4S15

Crystal structure of the orphan nuclear receptor RORalpha ligand-binding domain in complex with 4alpha-caboxyl, 4beta-methyl-zymosterol (4ACD8)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Identification of Natural ROR gamma Ligands that Regulate the Development of Lymphoid Cells.

Santori, F.R.Huang, P.van de Pavert, S.A.Douglass, E.F.Leaver, D.J.Haubrich, B.A.Keber, R.Lorbek, G.Konijn, T.Rosales, B.N.Rozman, D.Horvat, S.Rahier, A.Mebius, R.E.Rastinejad, F.Nes, W.D.Littman, D.R.

(2015) Cell Metab 21: 286-297

  • DOI: https://doi.org/10.1016/j.cmet.2015.01.004
  • Primary Citation of Related Structures:  
    4S14, 4S15

  • PubMed Abstract: 

    Mice deficient in the nuclear hormone receptor RORγt have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORγt binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORγ-dependent transcription. Our results are consistent with the RORγt ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORγ identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORγ ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORγt-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORγt.


  • Organizational Affiliation

    The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA. Electronic address: fsantof01@gmail.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor ROR-alphaA,
C [auth B]
256Homo sapiensMutation(s): 0 
Gene Names: NR1F1RORARZRA
UniProt & NIH Common Fund Data Resources
Find proteins for P35398 (Homo sapiens)
Explore P35398 
Go to UniProtKB:  P35398
PHAROS:  P35398
GTEx:  ENSG00000069667 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35398
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor-interacting protein 1B [auth C],
D
12Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P48552 (Homo sapiens)
Explore P48552 
Go to UniProtKB:  P48552
PHAROS:  P48552
GTEx:  ENSG00000180530 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP48552
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.194α = 90
b = 80.305β = 90
c = 113.104γ = 90
Software Package:
Software NamePurpose
HKL-3000data collection
PHASERphasing
PHENIXrefinement
HKL-3000data reduction
HKL-3000data 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: 2015-02-11
    Type: Initial release
  • Version 1.1: 2015-02-25
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations