Molecular mechanism of Androgen Receptor mediated transcription

雄激素受体介导转录的分子机制

• 批准号: 10279240
• 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
• 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/10279240
• 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; 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; Work; androgen sensitive; base; 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; particle; promoter; protein protein interaction; recruit; small molecular inhibitor; targeted treatment; therapeutic target; transcription factor

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。