Ligand binding and heterodimerization with retinoid X receptor α (RXRα) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding
Ligand binding and heterodimerization with retinoid X receptor α (RXRα) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding
复制标题
配体结合和与视黄醇 X 受体 α (RXR α) 的异二聚化诱导影响共激活剂结合的法尼醇 X 受体 (FXR) 构象变化
DOI：
10.1074/jbc.ra118.004652
复制
发表时间：
2018-11-23
影响因子：
4.8
通讯作者：
Liu, Jinsong
中科院分区：
文献类型：
--
作者：
Wang, Na;Zou, Qingan;Liu, Jinsong
核受体法内甾体X受体（FXR）作为主要的胆汁酸传感器，协调胆固醇代谢、脂质稳态以及膳食脂肪和维生素的吸收。由于其在代谢中的核心作用，FXR是治疗代谢和其他疾病（如原发性胆汁性肝硬化和非酒精性脂肪性肝炎）的重要药物靶点。FXR和核受体类视黄醇X受体（RXR）形成异源二聚体，控制许多下游基因的表达。迄今为止，FXR/RXR异源二聚体相互作用的结构基础和功能后果仍不清楚。在此，我们展示了人类FXR和RXR的配体结合区域之间形成的异二聚体复合物的晶体结构。我们发现，当FXR和RXR作为异源二聚体复合物的一部分时，它们与转录共调节剂类固醇受体共激活因子1的结合比它们各自处于单体状态时具有更高的亲和力。此外，对FXR/RXR异源二聚体和与不同配体结合的FXR单体的结构比较表明，异源二聚和配体结合都会引起FXR中11螺旋C端构象的变化，从而影响FXR中辅激活剂结合表面和辅激活剂结合的稳定性。综上所述，我们的研究结果揭示了FXR/RXR异源二聚体的变构信号转导，这可能为未来针对FXR的药物开发提供依据。
Nuclear receptor farnesoid X receptor (FXR) functions as the major bile acid sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. Because of its central role in metabolism, FXR represents an important drug target to manage metabolic and other diseases, such as primary biliary cirrhosis and nonalcoholic steatohepatitis. FXR and nuclear receptor retinoid X receptor (RXR) form a heterodimer that controls the expression of numerous downstream genes. To date, the structural basis and functional consequences of the FXR/RXR heterodimer interaction have remained unclear. Herein, we present the crystal structures of the heterodimeric complex formed between the ligand-binding domains of human FXR and RXR. We show that both FXR and RXR bind to the transcriptional coregulator steroid receptor coactivator 1 with higher affinity when they are part of the heterodimer complex than when they are in their respective monomeric states. Furthermore, structural comparisons of the FXR/RXR heterodimers and the FXR monomers bound with different ligands indicated that both heterodimerization and ligand binding induce conformational changes in the C terminus of helix 11 in FXR that affect the stability of the coactivator binding surface and the coactivator binding in FXR. In summary, our findings shed light on the allosteric signal transduction in the FXR/RXR heterodimer, which may be utilized for future drug development targeting FXR.