Structural basis for bile acid binding and activation of the nuclear receptor FXR.

Mi LZ, Devarakonda S, Harp JM, Han Q, Pellicciari R, Willson TM, Khorasanizadeh S, Rastinejad F
Mol Cell. 2003 11 (4): 1093-100

PMID: 12718893 · DOI:10.1016/s1097-2765(03)00112-6

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 coactivator 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.

MeSH Terms (18)

Amino Acid Sequence Animals Bile Acids and Salts Binding Sites Cations Chemical Engineering DNA-Binding Proteins Hepatocytes Humans Hyperlipidemias Ligands Liver Molecular Conformation Molecular Sequence Data Molecular Structure Protein Structure, Tertiary Receptors, Cytoplasmic and Nuclear Transcription Factors

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