4IS8

Divergent sequence tunes ligand sensitivity in phospholipid-regulated hormone receptors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.78 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.225 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Divergent Sequence Tunes Ligand Sensitivity in Phospholipid-regulated Hormone Receptors.

Musille, P.M.Pathak, M.Lauer, J.L.Griffin, P.R.Ortlund, E.A.

(2013) J Biol Chem 288: 20702-20712

  • DOI: https://doi.org/10.1074/jbc.M113.472837
  • Primary Citation of Related Structures:  
    4IS8

  • PubMed Abstract: 

    The members of the NR5A subfamily of nuclear receptors (NRs) are important regulators of pluripotency, lipid and glucose homeostasis, and steroidogenesis. Liver receptor homologue 1 (LRH-1; NR5A2) and steroidogenic factor 1 (SF-1; NR5A1) have therapeutic potential for the treatment of metabolic and neoplastic disease; however, a poor understanding of their ligand regulation has hampered the pursuit of these proteins as pharmaceutical targets. In this study, we dissect how sequence variation among LRH-1 orthologs affects phospholipid (PL) binding and regulation. Both human LRH-1 (hLRH-1) and mouse LRH-1 (mLRH-1) respond to newly discovered medium chain PL agonists to modulate lipid and glucose homeostasis. These PLs activate hLRH-1 by altering receptor dynamics in a newly identified alternate activation function region. Mouse and Drosophila orthologs contain divergent sequences in this region potentially altering PL-driven activation. Structural evidence suggests that these sequence differences in mLRH-1 and Drosophila FTZ-f1 (dmFTZ-f1) confer at least partial ligand independence, making them poor models for hLRH-1 studies; however, the mechanisms of ligand independence remain untested. We show using structural and biochemical methods that the recent evolutionary divergence of the mLRH-1 stabilizes the active conformation in the absence of ligand, yet does not abrogate PL-dependent activation. We also show by mass spectrometry and biochemical assays that FTZ-f1 is incapable of PL binding. This work provides a structural mechanism for the differential tuning of PL sensitivity in NR5A orthologs and supports the use of mice as viable therapeutic models for LRH-1-dependent diseases.


  • Organizational Affiliation

    Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor subfamily 5 group A member 2
A, B
239Homo sapiensMutation(s): 6 
Gene Names: B1FCPFFTFNR5A2
UniProt & NIH Common Fund Data Resources
Find proteins for O00482 (Homo sapiens)
Explore O00482 
Go to UniProtKB:  O00482
PHAROS:  O00482
GTEx:  ENSG00000116833 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO00482
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.78 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.225 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 36.305α = 90
b = 120.029β = 90
c = 123.838γ = 90
Software Package:
Software NamePurpose
SERGUIdata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-06-12
    Type: Initial release
  • Version 1.1: 2013-07-03
    Changes: Database references
  • Version 1.2: 2013-07-31
    Changes: Database references
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references