5Z12

A structure of FXR/RXR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.290 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.233 

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This is version 1.4 of the entry. See complete history


Literature

Structural insights into the heterodimeric complex of the nuclear receptors FXR and RXR

Zheng, W.Lu, Y.Tian, S.Ma, F.Wei, Y.Xu, S.Li, Y.

(2018) J Biol Chem 293: 12535-12541

  • DOI: https://doi.org/10.1074/jbc.RA118.004188
  • Primary Citation of Related Structures:  
    5Z12

  • PubMed Abstract: 

    Farnesoid X receptor (FXR) is a member of the family of ligand-activated nuclear receptors. FXR plays critical roles in maintaining many metabolic pathways, including bile acid regulation and glucose and lipid homeostasis, and forms a heterodimeric complex with the retinoid X receptor (RXR). Despite the important roles of the FXR/RXR heterodimerization in human physiology, the molecular basis underlying the FXR/RXR interaction is still uncertain in the absence of a complex structure. Here, we report the heterodimeric structure of FXR and RXR in the presence of an FXR agonist (WAY-362450), RXR agonist (9- cis -retinoic acid), and a peptide derived from a steroid receptor coactivator (SRC2), revealing both unique and conserved modes for FXR heterodimerization. We found that the dimerization with RXR induced allosteric conformational changes on the coactivator-binding site of FXR. These changes enhanced the transcriptional activity of FXR by promoting the coactivator binding, thus suggesting a structural basis for the functional permissiveness of the FXR/RXR heterodimer complex. Furthermore, sequence analyses together with functional mutagenesis studies indicated that the helix H10 largely responsible for the dimerization is highly conserved and also critical for the FXR transcriptional activity. Our findings highlight the important roles of RXR heterodimerization in the nuclear receptor signaling, providing a potential framework to develop pharmaceutical agents in treating FXR/RXR-related diseases.


  • Organizational Affiliation

    From the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361005, China [email protected].


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bile acid receptorA,
E [auth D]
228Homo sapiensMutation(s): 0 
Gene Names: NR1H4BARFXRHRR1RIP14
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Find proteins for Q96RI1 (Homo sapiens)
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Go to UniProtKB:  Q96RI1
PHAROS:  Q96RI1
GTEx:  ENSG00000012504 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ96RI1
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Retinoic acid receptor RXR-alphaB [auth C],
G [auth B]
231Homo sapiensMutation(s): 0 
Gene Names: RXRANR2B1
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Find proteins for P19793 (Homo sapiens)
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PHAROS:  P19793
GTEx:  ENSG00000186350 
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UniProt GroupP19793
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Peptide from Nuclear receptor coactivator 2C [auth F],
H [auth I]
9Homo sapiensMutation(s): 0 
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Find proteins for Q15596 (Homo sapiens)
Explore Q15596 
Go to UniProtKB:  Q15596
PHAROS:  Q15596
GTEx:  ENSG00000140396 
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UniProt GroupQ15596
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  • Reference Sequence

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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Peptide from Nuclear receptor coactivator 2D [auth J],
F [auth H]
6Homo sapiensMutation(s): 0 
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Find proteins for Q15596 (Homo sapiens)
Explore Q15596 
Go to UniProtKB:  Q15596
PHAROS:  Q15596
GTEx:  ENSG00000140396 
Entity Groups  
UniProt GroupQ15596
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.290 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.233 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 89.873α = 90
b = 95.484β = 90
c = 116.721γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data scaling
PDB_EXTRACTdata extraction
HKL-3000data reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2018-07-04 
  • Deposition Author(s): Lu, Y., Li, Y.

Revision History  (Full details and data files)

  • Version 1.0: 2018-07-04
    Type: Initial release
  • Version 1.1: 2018-07-25
    Changes: Data collection, Database references
  • Version 1.2: 2018-08-22
    Changes: Data collection, Database references
  • Version 1.3: 2019-12-25
    Changes: Derived calculations, Refinement description
  • Version 1.4: 2024-03-27
    Changes: Data collection, Database references