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布的报告表明， 这些耐药突变体是小分子结合的非常规治疗靶点。 调节它们的活性并抑制细胞增殖。然而，药物通过的机制-- 耐药突变作用于受体以调节激素信号以及在多大程度上 小分子抑制剂结合受体进行干预尚不清楚。 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 结构域的通讯和抑制ERα活性，突出了结构域的调制- 作为“变构”通道的界面，具有受体功能的丧失/获得。这一功能意义 提出了以下问题：(A)耐药突变是否改变了结构域域 组装和DBD-LBD相互作用的模式，以及(B)是否/如何结构域桥接 界面可以被小分子作为靶点来干扰受体的活动。我们的初步研究 表明重新调整用途的小分子通过结构域界面与受体结合并抑制 内质网α介导的细胞功能。根据这些发现和其他初步数据，我们 假设ERα结构域如何相互作用受到这些药物的影响- 耐药突变和这种结构域-结构域相互作用对于小分子结合到 改变受体功能。为了验证这一假设，我们将描述多域程序集 抗病突变体(Y537S/D538G)的分子和功能 抑制物-受体结合的相关性。与荷尔蒙绑定的口袋形成鲜明对比的是 目前的药物结合，本研究将为ERα结构域界面的研究提供新的见解 靶点为小分子结合，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.