6P2B

Tethered PXR-LBD/SRC-1p bound to Garcinoic Acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.188 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor.

Bartolini, D.De Franco, F.Torquato, P.Marinelli, R.Cerra, B.Ronchetti, R.Schon, A.Fallarino, F.De Luca, A.Bellezza, G.Ferri, I.Sidoni, A.Walton, W.G.Pellock, S.J.Redinbo, M.R.Mani, S.Pellicciari, R.Gioiello, A.Galli, F.

(2020) J Med Chem 63: 3701-3712

  • DOI: https://doi.org/10.1021/acs.jmedchem.0c00012
  • Primary Citation of Related Structures:  
    6P2B

  • PubMed Abstract: 

    Pregnane X receptor (PXR) is a master xenobiotic-sensing transcription factor and a validated target for immune and inflammatory diseases. The identification of chemical probes to investigate the therapeutic relevance of the receptor is still highly desired. In fact, currently available PXR ligands are not highly selective and can exhibit toxicity and/or potential off-target effects. In this study, we have identified garcinoic acid as a selective and efficient PXR agonist. The properties of this natural molecule as a specific PXR agonist were demonstrated by the screening on a panel of nuclear receptors, the assessment of the physical and thermodynamic binding affinity, and the determination of the PXR-garcinoic acid complex crystal structure. Cytotoxicity, transcriptional, and functional properties were investigated in human liver cells, and compound activity and target engagement were confirmed in vivo in mouse liver and gut tissue. In conclusion, garcinoic acid is a selective natural agonist of PXR and a promising lead compound toward the development of new PXR-regulating modulators.


  • Organizational Affiliation

    Department of Pharmaceutical Sciences, University of Perugia, Perugia 06122, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor subfamily 1 group I member 2
A, B
344Homo sapiensMutation(s): 0 
Gene Names: NR1I2PXR
UniProt & NIH Common Fund Data Resources
Find proteins for O75469 (Homo sapiens)
Explore O75469 
Go to UniProtKB:  O75469
PHAROS:  O75469
GTEx:  ENSG00000144852 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO75469
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.188 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 84.992α = 90
b = 89.547β = 90
c = 107.531γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)United StatesCA222469

Revision History  (Full details and data files)

  • Version 1.0: 2020-04-01
    Type: Initial release
  • Version 1.1: 2020-04-22
    Changes: Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description, Structure summary