4N5G

Crystal Structure of RXRa LBD complexed with a synthetic modulator K8012


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Sulindac-Derived RXR alpha Modulators Inhibit Cancer Cell Growth by Binding to a Novel Site.

Chen, L.Wang, Z.G.Aleshin, A.E.Chen, F.Chen, J.Jiang, F.Alitongbieke, G.Zeng, Z.Ma, Y.Huang, M.Zhou, H.Cadwell, G.Zheng, J.F.Huang, P.Q.Liddington, R.C.Zhang, X.K.Su, Y.

(2014) Chem Biol 21: 596-607

  • DOI: https://doi.org/10.1016/j.chembiol.2014.02.017
  • Primary Citation of Related Structures:  
    4N5G, 4N8R

  • PubMed Abstract: 

    Retinoid X receptor-alpha (RXRα), an intriguing and unique drug target, can serve as an intracellular target mediating the anticancer effects of certain nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac. We report the synthesis and characterization of two sulindac analogs, K-8008 and K-8012, which exert improved anticancer activities over sulindac in a RXRα-dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXRα (tRXRα) with the p85α subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRα ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRα LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXRα modulators and define a binding mechanism for regulating the nongenomic action of tRXRα.


  • Organizational Affiliation

    School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China; Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Retinoic acid receptor RXR-alpha
A, B, C, D
244Homo sapiensMutation(s): 0 
Gene Names: RXRANR2B1
UniProt & NIH Common Fund Data Resources
Find proteins for P19793 (Homo sapiens)
Explore P19793 
Go to UniProtKB:  P19793
PHAROS:  P19793
GTEx:  ENSG00000186350 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP19793
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
K09
Query on K09

Download Ideal Coordinates CCD File 
E [auth A],
F [auth D]
5-(2-{(1Z)-5-fluoro-2-methyl-1-[4-(propan-2-yl)benzylidene]-1H-inden-3-yl}ethyl)-1H-tetrazole
C23 H23 F N4
XBRDZHUUARVXDN-MTJSOVHGSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
K09 Binding MOAD:  4N5G IC50: 1.45e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.585α = 90
b = 98.83β = 99.02
c = 110.579γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
PHENIXrefinement
MOSFLMdata reduction
SCALAdata 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: 2014-05-14
    Type: Initial release
  • Version 1.1: 2014-06-11
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description