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A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR.
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.
Afiliación
  • Downes M; Howard Hughes Medical Institute, Gene Expression Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Mol Cell ; 11(4): 1079-92, 2003 Apr.
Article en En | MEDLINE | ID: mdl-12718892
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Ácido Quenodesoxicólico / Hepatocitos / Proteínas de Unión al ADN Límite: Animals / Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2003 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Ácido Quenodesoxicólico / Hepatocitos / Proteínas de Unión al ADN Límite: Animals / Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2003 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos