Structural Dynamics of Pas Domain Containing Transcription Factors

描述（由申请人提供）：在细胞发育、分裂和死亡过程中，转录激活的调控受到复杂蛋白复合物对细胞内和环境信号的严格调控。这种调控在异种和缺氧反应途径中得到了很好的体现，其中含有转录因子的异二聚体Per-ARNT-SIM （PAS）结构域通过蛋白质：蛋白质相互作用的改变来响应环境胁迫。特别是，芳烃受体（AhR）被多种外源性和内源性化合物激活，诱导构象反应，从而抑制蛋白质识别。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、动脉粥样硬化、氯痤疮和性发育的发生和进展中的作用，显示蛋白质机制的结构信息：依赖于配体身份的蛋白质识别和特异性在很大程度上仍然未知。此外，由于细胞和组织类型依赖的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）的大量串扰，识别AhR在人类疾病中的作用似乎相互矛盾的报道使其变得复杂。AhR对不同配体的激活反应的结构表征将有助于描述AhR的直接作用和由于替代途径激发而产生的间接作用。最重要的是确定由AhR激动剂和拮抗剂诱导的构象景观，以及不同的配体如何直接替代蛋白质：蛋白质相互作用。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使用核磁共振和x射线晶体学的组合来很好地表征。

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.