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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

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.