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：
10612440
负责人：
Zhao Wang
金额：
$ 33.6万
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

来源：
https://reporter.nih.gov/project-details/10612440
关键词：
3-Dimensional Address Affect Androgen Receptor Binding Biology C-terminal Cells Complex Computer Analysis Cryoelectron Microscopy DNA DNA Binding DNA Structure Data Collection Development Diabetes Mellitus Dimerization Disease Drug Targeting Drug resistance EP300 gene Estrogen Receptors Family Foundations Future Gene Expression Genes Genetic Transcription Goals Heterogeneity Hormonal Hormones Hypogonadism Imaging Techniques Knowledge Length Ligand Binding Domain Ligands Location Malignant Neoplasms Malignant neoplasm of prostate Mediating Molecular Molecular Conformation Monoclonal Antibodies Mutagenesis Mutation N-terminal Nuclear Hormone Receptors Nuclear Receptors Pathway interactions Patients Pattern Phenotype Play Productivity Proteins RNA Splicing Receptor Activation Recombinants Regulation Research Personnel Resistance Resolution Response Elements Site Structure System Techniques Testing Transactivation Transcription Process Transcriptional Activation Transcriptional Regulation Variant Visualization Work androgen sensitive antagonist computerized data processing design dimer effective therapy experimental study hormone binding protein hormone deficiency image processing improved innovation insight large scale data lipophilicity male member multidisciplinary nanometer resolution particle promoter protein protein interaction recruit small molecular inhibitor targeted treatment therapeutic target transcription factor

3-Dimensional Address Affect Androgen Receptor Binding Biology C-terminal Cells Complex Computer Analysis Cryoelectron Microscopy DNA DNA Binding DNA Structure Data Collection Development Diabetes Mellitus Dimerization Disease Drug Targeting Drug resistance EP300 gene Estrogen Receptors Family Foundations Future Gene Expression Genes Genetic Transcription Goals Heterogeneity Hormonal Hormones Hypogonadism Imaging Techniques Knowledge Length Ligand Binding Domain Ligands Location Malignant Neoplasms Malignant neoplasm of prostate Mediating Molecular Molecular Conformation Monoclonal Antibodies Mutagenesis Mutation N-terminal Nuclear Hormone Receptors Nuclear Receptors Pathway interactions Patients Pattern Phenotype Play Productivity Proteins RNA Splicing Receptor Activation Recombinants Regulation Research Personnel Resistance Resolution Response Elements Site Structure System Techniques Testing Transactivation Transcription Process Transcriptional Activation Transcriptional Regulation Variant Visualization Work androgen sensitive antagonist computerized data processing design dimer effective therapy experimental study hormone binding protein hormone deficiency image processing improved innovation insight large scale data lipophilicity male member multidisciplinary nanometer resolution particle promoter protein protein interaction recruit small molecular inhibitor targeted treatment therapeutic target transcription factor

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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者。亲脂性激素配体和参与共调节分子触发转录因子的活性，包括核骑马的成员受体（NR）家族。 AR及其分裂变体AR-V7是NR，在前列腺癌发展中起关键作用，特别是CRPC。针对AR的当前疗法主要集中于其配体结合域（LBD），该疗法 AR-V7中不存在。最初对这些疗法做出反应的患者在少数人中对他们具有抵抗力年。 AR和AR-V7都必须募集CORS具有功能活跃。 AR -COR接口的破坏抑制雄激素依赖性细胞和CRPC细胞中的AR活性。因此，了解AR变体的知识与特定的COR相互作用以形成具有转录活性的复合物对于治疗设计至关重要靶向AR和AR-V7。我们的初步研究提供了对主动NR – Cor的首次结构理解复杂的组装并证明构象变异性对NR介导的深远影响转录激活。在此提案中，我们假设AR及其变体具有一组通用的CORS，但组装和组合 AR综合体中这些CORS的三维布置是每个CORS的独特之处，并有助于转录活动的调节。我们建议利用调查人员的完整专业知识 NR生物学，冷冻和图像处理以确定转录活性AR的结构基础复合物。我们将通过两个具体目标来实现这一目标：1）解决高分辨率的DNA-AR结构详细识别域域相互作用，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来可视化功能性AR – Cor络合物。拟议的工作很重要，因为结构将描述确定应针对治疗调制的系统。一个结构了解AR如何形成功能二聚体并与COR相互作用以激活基因表达提供有关转录生物学的关键信息，并使未来的研究以寻找小型研究分子抑制剂会影响AR复合物排列。拟议的多学科工作是创新的因为它采用先进的成像技术来实现对结构和 AR -COR复合物，AR异二聚体和靶向它们的药物的功能。