4PLD

Human Nuclear Receptor Liver Receptor Homologue-1, LRH-1, in its apo State Bound to a Fragment of Human TIF-2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Unexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity.

Musille, P.M.Kossmann, B.R.Kohn, J.A.Ivanov, I.Ortlund, E.A.

(2016) J Biol Chem 291: 1411-1426

  • DOI: https://doi.org/10.1074/jbc.M115.662874
  • Primary Citation of Related Structures:  
    4PLD, 4PLE

  • PubMed Abstract: 

    Phospholipids (PLs) are unusual signaling hormones sensed by the nuclear receptor liver receptor homolog-1 (LRH-1), which has evolved a novel allosteric pathway to support appropriate interaction with co-regulators depending on ligand status. LRH-1 plays an important role in controlling lipid and cholesterol homeostasis and is a potential target for the treatment of metabolic and neoplastic diseases. Although the prospect of modulating LRH-1 via small molecules is exciting, the molecular mechanism linking PL structure to transcriptional co-regulator preference is unknown. Previous studies showed that binding to an activating PL ligand, such as dilauroylphosphatidylcholine, favors LRH-1's interaction with transcriptional co-activators to up-regulate gene expression. Both crystallographic and solution-based structural studies showed that dilauroylphosphatidylcholine binding drives unanticipated structural fluctuations outside of the canonical activation surface in an alternate activation function (AF) region, encompassing the β-sheet-H6 region of the protein. However, the mechanism by which dynamics in the alternate AF influences co-regulator selectivity remains elusive. Here, we pair x-ray crystallography with molecular modeling to identify an unexpected allosteric network that traverses the protein ligand binding pocket and links these two elements to dictate selectivity. We show that communication between the alternate AF region and classical AF2 is correlated with the strength of the co-regulator interaction. This work offers the first glimpse into the conformational dynamics that drive this unusual PL-mediated nuclear hormone receptor activation.


  • Organizational Affiliation

    From the Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322 and.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor subfamily 5 group A member 2245Homo sapiensMutation(s): 0 
Gene Names: NR5A2B1FCPFFTF
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

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor coactivator 214Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q15596 (Homo sapiens)
Explore Q15596 
Go to UniProtKB:  Q15596
PHAROS:  Q15596
GTEx:  ENSG00000140396 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15596
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CPS
Query on CPS

Download Ideal Coordinates CCD File 
C [auth A]3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE
C32 H58 N2 O7 S
UMCMPZBLKLEWAF-BCTGSCMUSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.813α = 90
b = 65.681β = 90
c = 83.482γ = 90
Software Package:
Software NamePurpose
PDB_EXTRACTdata extraction
Cootmodel building
PHENIXrefinement
PHASERphasing
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-12-16
    Type: Initial release
  • Version 1.1: 2016-01-27
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Database references, Derived calculations, Refinement description
  • Version 1.3: 2023-09-27
    Changes: Data collection, Database references, Refinement description