Structural mechanism and function of endogenous ligands targeting orphan NR4A receptors

靶向孤儿NR4A受体的内源配体的结构机制和功能

基本信息

批准号：
9070004
负责人：
Douglas Kojetin
金额：
$ 36.96万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9070004
关键词：
Acids Adipose tissue Adopted Affect Animal Model Arthritis Binding Binding Proteins Biochemical Biology Brain Cardiovascular Diseases Cardiovascular system Cell model Cells Cellular Assay Chemicals Classification Crystallography Data Deuterium Development Diabetes Mellitus Disease Docosahexaenoic Acids Dopamine Drug Targeting Dyslipidemias Event FDA approved Gene Expression Genetic Transcription Health Human Human body Hydrogen Inflammation Kidney Knowledge Ligand Binding Ligand Binding Domain Ligands Lipid Binding Liver Maintenance Malignant Neoplasms Mass Spectrum Analysis Mediating Metabolic Metabolic Diseases Mutagenesis NMR Spectroscopy Neuraxis Nuclear Orphan Receptor Nuclear Receptors Obesity Orphan Outcome Outcome Study Parkinson Disease Pharmaceutical Preparations Physiological Physiology Play Property Regulation Role Schizophrenia Skeletal Muscle Specificity Structure Testing Time Tissues Work base bone cell type empowered in vivo interdisciplinary approach member new therapeutic target pi bond receptor response stoichiometry structural biology therapeutic target tool transcription factor

Acids Adipose tissue Adopted Affect Animal Model Arthritis Binding Binding Proteins Biochemical Biology Brain Cardiovascular Diseases Cardiovascular system Cell model Cells Cellular Assay Chemicals Classification Crystallography Data Deuterium Development Diabetes Mellitus Disease Docosahexaenoic Acids Dopamine Drug Targeting Dyslipidemias Event FDA approved Gene Expression Genetic Transcription Health Human Human body Hydrogen Inflammation Kidney Knowledge Ligand Binding Ligand Binding Domain Ligands Lipid Binding Liver Maintenance Malignant Neoplasms Mass Spectrum Analysis Mediating Metabolic Metabolic Diseases Mutagenesis NMR Spectroscopy Neuraxis Nuclear Orphan Receptor Nuclear Receptors Obesity Orphan Outcome Outcome Study Parkinson Disease Pharmaceutical Preparations Physiological Physiology Play Property Regulation Role Schizophrenia Skeletal Muscle Specificity Structure Testing Time Tissues Work base bone cell type empowered in vivo interdisciplinary approach member new therapeutic target pi bond receptor response stoichiometry structural biology therapeutic target tool transcription factor

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项目摘要

DESCRIPTION (provided by applicant): The NR4A subclass of nuclear receptor (NR) transcription factors (Nurr1, Nur77 and NOR-1) have essential roles in the development, regulation and maintenance of many aspects of mammalian physiology. NR4As are especially abundant in the central nervous system (CNS) and play critical roles in brain development and maintenance. Therapeutics targeting NR4A activity may hold utility in treatment of Parkinson's disease (afflicts 1 million people in the US) and schizophrenia (afflicts >3 million people in the US). The NR4As are also expressed in skeletal muscle, adipose, cardiovascular, kidney and liver tissues, including aberrant expression in inflamed disease tissues, suggesting utility forNR4A modulators to treat inflammation, arthritis, cancer, and metabolic conditions (dysli idemia, obesity, diabetes and cardiovascular disease). However, efforts to probe the ligandability and drugga- bility of the NR4As have been significantly stunted because they are classified as "orphan" receptors. Thus far, no endogenous (natural) NR4A ligands have been discovered, and it is believed the NR4As function independent of binding ligand. This "orphan" classification was made in part based on a crystal structure of apoNurr1, which indicates Nurr1 lacks physical space within the conserved ligand biding pocket region used by nonorphan NRs to bind endogenous ligands. Although the apoNurr1 crystal structure shows a collapsed ligandbinding pocket, NMR studies indicate this region is dynamic on the µs-ms timescale, suggesting the ability to expand. Our preliminary work using an array of structural and functional approaches shows that Nurr1 can bind an endogenous ligand in its putative LBP and that endogenous ligands can affect Nurr1 function. Our data also indicate that Nurr1 and Nur77 may have different specificities for endogenous ligands. Detailing the structural mechanism and function of endo- genous ligands targeting the NR4As will demonstrate these orphan receptors are indeed ligand regulated and empower others to use these natural chemical tools to explore NR4A function in vivo. We propose a multidisciplinary approach combining structural biology with biochemical, biophysical and cellular assays to determine the ligand specificity, structural and functional effects, and cellula outcomes of endogenous ligands targeting the NR4As. Outcomes from these studies would demonstrate that the NR4As are bone fide ligand-binding receptors. Because NRs with known endogenous ligands are targets of significant number of current FDA approved drugs (estimated at 13% in 2006), this knowledge will stimulate the development of NR4A drug targeting strategies for Parkinson's disease, schizophrenia, and other human health conditions.

描述（由适用提供）：核接收器（NR）转录因子的NR4A子类（NURR1，NUR77和NOR-1）在哺乳动物许多方面的开发，法规和维护中具有重要作用生理。 NR4A在中枢神经系统（CNS）中特别丰富，并发挥关键作用在大脑发育和维护方面。针对NR4A活动的治疗剂可能会持有效用治疗帕金森氏病（美国100万人）和精神分裂症（折磨> 3 美国百万人）。 NR4A也以骨骼肌，脂肪，心血管，心血管，肾脏和肝组织，包括炎症组织中异常表达，表明实用性fornr4a调节剂治疗炎症，关节炎，癌症和代谢状况（Dysli） idemiia，肥胖，糖尿病和心血管疾病）。但是，努力探测可韧性和药物 NR4A的能力已被显着阻碍，因为它们被归类为“孤儿”受体。远没有发现内源性（自然）NR4A配体，并且据信NR4AS 功能与结合配体无关。这种“孤儿”分类部分基于晶体 Aponurr1的结构，表明Nurr1缺少非孔NRS使用的配置配体串行袋区域内的物理空间，用于结合内源性配体。虽然aponurr1晶体结构显示了折叠的配体袋，NMR研究表明该区域是动态的 µS-MS时间尺度，表明扩展的能力。我们使用一系列结构和功能性方法表明，Nurr1可以在其假定的LBP中结合内源配体，并且内源配体会影响Nurr1功能。我们的数据还表明Nurr1和Nur77可能有内源配体的不同规格。详细说明内部的结构机制和功能靶向NR4AS的原始配体将证明这些孤儿受体确实是配体调节并授权其他人使用这些天然化学工具在体内探索NR4A功能。我们提出了一种多学科方法，将结构生物学与生化，生物物理和细胞分析相结合，以确定配体特异性，结构和功能效应以及细胞菌靶向NR4A的内源配体的结果。这些研究的结果将表明NR4AS是骨fide配体结合受体。由于具有已知内源配体的NRS是当前FDA批准的药物的靶标（2006年为13％），因此该知识将刺激NR4A药物靶向帕金森氏病，精神分裂症和其他人类健康状况的发展。