Structural basis for bile acid binding and activation of the nuclear receptor FXR
Structural basis for bile acid binding and activation of the nuclear receptor FXR
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DOI：
10.1016/s1097-2765(03)00112-6
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发表时间：
2003-04-01
期刊：
影响因子：
16
通讯作者：
Rastinejad, F
中科院分区：
文献类型：
--
作者：
Mi, LZ;Devarakonda, S;Rastinejad, F
核受体FXR是肠肝胆汁酸生理水平的传感器，胆汁酸是胆固醇分解代谢的最终产物。本文报道了FXR配体结合区域与辅激活剂肽和两种不同胆汁酸复合物的晶体结构。一个不寻常的A/B环接合点，一个与胆汁酸而非其他类固醇相关的特征，提供配体识别并触发激活FXR的pi-cation开关。受体的激活功能2螺旋12采用激动剂构象，稳定辅激活肽结合。FXR能够同时与两个共激活子基序相互作用，通过LXXLL序列之间的分子间接触提供了一种增强共激活子结合的机制。这些FXR复合物为设计治疗性胆汁酸治疗高脂血症和胆汁淤积症提供了直接的见解。
The nuclear receptor FXR is the sensor of physiological levels of enterohepatic bile acids, the end products of cholesterol catabolism. Here we report crystal structures of the FXR ligand binding domain in complex with coactivator peptide and two different bile acids. An unusual A/B ring juncture, a feature associated with bile acids and no other steroids, provides ligand discrimination and triggers a pi-cation switch that activates FXR. Helix 12, the activation function 2 of the receptor, adopts the agonist conformation and stabilizes coactivaltor peptide binding. FXR is able to interact simultaneously with two coactivator motifs, providing a mechanism for enhanced binding of coactivators through intermolecular contacts between their LXXLL sequences. These FXR complexes provide direct insights into the design of therapeutic bile acids for treatment of hyperlipidemia and cholestasis.