1OSV

STRUCTURAL BASIS FOR BILE ACID BINDING AND ACTIVATION OF THE NUCLEAR RECEPTOR FXR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.242 
  • R-Value Observed: 0.242 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural Basis for Bile Acid Binding and Activation of the Nuclear Receptor FXR

Mi, L.Z.Devarakonda, S.Harp, J.M.Han, Q.Pellicciari, R.Willson, T.M.Khorasanizadeh, S.Rastinejad, F.

(2003) Mol Cell 11: 1093-1100

  • DOI: https://doi.org/10.1016/s1097-2765(03)00112-6
  • Primary Citation of Related Structures:  
    1OSV, 1OT7

  • 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.


  • Organizational Affiliation

    Department of Pharmacology, University of Virginia Health System, Charlottesville 22908, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bile acid receptor
A, B
230Rattus norvegicusMutation(s): 0 
UniProt
Find proteins for Q62735 (Rattus norvegicus)
Explore Q62735 
Go to UniProtKB:  Q62735
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ62735
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor coactivator 2
C, D, E
12N/AMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q61026 (Mus musculus)
Explore Q61026 
Go to UniProtKB:  Q61026
IMPC:  MGI:1276533
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ61026
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
CHC BindingDB:  1OSV EC50: min: 10, max: 9.90e+4 (nM) from 20 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.242 
  • R-Value Observed: 0.242 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.97α = 90
b = 108.518β = 90
c = 69.464γ = 90
Software Package:
Software NamePurpose
CNSrefinement
HKL-2000data reduction
SCALEPACKdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-03-23
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2024-02-14
    Changes: Data collection, Database references, Derived calculations