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

• 批准号: 7805971
• 负责人: Brian David Zoltowski
• 金额: $ 4.76万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805971
• 关键词: 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; cellular development; dimer; human disease; in vivo; protein complex; protein protein interaction; public health relevance; response; scaffold; small molecule; transcription factor; tumor progression

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）：通过复杂的蛋白质复合物对细胞内和环境线索的响应，对细胞发育，分裂和死亡过程中转录激活的调节受到严格调节。这种调节由异种生物和缺氧反应途径很好地表示，其中含有转录因子的异二聚体均通过蛋白质相互作用的改变来响应环境压力。特别是，芳基碳氢化合物受体（AHR）被多种外源和内源性化合物激活，以诱导构象反应，使蛋白质识别。尽管对AHR进行了广泛的毒理学和细胞生物学研究，但由于其在癌症的发展和进展中的作用，动脉粥样硬化，氯酸和性发育，结构信息证明了蛋白质的机制：蛋白质识别和根据配体认同的特异性，这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通路（即雌激素受体，炎症反应，内分泌系统），由于细胞和组织类型依赖性功能以及实质性的串扰，辨别AHR在人类疾病中的作用变得复杂。 AHR激活对各种配体的结构表征将有助于描述由于替代途径激发引起的间接效应的直接影响。最重要的是确定AHR激动剂和拮抗剂引起的构象景观，以及不同的配体如何直接替代蛋白质：蛋白质相互作用。通过NMR和X射线晶体学的组合，可以很好地表征配体诱导的构象动力学和随后的蛋白质识别的分子理解。 公共卫生相关性：对配体诱导的构象状态及其在蛋白质中的作用的详细理解：蛋白质相互作用将有助于指导AHR激活和基因调节。此外，鉴定选择用于离散AHR激活模式的新AHR配体将在癌症治疗中直接使用治疗。