Multifaceted integration for estrogen receptor

摘要 人雌激素受体α(ER-α)是激素反应细胞的分子驱动因子 乳腺癌中的增殖。获得性ERα突变-Y537S和D538G是最多的两个 通常发现-代表了一种新认识的耐药机制，由于它们的 结构性转录活性。我们的初步数据和最近发表的报告表明，这些药物- 耐药突变体是小分子结合调节其活性的非常规治疗靶点 并抑制细胞增殖。然而，耐药突变作用于受体的机制 调节激素信号和小分子抑制剂与受体结合以进行干预的程度 还不为人所知。 内质网α包含两个主要的功能实体，即DNA结合域和 配体结合区(LBD)。我们最近报道了多域组装，并揭示了 这两个领域之间的交互模式，通过以前未曾描述过的 域桥接接口。具体地说，结构域界面上的突变阻止了这两种 结构域的通信和抑制ERα活性，突出了结构域接口的调制为 一种具有受体功能丧失/获得的“变构”通道。这种功能意义提出了以下问题 (A)耐药突变是否改变了DBD-LBD的结构域组装和模式 相互作用，以及(B)结构域桥接界面是否/如何能被小分子靶向破坏 感受器活性。我们的初步研究表明，重新调整用途的小分子通过 并抑制ERα介导的细胞功能。基于这些发现和其他初步的 数据，我们假设ERα结构域如何相互作用受到这些耐药基因的影响 突变和这种结构域间的相互作用是小分子结合改变受体功能的关键。至 检验这一假设，我们将表征抗病突变体的多结构域组装 (Y537S/D538G)，并检测抑制物-受体结合的分子和功能相关性。相比之下， 对于所有当前药物都绑定的激素结合口袋，这项研究将为ERα提供新的见解 结构域-界面作为小分子结合的新靶点，并最终提供急需的分子 对ER阳性乳腺癌治疗抵抗的认识。

Abstract Human estrogen receptor alpha (ERα) is a molecular driver of hormone-responsive cell proliferation in breast cancer. Acquired ERα mutations—Y537S and D538G being the two most commonly found—represent a newly recognized mechanism of drug resistance due to their constitutive transcription activity. Our preliminary data and recently published reports indicate that these drug- resistant mutants are non-conventional therapeutic targets for small molecule binding to modulate their activity and inhibit cell proliferation. However, the mechanisms by which drug-resistant mutations act on the receptor to regulate hormonal signaling and the extent to which small molecule inhibitors bind the receptor for intervention are not yet known. The ERα harbors two major functional entities, i.e., the DNA-binding domain (DBD) and the ligand-binding domain (LBD). We recently reported the multi-domain assembly and revealed the mode of interactions between these two domains, through a previously uncharacterized domain-bridging interface. Specifically, mutations at the domain-interface prevent the two domains from communicating and inhibit ERα activity, highlighting the modulation of the domain interface as an “allosteric” channel with loss/gain of receptor function. This functional significance raises the questions of (a) whether the drug-resistant mutations alter the domain-domain assembly and the mode of DBD-LBD interactions, and (b) whether/how the domain-bridging interface can be targeted by small molecules to disrupt receptor activity. Our preliminary studies show that a repurposed small molecule binds the receptor via the domain-interface and inhibits ERα-mediated cellular function. Based on these findings and other preliminary data, we hypothesize that how the ERα domains interact with one another is influenced by these drug-resistant mutations and this domain-domain interaction is critical for small molecule binding to alter receptor function. To test this hypothesis, we will characterize the multi-domain assemblies of disease-resistant mutants (Y537S/D538G) and examine the molecular and functional correlation of inhibitor-receptor binding. In contrast to the hormone-binding pocket where all current drugs bind, this study will provide novel insights into the ERα domain-interface as a new target site for small molecule binding, and ultimately offer a much-needed molecular understanding of ER-positive breast cancer therapy resistance.