Direct inhibition of the protein–protein interaction of ERα and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ERα positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ERα ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERα with selective antiproliferative activity in ERα positive breast cancer cells. The co-crystal structure of the TD-stabilized peptide 6 in complex with ERα LBD further demonstrates that it forms an α helical conformation and directly binds at the coactivator binding site of ERα. Further studies showed that peptide 6_W could potently inhibit cellular ERα’s transcriptional activity. This approach demonstrates the potential of TD stabilized peptides to modulate various intracellular protein–protein interactions involved in a range of disorders.

中文翻译：

---

高亲和力N末端异天冬氨酸束缚的螺旋肽抑制ERα-共激活因子相互作用的结构基础

用细胞可渗透的稳定肽直接抑制ERα及其内源性共激活因子的蛋白相互作用可能为对抗ERα阳性乳腺癌提供了一种新颖而有希望的策略。在这里，我们报告了由N末端非天然交联的天冬氨酸（TD）与ERα配体结合域（LBD）配合稳定的螺旋肽的共晶体结构。我们设计了一系列肽和肽6，它们在ERα阳性乳腺癌细胞中表现出与ERα的直接和高亲和力结合，并具有选择性的抗增殖活性。TD稳定肽6的共晶体结构与ERα复合的LBD进一步证明其形成α螺旋构象并直接在ERα的共激活子结合位点结合。进一步的研究表明，肽6 _W可以有效抑制细胞ERα的转录活性。这种方法证明了TD稳定肽调节多种与多种疾病有关的细胞内蛋白质与蛋白质相互作用的潜力。