法尼甾体X受体
调节器
核受体
兴奋剂
配体(生物化学)
化学
抑制因子
细胞生物学
生物物理学
受体
生物
生物化学
基因表达
基因
转录因子
作者
Jan Heering,Nathalie Jores,Whitney Kilu,Espen Schallmayer,Evelyn Peelen,Andreas Muehler,Hella Kohlhof,Daniel Vitt,V.L. Linhard,S.L. Gande,A. Chaikuad,Sridhar Sreeramulu,Harald Schwalbe,Daniel Merk
标识
DOI:10.1021/acschembio.2c00599
摘要
The bile-acid sensing nuclear farnesoid X receptor (FXR) is an attractive target for the treatment of hepatic and metabolic diseases, but application of this chemotherapeutic concept remains limited due to adverse effects of FXR activation observed in clinical trials. To elucidate the mechanistic basis of FXR activation at the molecular level, we have systematically studied FXR co-regulator interactions and dimerization in response to seven chemically diverse FXR ligands. Different molecular effects on FXR activation mediated by different scaffolds were evident and aligned with characteristic structural changes within the ligand binding domain of FXR. A partial FXR agonist acted mainly through co-repressor displacement from FXR and caused an FXR-regulated gene expression pattern markedly differing from FXR agonist effects. These results suggest selective modulation of FXR dimerization and co-regulator interactions for different ligands, offering a potential avenue for the design of gene- or tissue-selective FXR modulators.
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