Design of Potent Inhibitors of Human RAD51 Recombinase Based on BRC Motifs of BRCA2 Protein: Modeling and Experimental Validation of a Chimera Peptide
Design of Potent Inhibitors of Human RAD51 Recombinase Based on BRC Motifs of BRCA2 Protein: Modeling and Experimental Validation of a Chimera Peptide
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DOI：
10.1021/jm1002974
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发表时间：
2010-08-12
影响因子：
7.3
通讯作者：
Takahashi, Masayuki
中科院分区：
文献类型：
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作者：
Nomme, Julian;Renodon-Corniere, Axelle;Takahashi, Masayuki
我们先前已经证明，来自BRCA2肿瘤抑制因子BRC4基序的28个氨基酸的多肽选择性地抑制人RAD51重组酶(HsRad51)。为了设计更好的癌症治疗抑制剂，我们将电子对接方法与体外生化测试相结合，从现有的8个人BRC基序中构建了一个高效的嵌合体多肽。我们根据BRC4基序-HsRad51络合物的晶体结构建立了所有BRC基序与HsRad51络合的分子模型，计算了每个BRC基序中每个残基的相互作用能，并在每个结合位置选择了最佳的氨基酸残基。这一分析使我们能够提出BRC4基序中的四个氨基酸替换。其中三个在体外增强了抑制作用，而且这种作用是相加的。因此，我们获得了一种抑制HsRad51-ssDNA复合体形成的多肽，其抑制效率约为原始多肽的10倍。
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.