Molecular Characterization of Mammalian bHLH-PAS Transcription Factors

哺乳动物 bHLH-PAS 转录因子的分子表征

基本信息

批准号：
9113818
负责人：
FRAYDOON RASTINEJAD
金额：
$ 38.51万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113818
关键词：
ARNT gene Agonist Architecture Aryl Hydrocarbon Receptor Binding Biochemical Biological Assay Biology Biopsy Cell physiology Cells Cellular biology Chemicals Complement Complex DNA DNA Binding DNA Binding Domain Dimerization Disease Drug Metabolic Detoxication Family Family member Gene Expression Genes Genetic Genetic Programming Genetic Transcription Goals Helix-Turn-Helix Motifs Heterodimerization Human Hypoxia Inducible Factor Immunity Investigation Knowledge Ligand Binding Ligands Link Location Malignant Neoplasms Mammals Maps Mediating Metabolic Molecular Mutation Neoplasm Metastasis Neurons Pathway interactions Positioning Attribute Property Proteins Reporting Response Elements Schizophrenia Series Signal Transduction Structure Structure-Activity Relationship Subgroup Tissues Transcriptional Regulation X-Ray Crystallography Xenobiotics aryl hydrocarbon receptor ligand autism spectrum disorder bHLH-PAS factor HLF base high throughput screening human tissue hypoxia inducible factor 1 neuropsychiatric disorder programs protein function public health relevance response sensor small molecule tool transcription factor tumor initiation

项目摘要

DESCRIPTION (provided by applicant): The basic Helix-Loop-Helix-Per/Arnt/Sim (bHLH-PAS) family is a major group of transcription factors in mammals. Functional heterodimers in this family form via a tissue-restricted subunit, such as the hypoxia- inducible factors (HIFs), neuronal PAS (NPAS) proteins, or aryl hydrocarbon receptor (AHR), and a common dimerization subunit, such as aryl hydrocarbon receptor nuclear translocator (ARNT). Family members contain tandem PAS domains and a DNA-binding domain. PAS domains have the potential to act as molecular sensors and transmit signals to regulate the activities of these transcription factors. The HIF subgroup within the family regulates genetic programs critical in human tumor initiation, progression, invasion and metastasis. Several NPAS proteins have been genetically linked to human neuropsychiatric disorders. AHR recognizes and responds to a spectrum of xenobiotic molecules and drives gene programs necessary for detoxification. Our current knowledge about the architectures of these heterodimers, their ligand-binding pockets, and ligand- responsive activities is limited. Therefore, we have begun to conduct detailed structural investigations into several bHLH-PAS heterodimers in complexes that include bound DNA and small-molecule ligands. Our proposed structural characterizations will be complemented with chemical biology and cell-based studies to deepen our understanding of structure-function relationships in this family. The overall goals of this proposal include characterizing distinct bHLH-PAS heterodimers by X-ray crystallography, interrogating the location and composition of their ligand-binding pockets, identifying new tool compounds, and examining how ligands and disease-linked mutations manifest their actions through protein architectures.

描述（由适用提供）：基本的Helix-Loop-helix-per/arnt/sim（BHLH-PAS）家族是哺乳动物的主要转录因子。通过组织限制的亚基（例如低氧诱导因子（HIF），神经元PAS（NPAS）蛋白或芳基烃受体（AHR）和常见的二聚化亚基，例如芳基氢核核核核转运器（ART））。家庭成员包含串联PAS域和DNA结合域。 PAS结构域有可能充当分子传感器并发射信号以调节这些转录因子的活性。家族中的HIF亚组调节对人类肿瘤起始，进展，入侵和转移至关重要的遗传程序。几种NPA蛋白已与人类神经精神疾病有关。 AHR识别并响应了异种生物分子的光谱，并驱动了排毒所需的基因程序。我们目前对这些异二聚体，配体结合口袋和配体反应性活动的架构的了解是有限的。因此，我们已经开始在包括结合DNA和小分子配体的复合物中对几个BHLH-PAS异二聚体进行详细的结构投资。我们提出的结构特征将通过化学生物学和基于细胞的研究完成，以加深我们对这个家庭结构功能关系的理解。该提案的总体目标包括通过X射线晶体学表征不同的BHLH-PAS异二聚体，询问其配体结合口袋的位置和组成，识别新的工具化合物，并检查如何通过蛋白质建筑表现出配体和疾病链接的突变。