STRUCTURAL BASIS OF NUCLEAR HORMONE RECEPTOR LIGAND INTERACTIONS

核激素受体配体相互作用的结构基础

• 批准号: 7954316
• 负责人: Kendall W Nettles
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954316
• 关键词: Agonist; Binding; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystallography; Diabetes Mellitus; Drug Design; Estrogen Receptor alpha; Funding; Goals; Grant; Hormones; Institution; Ligand Binding Domain; Ligands; Liver diseases; Malignant Neoplasms; Nuclear; Nuclear Hormone Receptors; Obesity; PPAR gamma; Peroxisome Proliferator-Activated Receptors; Protein Family; Proteins; Research; Research Personnel; Resources; Source; Structure; United States National Institutes of Health; Work; base; human disease; receptor; structural biology; synchrotron radiation; transcription factor

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. Our research focuses on the nuclear hormone family of proteins. Nuclear hormone receptor proteins are ligand inducible transcription factors. Nuclear hormone receptors are involved in several human diseases including cancer, liver disease, obesity, and diabetes. Specifically, we are working with the ligand binding domains of estrogen receptor alpha (ERalpha LBD) and peroxisome proliferator activated receptor gamma (PPAR-gamma). Our goal is to acquire a better understanding of the partial agonism mechanism of these proteins in order to carry out structure based drug design. Experimentally, we desire to characterize several partial agonists bound to PPAR and ER, solve the structures by x-ray crystallography, dissect the atomic level interactions of the ligands, and compare and contrast these interactions and induced allostery with full agonists and antagonists. To this end, we have purified these proteins, synthesized several partial agonists, and formed large crystals of these complexes.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的研究重点是核激素蛋白质家族。核激素受体蛋白是配体诱导的转录因子。核激素受体与多种人类疾病有关，包括癌症、肝病、肥胖症和糖尿病。具体地说，我们正在研究雌激素受体α(ERAlpha LBD)和过氧化物酶体增殖物激活受体γ(PPAR-Gamma)的配体结合域。我们的目标是更好地了解这些蛋白质的部分激活性机制，以便进行基于结构的药物设计。在实验上，我们希望表征几种与PPAR和ER结合的部分激动剂，通过X射线结晶学解析结构，剖析配体的原子水平相互作用，并将这些相互作用和诱导变构与完全激动剂和拮抗剂进行比较和对比。为此，我们提纯了这些蛋白质，合成了几种部分激动剂，并形成了这些复合体的大晶体。