4GHI

Crystal structure of the high affinity heterodimer of HIF2 alpha and ARNT C-terminal PAS domains in complex with a benzoxadiazole antagonist


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Allosteric inhibition of hypoxia inducible factor-2 with small molecules.

Scheuermann, T.H.Li, Q.Ma, H.W.Key, J.Zhang, L.Chen, R.Garcia, J.A.Naidoo, J.Longgood, J.Frantz, D.E.Tambar, U.K.Gardner, K.H.Bruick, R.K.

(2013) Nat Chem Biol 9: 271-276

  • DOI: https://doi.org/10.1038/nchembio.1185
  • Primary Citation of Related Structures:  
    4GHI

  • PubMed Abstract: 

    Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in many cancers where they frequently promote the expression of protumorigenic pathways. Though transcription factors are typically considered 'undruggable', the PAS-B domain of the HIF-2α subunit contains a large cavity within its hydrophobic core that offers a unique foothold for small-molecule regulation. Here we identify artificial ligands that bind within this pocket and characterize the resulting structural and functional changes caused by binding. Notably, these ligands antagonize HIF-2 heterodimerization and DNA-binding activity in vitro and in cultured cells, reducing HIF-2 target gene expression. Despite the high sequence identity between HIF-2α and HIF-1α, these ligands are highly selective and do not affect HIF-1 function. These chemical tools establish the molecular basis for selective regulation of HIF-2, providing potential therapeutic opportunities to intervene in HIF-2-driven tumors, such as renal cell carcinomas.


  • Organizational Affiliation

    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Endothelial PAS domain-containing protein 1117Homo sapiensMutation(s): 1 
Gene Names: BHLHE73EPAS1HIF2AMOP2PASD2
UniProt & NIH Common Fund Data Resources
Find proteins for Q99814 (Homo sapiens)
Explore Q99814 
Go to UniProtKB:  Q99814
PHAROS:  Q99814
GTEx:  ENSG00000116016 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ99814
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Aryl hydrocarbon receptor nuclear translocator121Homo sapiensMutation(s): 1 
Gene Names: ARNTBHLHE2
UniProt & NIH Common Fund Data Resources
Find proteins for P27540 (Homo sapiens)
Explore P27540 
Go to UniProtKB:  P27540
PHAROS:  P27540
GTEx:  ENSG00000143437 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27540
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0X3
Query on 0X3

Download Ideal Coordinates CCD File 
C [auth A]N-(3-chloro-5-fluorophenyl)-4-nitro-2,1,3-benzoxadiazol-5-amine
C12 H6 Cl F N4 O3
CDQUJZKBRAFWNG-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0X3 BindingDB:  4GHI Kd: 90 (nM) from 1 assay(s)
IC50: 490 (nM) from 1 assay(s)
PDBBind:  4GHI Kd: 81 (nM) from 1 assay(s)
Binding MOAD:  4GHI Kd: 81 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.170 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.353α = 90
b = 83β = 105.98
c = 41.02γ = 90
Software Package:
Software NamePurpose
HKL-3000data collection
PHENIXmodel building
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-02-27
    Type: Initial release
  • Version 1.1: 2013-04-03
    Changes: Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description