Multifaceted integration for estrogen receptor

雌激素受体的多方面整合

• 批准号: 10798568
• 负责人: Sichun Yang
• 金额: $ 10.73万
• 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/10798568
• 关键词: Binding; Breast Cancer therapy; Cell Proliferation; Cell physiology; Communication; DNA Binding Domain; Data; Disease Resistance; Drug resistance; Estrogen Receptor alpha; Estrogen Receptors; Estrogen receptor positive; Genetic Transcription; Hormone Responsive; Hormones; Human; Inhibition of Cell Proliferation; Intervention; Ligand Binding; Ligand Binding Domain; Mediating; Molecular; Mutation; Pharmaceutical Preparations; Publishing; Reporting; Resistance; Site; Structure-Activity Relationship; Testing; hormonal signals; hormone therapy; inhibitor; insight; malignant breast neoplasm; mutant; novel; prevent; receptor; receptor binding; receptor function; resistance mutation; 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.

抽象的 人类雌激素受体α（ERα）是激素反应细胞的分子驱动因素 乳腺癌的增殖。获得性 ERα 突变——Y537S 和 D538G 是最常见的两种突变 常见——代表了一种新认识的耐药机制，因为它们 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 调节激素信号传导以及小分子抑制剂结合受体进行干预的程度 目前尚不清楚。 ERα 具有两个主要功能实体，即 DNA 结合域 (DBD) 和 配体结合域（LBD）。我们最近报道了多域组装并揭示了 这两个域之间的交互模式，通过以前未表征的 域桥接接口。具体来说，域接口处的突变阻止了这两种情况 结构域阻止通讯并抑制 ERα 活性，突出显示结构域界面的调节 受体功能丧失/增强的“变构”通道。这种功能意义引发了以下问题： (a) 耐药突变是否改变结构域-结构域组装和 DBD-LBD 模式 相互作用，以及（b）域桥接界面是否/如何可以被小分子靶向以破坏 受体活性。我们的初步研究表明，重新调整用途的小分子通过 结构域界面并抑制 ERα 介导的细胞功能。根据这些发现和其他初步结果 根据数据，我们假设 ERα 结构域如何相互作用受到这些耐药性的影响 突变和这种结构域-结构域相互作用对于小分子结合改变受体功能至关重要。到 为了检验这个假设，我们将表征抗病突变体的多域组装 (Y537S/D538G) 并检查抑制剂-受体结合的分子和功能相关性。相比之下 到目前所有药物都结合的激素结合口袋，这项研究将为 ERα 提供新的见解 域界面作为小分子结合的新靶位点，并最终提供急需的分子 了解 ER 阳性乳腺癌治疗耐药性。

项目成果

Incorporation of D2O-Induced Fluorine Chemical Shift Perturbations into Ensemble-Structure Characterization of the ERalpha Disordered Region.

• DOI: 10.1021/acs.jpcb.2c05456
• 发表时间: 2022-11
• 期刊: The journal of physical chemistry. B
• 作者: Wenwei Zheng;Zhanwen Du;Soobin Ko;Nalinda P. Wickramasinghe;Sichun Yang

Integrative Biophysics: Protein Interaction and Disorder.

综合生物物理学：蛋白质相互作用和紊乱。

• DOI: 10.1016/j.jmb.2020.04.001
• 发表时间: 2020
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Yang,Sichun;Bernadó,Pau
• 通讯作者: Bernadó,Pau

Glycine substitution in SH3-SH2 connector of Hck tyrosine kinase causes population shift from assembled to disassembled state.

Hck 酪氨酸激酶的 SH3-SH2 连接器中的甘氨酸取代导致群体从组装状态转变为分解状态。

• DOI: 10.1016/j.bbagen.2020.129604
• 发表时间: 2020
• 期刊: Biochimica et biophysica acta. General subjects
• 作者: Huang,Lei;Wright,Michelle;Yang,Sichun;Blachowicz,Lydia;Makowski,Lee;Roux,Benoît
• 通讯作者: Roux,Benoît

Accurate optimization of amino acid form factors for computing small-angle X-ray scattering intensity of atomistic protein structures.

精确优化氨基酸形状因子，用于计算原子蛋白质结构的小角 X 射线散射强度。

• DOI: 10.1107/s1600576716007962
• 发表时间: 2016
• 期刊: Journal of applied crystallography
• 影响因子: 6.1
• 作者: Tong,Dudu;Yang,Sichun;Lu,Lanyuan
• 通讯作者: Lu,Lanyuan

Theoretical modeling of multiprotein complexes by iSPOT: Integration of small-angle X-ray scattering, hydroxyl radical footprinting, and computational docking.

通过 iSPOT 进行多蛋白复合物的理论建模：小角度 X 射线散射、羟基自由基足迹和计算对接的集成。

• DOI: 10.1016/j.jsb.2016.08.001
• 发表时间: 2016-12
• 期刊: JOURNAL OF STRUCTURAL BIOLOGY
• 影响因子: 3
• 作者: Huang, Wei;Ravikumar, Krishnakumar M.;Parisien, Marc;Yang, Sichun
• 通讯作者: Yang, Sichun