4RZE

Crystal Structure Analysis of the NUR77 Ligand Binding Domain, L437W,D594E mutant


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.49 Å
  • R-Value Free: 0.309 
  • R-Value Work: 0.250 
  • R-Value Observed: 0.253 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation.

Li, L.Liu, Y.Chen, H.Z.Li, F.W.Wu, J.F.Zhang, H.K.He, J.P.Xing, Y.Z.Chen, Y.Wang, W.J.Tian, X.Y.Li, A.Z.Zhang, Q.Huang, P.Q.Han, J.Lin, T.Wu, Q.

(2015) Nat Chem Biol 11: 339-346

  • DOI: https://doi.org/10.1038/nchembio.1788
  • Primary Citation of Related Structures:  
    4RZE, 4RZF, 4RZG

  • PubMed Abstract: 

    Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.


  • Organizational Affiliation

    State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor subfamily 4 group A member 1A [auth B],
B [auth A]
256Homo sapiensMutation(s): 2 
Gene Names: GFRP1HMRNAK1NR4A1
UniProt & NIH Common Fund Data Resources
Find proteins for P22736 (Homo sapiens)
Explore P22736 
Go to UniProtKB:  P22736
PHAROS:  P22736
GTEx:  ENSG00000123358 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22736
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.49 Å
  • R-Value Free: 0.309 
  • R-Value Work: 0.250 
  • R-Value Observed: 0.253 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.266α = 90
b = 76.893β = 90
c = 128.518γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
MAR345dtbdata collection
AUTOMARdata reduction
PHASESphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-03-18
    Type: Initial release
  • Version 1.1: 2015-04-22
    Changes: Database references
  • Version 1.2: 2015-05-06
    Changes: Database references
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations, Refinement description