RGD Reference Report - Structural basis for bile acid binding and activation of the nuclear receptor FXR. - Rat Genome Database

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

Authors: Mi, LZ  Devarakonda, S  Harp, JM  Han, Q  Pellicciari, R  Willson, TM  Khorasanizadeh, S  Rastinejad, F 
Citation: Mi LZ, etal., Mol Cell. 2003 Apr;11(4):1093-100.
RGD ID: 1625198
Pubmed: PMID:12718893   (View Abstract at PubMed)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Nr1h4Ratbile acid binding enablesIPIobeticholic acidPMID:12718893UniProt 
Nr1h4Ratbile acid binding enablesIPI3-deoxychenodeoxycholic acidPMID:12718893UniProt 
Nr1h4Ratbile acid binding  IDA  RGD 
Nr1h4Ratbile acid nuclear receptor activity enablesIDA PMID:12718893UniProt 
Nr1h4Ratpeptide binding  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Nr1h4  (nuclear receptor subfamily 1, group H, member 4)


Additional Information