Biophysical Studies on Nuclear Receptor LBDs

核受体LBD的生物物理研究

基本信息

批准号：
8539864
负责人：
ELIAS J FERNANDEZ
金额：
$ 5.96万
依托单位：
UNIVERSITY OF TENNESSEE KNOXVILLE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-18 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8539864
关键词：
Abbreviations Affect Affinity Aging Agonist Benzene Binding Binding Sites Biological Assay CV-1 Calorimetry Cell Nucleus Cells Complex DNA Binding Domain Data Diabetes Mellitus Disease Distant Electron Spin Resonance Spectroscopy Fluorescence Spectroscopy Gene Expression Gene Targeting Genetic Genetic Transcription Glucocorticoids Goals Heart Diseases Heterodimerization Hormonal Hormone Responsive Hormones Human Lead Ligand Binding Ligand Binding Domain Ligands Luc Gene Malignant neoplasm of prostate Measurement Mediating Mediator of activation protein Methods Molecular Molecular Conformation Movement Mutagenesis Mutate Mutation Nature Nuclear Receptors Obesity Osteoporosis Pathway interactions Peptides Physiology Plastics Point Mutation Process Protein Dynamics Proteins RXR Regulation Regulatory Pathway Retinoids Signal Transduction Site Steroid Receptors Structure Surface Plasmon Resonance Testing Thyroid Gland Thyroid Hormone Receptor Titrations Transactivation Vitamins X-Ray Crystallography alitretinoin base constitutive androstane receptor dimer effective therapy genetic regulatory protein hormone response element malignant breast neoplasm member monomer mutant receptor research study small molecule three dimensional structure tool transcription factor

项目摘要

The goal of this project is to determine the mechanism of action of hormone-regulated transcription factors, called nuclear receptors (NR) at the atomic level. Hormonal molecules such as glucocorticoids, retinoids, thyroid and vitamin-derived hormones exert their effects by regulating the transcription of hormone-responsive target genes within the nucleus of cells. These hormones function by directly binding to and modulating the activity of NRs. These hormone-regulated proteins direct almost every aspect of human physiology and improper function can lead to several disease states such as prostate and breast cancer, diabetes, obesity, heart disease, osteoporosis, and processes associated with aging. NRs often function as heterodimers such as the thyroid receptor: retinoid X receptor (TR:RXR) and the constitutive androstane receptor (CAR:RXR) complexes where TR, CAR and RXR can each recognize specific hormonal signals. Despite the wealth of data on the genetics and cellular localization of NRs, there is relatively little known of the precise molecular mechanisms of regulation of these proteins. The ligand binding domain (LBD) of these receptors is central to the allostery that is essential for NR transactivation. Using a combination of biophysical tools and cell- based transcription assays this project will determine the how hormone-binding and point mutations at distant sites can affect the recruitment of co-regulatory proteins and how the two hormone-binding sites communicate to regulate the transcriptional activity of heterodimeric TR:RXR and CAR:RXR. Structures will be determined by X-ray crystallography to guide biophysical analyses of conformational movements and transcriptional activity. An important consequence of these studies on the structure and dynamics of NRs is the potential for developing more effective therapies.

该项目的目的是确定激素调节的作用机理转录因子，称为原子水平的核受体（NR）。激素分子，例如糖皮质激素，视黄素，甲状腺和维生素衍生的激素通过调节激素反应性靶基因的转录，它们的影响细胞核。这些激素通过直接结合并调节 NRS的活性。这些激素调节的蛋白几乎指导人的各个方面生理学和功能不当会导致几种疾病状态，例如前列腺以及乳腺癌，糖尿病，肥胖，心脏病，骨质疏松症和过程与衰老有关。 NR通常充当甲状腺受体等异二聚体：类视黄素X受体（TR：RXR）和构型雄激素受体（CAR：RXR） TR，CAR和RXR的复合物各自识别特定的激素信号。尽管关于NRS的遗传学和细胞定位的数据丰富，但仍有对这些调节的精确分子机制相对鲜为人知蛋白质。这些受体的配体结合结构域（LBD）是变构的核心这对于NR反式激活至关重要。结合生物物理工具和细胞的组合基于转录测定该项目将确定激素结合和远处位点的点突变会影响共同调节蛋白的募集和两种激素结合位点如何传达以调节转录活性异二聚体TR：RXR和CAR：RXR。结构将由X射线确定晶体学以指导构象运动的生物物理分析和转录活动。这些研究对结构和 NRS的动态是开发更有效疗法的潜力。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mapping allostery through computational glycine scanning and correlation analysis of residue-residue contacts.

DOI：
10.1021/bi501152d
发表时间：
2015-02-24
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Johnson, Quentin R.;Lindsay, Richard J.;Nellas, Ricky B.;Fernandez, Elias J.;Shen, Tongye
通讯作者：
Shen, Tongye