Exploiting the P-1 Pocket of BRCT Domains Toward a Structure Guided Inhibitor Design
Exploiting the P-1 Pocket of BRCT Domains Toward a Structure Guided Inhibitor Design
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DOI：
10.1021/ml200147a
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发表时间：
2011-10-01
影响因子：
4.2
通讯作者：
Natarajan, Amarnath
中科院分区：
文献类型：
--
作者：
Yuan, Ziyan;Kumar, Eric A.;Natarajan, Amarnath
乳腺癌基因1羧基末端(BRCT)结构域存在于多种对DNA损伤反应(DDR)起重要作用的蛋白质中。BRCT结构域与磷酸化的蛋白质结合，这些蛋白质-蛋白质相互作用对于DDR和DNA修复是必不可少的。需要高亲和力结构域特异性抑制剂来促进DDR信号中蛋白质-蛋白质相互作用的剖析。BRCA1的BRCT结构域通过pSXXF共同识别基序与磷酸化蛋白结合，我们在pSXXF结合位点的P-1位置发现了一个疏水口袋。在这里，我们进行了P-1位带有疏水官能团的多肽类似物的结构指导合成。对这些的评价导致了对BRCT(BRCA1)的抑制常数(K(I))为40 nM的多肽模拟物15的鉴定。对TopBP1和MDC1BRCT结构域的分析表明，类似的方法是可行的，以设计高亲和力抑制剂。
Breast cancer gene 1 carboxy terminus (BRCT) domains are found in a number of proteins that are important for DNA damage response (DDR). The BRCT domains bind phosphorylated proteins, and these protein-protein interactions are essential for DDR and DNA repair. High affinity domain specific inhibitors are needed to facilitate the dissection of the protein-protein interactions in the DDR signaling. The BRCT domains of BRCA1 bind phosphorylated protein through a pSXXF consensus recognition motif We identified a hydrophobic pocket at the P-1 position of the pSXXF binding site. Here we conducted a structure-guided synthesis of peptide analogues with hydrophobic functional groups at the P-1 position. Evaluation of these led to the identification of a peptide mimic 15 with a inhibitory constant (K(i)) of 40 nM for BRCT(BRCA1). Analysis of the TopBP1 and MDC1 BRCT domains suggests a similar approach is viable to design high affinity inhibitors.