Multifaceted integration for estrogen receptor

雌激素受体的多方面整合

• 批准号: 10693196
• 负责人: Sichun Yang
• 金额: $ 34.78万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693196
• 关键词: Adopted; Affect; Amino Acids; Binding; Breast Cancer Cell; Breast Cancer therapy; Cell Proliferation; Cell physiology; Cells; Communication; Comprehension; Computer Analysis; Computer Models; Cryoelectron Microscopy; DNA Binding Domain; Data; Disease Resistance; Drug resistance; Estrogen Receptor alpha; Estrogen Receptors; Estrogen receptor positive; FDA approved; Fluorescence; Fluorescence Polarization; Genetic Transcription; Hormone Responsive; Hormones; Human; Hydroxyl Radical; Individual; Inhibition of Cell Proliferation; Intervention; Joints; Ligand Binding; Ligand Binding Domain; Maps; Measurement; Mediating; Membrane Proteins; Modeling; Molecular; Molecular Conformation; Mutagenesis; Mutation; Peptides; Phage Display; Pharmaceutical Preparations; Proliferating; Property; Protein Footprinting; Publishing; Reporting; Resistance; Resolution; Rest; Roentgen Rays; Role; Site; Site-Directed Mutagenesis; Solvents; Structure; Structure-Activity Relationship; Surface; Techniques; Testing; Tryptophan; density; experimental study; hormonal signals; hormone therapy; improved; inhibitor; insight; malignant breast neoplasm; mutant; novel; prevent; receptor; receptor binding; receptor function; resistance mutation; response; small molecule; small molecule inhibitor; therapeutic target

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.

摘要 人雌激素受体α（ERα）是雌激素应答细胞的分子驱动因子， 乳腺癌的扩散。获得性ERα突变-Y 537 S和D538 G是最常见的两种 通常发现-代表一种新认识的耐药机制， 组成型转录活性。我们的初步数据和最近发表的报告表明， 这些耐药突变体是小分子结合的非常规治疗靶点 以调节它们的活性并抑制细胞增殖。然而，药物的机制- 抗性突变作用于受体以调节激素信号传导， 小分子抑制剂与受体结合用于干预尚不清楚。 ERα具有两个主要的功能实体，即，DNA结合结构域（DBD）和 配体结合域（LBD）。我们最近报道了多域组装， 这两个领域之间的相互作用模式，通过一个以前没有特征的 域桥接接口。具体地说，域接口的突变阻止了这两个 结构域的沟通和抑制ERα活性，突出了结构域的调节- 作为“变构”通道与受体功能的丧失/获得界面。这种功能意义 提出了以下问题：（a）耐药突变是否改变了结构域-结构域 组装和DBD-LBD相互作用的模式，以及（B）域桥接是否/如何 小分子可以靶向界面以破坏受体活性。我们的初步研究 表明一个重新利用的小分子通过结构域界面与受体结合， ERα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- 这种结构域-结构域相互作用对于小分子结合至 改变受体功能为了检验这个假设，我们将描述多域程序集的特征 抗病突变体（Y 537 S/D538 G）的分子和功能研究 受体结合的相关性。与之相反的是， 目前的药物结合，这项研究将提供新的见解ERα结构域接口作为一个新的 小分子结合靶位点，并最终提供急需的分子 了解ER阳性乳腺癌的治疗耐药性。