STRUCTURAL BIOLOGY OF NUCLEAR HORMONE RECEPTORS

核激素受体的结构生物学

• 批准号: 7955133
• 负责人: H Eric Xu
• 金额: $ 0.21万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955133
• 关键词: Biological Assay; COUP transcription factor I; Cells; Computer Retrieval of Information on Scientific Projects Database; Crystallization; DNA Binding; Dimerization; Elements; Funding; Gene Expression; Grant; Human; Institution; Ligand Binding; Ligand Binding Domain; Ligands; Mediating; Medical center; Medicine; Michigan; Molecular; Nuclear Hormone Receptors; Nuclear Orphan Receptor; Nuclear Receptors; Pharmacologic Substance; Physiology; Research; Research Personnel; Resources; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Source; Specificity; Structure; Surface; Texas; Transcriptional Regulation; United States National Institutes of Health; Universities; base; college; drug discovery; receptor; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term objective of this study is to determine the crystal structures of the remaining orphan nuclear receptor ligand-binding domains (LBDs) and to reveal the functional implications of these structures in their respective signaling pathways. Nuclear receptors are DNA-binding and ligand-dependent transcriptional factors that modulate gene expression involved in a broad spectrum of physiology. The LBD is the key structural domain that mediates the ligand signaling of nuclear receptors. In addition to ligand binding, the LBD contains dimerization motifs and a conserved surface that mediates ligand-dependent or independent recruitment of coactivators and corepressors for transcriptional regulation. The LBD has thus been the focus of intense structural studies and pharmaceutical discovery. Crystal structures of more than half of the 48 human nuclear hormone receptor LBDs have been determined and there are only a few orphan nuclear receptors for which LBD structure remains to be solved. The hypotheses of these applications are: 1) the specificity of diverse signaling pathways mediated by nuclear hormone receptors is in large part contained within the structural components of their LBDs, and 2) the structure of each LBD will provide key information for understanding the molecular basis of ligand recognition, receptor dimerization, and protein-interacting surfaces that mediate specific signaling pathways by each receptor. Our specific aims are focused on crystallization and structural determination of the remaining orphan nuclear receptor LBDs, particularly, 1) the CAR LBD, 2) the COUP-TFI or TFII LBD, 3) the TR2 or TR4 LBD, and 4) the SHP LBD. Following the structural determination, we will identify key structural elements by scrutinizing and analyzing the structures, and we will collaborate with Ming-Jer Tsai (Baylor College of Medicine), Steve Kliewer (University of Texas Southwestern Medical Center), and Doug Engel (University of Michigan), on site-directed mutagenesis and cell-based assays to validate the functional significance of these key structural elements. Significance: The structural information generated in this application will significantly enhance our understanding of the molecular mechanisms of how these orphan nuclear receptors have evolved for their respective ligand-dependent or independent signaling pathways, and can serve as rational templates for drug discovery that targets these receptors.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 这项研究的长期目标是确定其余孤儿核受体配体结合域（LBD）的晶体结构，并揭示这些结构在其各自的信号传导途径中的功能意义。核受体是DNA结合和配体依赖性转录因子，这些因子调节了与广泛生理学相关的基因表达。 LBD是介导核受体的配体信号传导的关键结构结构域。除配体结合外，LBD还含有二聚基序和保守的表面，可介导配体依赖或独立募集的共激活因子和核压杆，以进行转录调节。因此，LBD一直是激烈的结构研究和药物发现的重点。已经确定了48种人类核激素受体LBD的一半以上的晶体结构，并且只有少数孤儿核受体仍有待解决的孤儿核受体。这些应用的假设是：1）核激素受体介导的多种信号通路的特异性在很大程度上包含在其LBD的结构成分中，以及2）每个LBD的结构将提供关键信息，以了解与每个受体介导的配体识别，受体介导的特定信号的分子基础的分子基础。我们的具体目的集中在剩余的孤儿核受体LBD的结晶和结构确定上，特别是1）CAR LBD，2）COUP-TFI或TFII LBD，3）TR2或TR4 LBD，以及4）SHP LBD。遵循结构性的确定，我们将通过审查和分析结构来确定关键的结构要素，并将与Ming-Jer Tsai（贝勒医学院），史蒂夫·克莱沃尔（Steve Kliewer）（德克萨斯州西南部医学中心）和道格·恩格尔（Doug Engel）（密歇根大学）合作，在基于站点的celleissis essyers and Incelitions intivity pactiatiations以下功能。意义：本应用中产生的结构信息将显着增强我们对这些孤儿核受体如何发展为它们各自的配体依赖性或独立信号通路的分子机制的理解，并可以用作靶向这些受体的药物发现的合理模板。