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Structural Dynamics of Pas Domain Containing Transcription Factors

含有转录因子的 Pas 结构域的结构动力学

基本信息

批准号：
8021775
负责人：
Brian David Zoltowski
金额：
$ 2.97万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2011-08-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8021775
关键词：
ARNT gene ARNT protein Active Sites Affect Affinity Agonist Architecture Aryl Hydrocarbon Receptor Atherosclerosis Binding Binding Sites Biological Biological Assay Cells Cessation of life Complex Crystallography Cues DNA Development Disease Progression Elements Endocrine system Equilibrium Estrogen Receptors Family Gene Activation Gene Expression Regulation Generations Genetic Transcription Goals Histocompatibility Testing Hypoxia In Vitro Inflammation Kinetics Libraries Ligand Binding Ligands Link Malignant Neoplasms Measurement Mediating Modeling Molecular Molecular Conformation Motion Output Pathway interactions Population Principal Component Analysis Proteins Receptor Activation Regulation Relative (related person)Reporting Response Elements Role Sexual Development Signal Pathway Signal Transduction Solutions Specificity Stress Structure System Techniques Therapeutic Uses Transcriptional Activation Transcriptional Regulation X-Ray Crystallography Xenobiotics aryl hydrocarbon receptor ligand base cancer therapy cell type cellular development dimer human disease in vivo protein complex protein protein interaction public health relevance response scaffold small molecule transcription factor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Regulation of transcription activation during cellular development, division and death are tightly regulated in response to intracellular and environmental cues by intricate protein complexes. Such regulation is well represented by the xenobiotic and hypoxia response pathways, where heterodimeric Per-ARNT-SIM (PAS) domain containing transcription factors respond to environmental stress through alterations in protein:protein interactions. In particular, the Aryl hydrocarbon Receptor (AhR) is activated by diverse exogenous and endogenous compounds to induce a conformational response that gates protein recognition. Despite extensive toxicological and cell biological studies of AhR, due to its role in the development and progression of cancer, atherosclerosis, chloracne and sexual development, structural information demonstrating the mechanisms of protein:protein recognition and specificity depending on ligand identity remain largely unknown. Moreover, discerning the role of AhR in human diseases is complicated by seemingly contradictory reports due to cell and tissue type dependent functions and substantial crosstalk with alternative signaling pathways (i.e. estrogen receptor, inflammation response, endocrine system). Structural characterization of AhR activation in response to diverse ligands will aid in delineating direct effects of AhR from indirect effects due to alternative pathway excitation. Of primary importance is determining the conformational landscape induced by AhR agonists and antagonists, and how different ligands direct alternative protein:protein interactions. A molecular understanding of ligand-induced conformational dynamics and subsequent protein recognition can be well characterized using a combination of NMR and X-ray crystallography. PUBLIC HEALTH RELEVANCE: A detailed understanding of ligand-induced conformational states and their role in protein:protein interactions will aid in directing AhR activation and gene regulation. Further, identification of new AhR ligands that select for discrete modes of AhR activation will be of direct therapeutic use in the treatment of cancer.

描述（由申请人提供）：在细胞发育、分裂和死亡期间，转录激活的调节通过复杂的蛋白质复合物响应于细胞内和环境线索而受到严格调节。这种调节由异生素和缺氧反应途径很好地代表，其中含有异二聚体Per-ARNT-SIM（PAS）结构域的转录因子通过改变蛋白质：蛋白质相互作用来响应环境应激。特别地，芳烃受体（AhR）被多种外源性和内源性化合物激活以诱导门控蛋白质识别的构象响应。尽管广泛的毒理学和细胞生物学研究的AhR，由于其在癌症，动脉粥样硬化，氯痤疮和性发育的发展和进展中的作用，结构信息表明蛋白质的机制：蛋白质识别和特异性依赖于配体的身份仍然在很大程度上是未知的。此外，由于细胞和组织类型依赖性功能以及与替代信号传导途径（即雌激素受体、炎症反应、内分泌系统）的实质性串扰，识别AhR在人类疾病中的作用被看似矛盾的报道复杂化。AhR激活响应于不同的配体的结构表征将有助于描绘AhR的直接影响，间接影响，由于替代途径的兴奋。最重要的是确定AhR激动剂和拮抗剂诱导的构象景观，以及不同的配体如何指导替代蛋白质：蛋白质相互作用。配体诱导的构象动力学和随后的蛋白质识别的分子理解，可以很好地使用NMR和X射线晶体学的组合来表征。公共卫生相关性：详细了解配体诱导的构象状态及其在蛋白质：蛋白质相互作用中的作用将有助于指导AhR激活和基因调控。此外，选择AhR活化的离散模式的新AhR配体的鉴定将在癌症的治疗中具有直接的治疗用途。