Downes Michael, Verdecia Mark A, Roecker A J, Hughes Robert, Hogenesch John B, Kast-Woelbern Heidi R, Bowman Marianne E, Ferrer Jean-Luc, Anisfeld Andrew M, Edwards Peter A, Rosenfeld John M, Alvarez Jacqueline G A, Noel Joseph P, Nicolaou K C, Evans Ronald M
Howard Hughes Medical Institute, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Mol Cell. 2003 Apr;11(4):1079-92. doi: 10.1016/s1097-2765(03)00104-7.
The farnesoid X receptor (FXR) functions as a bile acid (BA) sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. However, BAs are poor reagents for characterizing FXR functions due to multiple receptor independent properties. Accordingly, using combinatorial chemistry we evolved a small molecule agonist termed fexaramine with 100-fold increased affinity relative to natural compounds. Gene-profiling experiments conducted in hepatocytes with FXR-specific fexaramine versus the primary BA chenodeoxycholic acid (CDCA) produced remarkably distinct genomic targets. Highly diffracting cocrystals (1.78 A) of fexaramine bound to the ligand binding domain of FXR revealed the agonist sequestered in a 726 A(3) hydrophobic cavity and suggest a mechanistic basis for the initial step in the BA signaling pathway. The discovery of fexaramine will allow us to unravel the FXR genetic network from the BA network and selectively manipulate components of the cholesterol pathway that may be useful in treating cholesterol-related human diseases.
法尼醇X受体（FXR）作为胆汁酸（BA）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。然而，由于多种受体独立特性，胆汁酸并非用于表征FXR功能的理想试剂。因此，我们利用组合化学方法研发出一种小分子激动剂，称为非瑟明，其与天然化合物相比亲和力提高了100倍。在肝细胞中使用FXR特异性非瑟明与初级胆汁酸鹅去氧胆酸（CDCA）进行基因谱实验，产生了截然不同的基因组靶点。非瑟明与FXR配体结合域的高衍射共晶体（1.78 Å）显示，激动剂被隔离在一个726 ų的疏水腔中，这为胆汁酸信号通路初始步骤提供了机制基础。非瑟明的发现将使我们能够从胆汁酸网络中解析FXR基因网络，并选择性地调控胆固醇途径的组成部分，这可能对治疗与胆固醇相关的人类疾病有用。
