4QJR

Crystal structure of human nuclear receptor sf-1 (nr5a1) bound to its hormone pip3 at 2.4 a resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.191 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1.

Blind, R.D.Sablin, E.P.Kuchenbecker, K.M.Chiu, H.J.Deacon, A.M.Das, D.Fletterick, R.J.Ingraham, H.A.

(2014) Proc Natl Acad Sci U S A 111: 15054-15059

  • DOI: https://doi.org/10.1073/pnas.1416740111
  • Primary Citation of Related Structures:  
    4QJR, 4QK4

  • PubMed Abstract: 

    The signaling phosphatidylinositol lipids PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) bind nuclear receptor 5A family (NR5As), but their regulatory mechanisms remain unknown. Here, the crystal structures of human NR5A1 (steroidogenic factor-1, SF-1) ligand binding domain (LBD) bound to PIP2 and PIP3 show the lipid hydrophobic tails sequestered in the hormone pocket, as predicted. However, unlike classic nuclear receptor hormones, the phosphoinositide head groups are fully solvent-exposed and complete the LBD fold by organizing the receptor architecture at the hormone pocket entrance. The highest affinity phosphoinositide ligand PIP3 stabilizes the coactivator binding groove and increases coactivator peptide recruitment. This receptor-ligand topology defines a previously unidentified regulatory protein-lipid surface on SF-1 with the phosphoinositide head group at its nexus and poised to interact with other proteins. This surface on SF-1 coincides with the predicted binding site of the corepressor DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region on chromosome X), and importantly harbors missense mutations associated with human endocrine disorders. Our data provide the structural basis for this poorly understood cluster of human SF-1 mutations and demonstrates how signaling phosphoinositides function as regulatory ligands for NR5As.


  • Organizational Affiliation

    Departments of Cellular and Molecular Pharmacology and.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Steroidogenic factor 1245Homo sapiensMutation(s): 2 
Gene Names: AD4BPFTZF1NR5A1RC2003BSF1
UniProt & NIH Common Fund Data Resources
Find proteins for Q13285 (Homo sapiens)
Explore Q13285 
Go to UniProtKB:  Q13285
PHAROS:  Q13285
GTEx:  ENSG00000136931 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13285
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha14Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UBK2 (Homo sapiens)
Explore Q9UBK2 
Go to UniProtKB:  Q9UBK2
PHAROS:  Q9UBK2
GTEx:  ENSG00000109819 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UBK2
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PIZ
Query on PIZ

Download Ideal Coordinates CCD File 
C [auth A](2S)-3-{[(R)-{[(1S,2S,3R,4S,5S,6S)-2,6-dihydroxy-3,4,5-tris(phosphonooxy)cyclohexyl]oxy}(hydroxy)phosphoryl]oxy}propane -1,2-diyl dihexadecanoate
C41 H82 O22 P4
ZSZXYWFCIKKZBT-XMZWCAJNSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
PIZ Binding MOAD:  4QJR Kd: 80 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.85α = 90
b = 74.85β = 90
c = 139.63γ = 90
Software Package:
Software NamePurpose
MolProbitymodel building
PDB_EXTRACTdata extraction
PHENIXrefinement
SCALAdata scaling
MOSFLMdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-30
    Type: Initial release
  • Version 1.1: 2014-11-12
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Refinement description
  • Version 1.3: 2023-02-01
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.4: 2023-09-20
    Changes: Data collection, Refinement description
  • Version 1.5: 2024-03-13
    Changes: Source and taxonomy, Structure summary