胆汁酸是胆固醇在肝中降解的代谢产物，也是胆汁的重要成分，对肝肠内疏水性化合物的吸收、清除和转运起着重要作用。胆汁酸代谢对维持人体正常生理功能意义重大。肥胖、Ⅱ型糖尿病及高胆固醇都能导致肝脏中自由脂肪酸的升高，从而造成非酒精性脂肪肝,进而发展为脂肪性肝炎。近来，作为体内胆汁酸感应器的核受体FXR已经成为治疗此类疾病重要的药物靶点。FXR通过与RXR形成异二聚体行使其生物学功能，目前对于该异二聚体调控下游信号的机制并不清楚。我们已经解析了FXR-LBD/RXR-LBD与辅因子及配体的复合物结构，本课题将进一步解析全长FXR/RXR蛋白与DNA反应元件及辅因子、配体的多元复合物晶体结构，揭示其信号通路调节机制的结构基础，进一步完善对核受体家族功能的认识。

Bile acid, an important ingredient of bile, is the metabolite of cholesterol degradation in the liver. It plays vital roles in the absorption, clearance and transportation of hydrophobic compounds in liver and gut. The normal metabolism of bile acid is imperative for maintaining physiological function in human body. Obesity, Type Ⅱ diabetes and high cholesterol can raise the free fatty acids level in the liver, leading to NAFLD or even NASH. Recent study confirmed FXR as a valid drug target for treating these diseases. FXR functions through dimerization with RXR. However, the mechanism of how FXR/RXR heterodimer regulate the downstream gene remains to be fully understood. We have already obtained the complex structure of FXR-LBD/RXR-LBD with their co-activators and ligands. In this proposal, we aim to determine the full-length FXR/RXR heterodimer complexed with their DNA response element, cofactors and ligands. This will help reveal the mechanism of FXR/RXR regulating signal pathway and provide a better understanding of the structure function relationship for nuclear receptor family in general.