肝病中芳香烃受体的三维结构和功能研究

Aromatic hydrocarbons are common environmental pollutants and can lead to liver injury, fatty liver disease and liver fibrosis. Aryl hydrocarbon receptor (AHR) is a key transcription factor mediating the toxic effect of aromatic hydrocarbons, hence plays an essential role in the development of liver disease closely related to pollutants. Upon binding of aromatic hydrocarbon, AHR translocates from cytosol to nucleus, and dimerizes with AHR nuclear translocator (ARNT). The AHR/ARNT dimer then binds to target DNA, and regulates target gene expression. However the mechanism of AHR activity is not well understood. In the proposed studies, we will use X-ray crystallography to solve the crystal structure of AHR/ARNT/DNA complex. We also plan to study the crystal structures of AHR in complex with aromatic hydrocarbon. We expect to make a series of major breakthroughs on the structure and function of AHR in the next several years that may help illustrate the mechanism by which aromatic hydrocarbons induce liver diseases, and provide basis for the prevention of such diseases and development of AHR-targeted therapeutics.

芳香烃化合物是环境中常见的有毒物质，其非致癌效应日益受到重视。肝脏作为最主要的解毒器官，常被引起肝细胞损伤、脂肪肝和肝纤维化等。芳香烃受体（AHR）作为介导外源性芳香烃致病的关键转录因子，在肝病发生发展中起着重要的作用。AHR结合芳香烃后，从细胞质中转位进入细胞核，与AHR核转位蛋白（ARNT）形成二聚体，与目标DNA作用，进而调控靶基因的转录和表达,但具体作用机制尚不清楚。本研究主要采用X-射线晶体学的方法解析AHR／ARNT/DNA复合体的三维结构，探讨AHR与ARNT形成二聚体并特异结合靶DNA的分子机制。同时将解析AHR与芳香烃结合的复合体三维结构，探寻芳香烃结合并调控AHR的机制。上述研究将有助于阐明AHR在肝病中的作用机制，对于预防芳香烃引起的肝损伤和研发AHR为靶标的小分子药物具有重要的科学意义。

芳香烃受体（AHR）作为介导多种环境污染物和细胞代谢的关键转录因子，在肝病发生发展中起着重要的作用。AHR结合芳香烃后，从细胞质中转位进入细胞核，与AHR核转位蛋白（ARNT）形成二聚体，与目标DNA作用，进而调控靶基因的转录和表达。本研究主要采用了蛋白晶体学方法研究AHR/ARNT/DNA复合物的晶体结构以及AHR/小分子化合物复合物的蛋白结构，成功纯化了AHR不同结构域蛋白，解析了AHR/ARNT/DNA复合物的晶体结构，初步筛选带了AHR/小分子化合物复合物的结晶条件。通过结构解析找到AHR/ARNT异二聚体之间的相互作用位点以及AHR/芳香烃化合物的相互作用模式，为了解芳香烃结合并调控AHR的机制及以AHR为靶标的小分子药物研发提供了理论依据。