor.institutionUniversitat Lausanne Schweiz, Lausanne, Switzerlanden
dc.contributor.institutionChalmers University of Technology, Göteborg, Swedenen
kaust.grant.numberKUK-11-008-23en

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