1OT7

Structural Basis for 3-deoxy-CDCA Binding and Activation of FXR

Summary for 1OT7

• Entry DOI: 10.2210/pdb1ot7/pdb
• Related: 1OSV
• Descriptor: Bile Acid Receptor, dodecamer peptide fragment of RPGR-interacting protein 1, 6-ETHYL-CHENODEOXYCHOLIC ACID, ... (5 entities in total)
• Functional Keywords: bile acid, nuclear receptor, coactivator, ligand binding domain, fxr, hormone-growth factor receptor complex, hormone/growth factor receptor
• Biological source: Rattus norvegicus (Norway rat); More
• Cellular location: Nucleus (Probable): Q62735
• Total number of polymer chains: 5
• Total formula weight: 58712.76

Authors

Mi, L.Z.,Devarakonda, S.,Harp, J.M.,Han, Q.,Pellicciari, R.,Willson, T.M.,Khorasanizadeh, S.,Rastinejad, F. (deposition date: 2003-03-21, release date: 2004-03-23, Last modification date: 2024-04-03)

Primary citation

Mi, L.Z.,Devarakonda, S.,Harp, J.M.,Han, Q.,Pellicciari, R.,Willson, T.M.,Khorasanizadeh, S.,Rastinejad, F.
Structural Basis for Bile Acid Binding and Activation of the Nuclear Receptor FXR
Mol.Cell, 11:1093-1100, 2003

PubMed Abstract: 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.

PubMed: 12718893
DOI: 10.1016/S1097-2765(03)00112-6

Experimental method

X-RAY DIFFRACTION (2.9 Å)