Molecular mechanism of Androgen Receptor mediated transcription

雄激素受体介导转录的分子机制

基本信息

批准号：
10810416
负责人：
Zhao Wang
金额：
$ 1.19万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-08 至 2026-04-30
项目状态：
未结题

项目摘要

Abstract Transcription factors are key determinants of gene expression. Lipophilic hormonal ligands and accompanying co-regulatory molecules trigger the activity of transcription factors, including members of the nuclear hormone receptor (NR) family. AR and its splice variant AR-V7 are NRs that play key roles in prostate cancer development, and particularly CRPC. Current therapies targeting AR mainly focus on its ligand-binding domain (LBD), which is not present in AR-V7. Patients that respond initially to those therapies become resistant to them within a few years. Both AR and AR-V7 must recruit CoRs to be functionally active. Disruption of the AR–CoR interface inhibits AR activity in both androgen-dependent cells and CRPC cells. Therefore, knowledge of how AR variants interact with specific CoRs to form a transcriptionally active complex is critical for the design of therapeutics targeting AR and AR-V7. Our preliminary studies provided the first structural understanding of active NR–CoR complex assembly and demonstrated that conformational variability has a profound impact on NR-mediated transcriptional activation. In this proposal, we hypothesize that AR and its variants have a common set of CoRs, but that the assembly and three-dimensional arrangement of those CoRs in AR complexes are unique to each and contribute to the regulation of transcriptional activities. We propose to leverage the complementary expertise of investigators in NR biology, cryoEM, and image processing to determine the structural basis of transcriptionally active AR complexes. We will pursue that goal through two specific aims: 1) Solve a high-resolution DNA–AR structure to identify domain-domain interactions in detail and then compare it to the structure of DNA–AR-V7; and 2) Improve the resolution of AR–CoR complexes structures to identify detailed interactions and determine the structural differences in comparison with AR-V7–CoR complexes. Both aims will utilize cryoEM to visualize functional AR– CoR complexes. The proposed work is significant because the structures will describe the overall interactions in the system to determine which components should be targeted for therapeutic modulation. A structural understanding of how AR forms functional dimers and interacts with CoRs to activates gene expression will provide critical information about the biology of transcription and enable future studies of looking for small- molecular inhibitors can affect the AR complex arrangement. The proposed multidisciplinary work is innovative because it employs advanced imaging techniques to achieve unprecedented insights into the structure and function of AR–CoR complexes, AR heterodimers, and the drugs that target them.

抽象的转录因子是基因表达的关键决定因素。协同调节分子触发转录因子的活性，包括核激素的成员 AR 受体 (NR) 家族及其剪接变体 AR-V7 是在前列腺癌发展中发挥关键作用的 NR，尤其是 CRPC。目前针对 AR 的治疗主要集中在其配体结合域（LBD）上。最初对这些疗法有反应的患者在几年内就会对其产生耐药性。 AR 和 AR-V7 都必须招募 CoR 才能破坏 AR-CoR 界面。抑制雄激素依赖性细胞和 CRPC 细胞中的 AR 活性因此，了解 AR 如何变异。与特定 CoR 相互作用形成转录活性复合物对于治疗药物的设计至关重要我们的初步研究提供了对活性 NR-CoR 的第一个结构理解。复杂的组装，并证明构象变异对 NR 介导的影响深远转录激活。在此提案中，我们追求 AR 及其变体具有一组通用的 CoR，但组装和 AR 复合物中这些 CoR 的三维排列对于每个 CoR 来说都是独一无二的，并且有助于我们建议利用研究人员的互补专业知识。 NR 生物学、冷冻电镜和图像处理，以确定转录活性 AR 的结构基础我们将通过两个具体目标来实现这一目标：1）解决高分辨率 DNA-AR 结构问题。详细识别域与域之间的相互作用，然后将其与 DNA–AR-V7 的结构进行比较；2) 改进 AR-CoR 复合物结构的分辨率，以识别详细的相互作用并确定结构与 AR-V7-CoR 复合物相比的差异。这两个目标都将利用冷冻电镜来可视化功能性 AR-。 CoR 复合物的工作意义重大，因为该结构将描述其中的整体相互作用。该系统确定哪些成分应该作为治疗调节的目标。了解 AR 如何形成功能性二聚体并与 CoR 相互作用以激活基因表达将提供有关转录生物学的关键信息，并使未来的研究能够寻找小分子分子抑制剂可以影响 AR 复合物的排列，所提出的多学科工作具有创新性。因为它采用先进的成像技术来获得对结构和结构的前所未有的洞察力 AR-CoR 复合物、AR 异二聚体以及针对它们的药物的功能。