4GS9

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Development of Inhibitors of the PAS-B Domain of the HIF-2 alpha Transcription Factor

Rogers, J.L.Bayeh, L.Scheuermann, T.H.Longgood, J.Key, J.Naidoo, J.Melito, L.Shokri, C.Frantz, D.E.Bruick, R.K.Gardner, K.H.Macmillan, J.B.Tambar, U.K.

(2013) J Med Chem 56: 1739-1747

  • DOI: https://doi.org/10.1021/jm301847z
  • Primary Citation of Related Structures:  
    4GS9

  • PubMed Abstract: 

    Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in a variety of pathophysiological settings, including cancer. We describe the first detailed structure-activity relationship study of small molecules designed to inhibit HIF-2α-ARNT heterodimerization by binding an internal cavity of the HIF-2α PAS-B domain. Through a series of biophysical characterizations of inhibitor-protein interactions (NMR and X-ray crystallography), we have established the structural requirements for artificial inhibitors of the HIF-2α-ARNT PAS-B interaction. These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action.


  • Organizational Affiliation

    Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.


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: BHLHE73EPAS1HIF2HIF2AMOP2PASD2
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PE8
Query on PE8

Download Ideal Coordinates CCD File 
D [auth A]3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL
C16 H34 O9
GLZWNFNQMJAZGY-UHFFFAOYSA-N
0XB
Query on 0XB

Download Ideal Coordinates CCD File 
C [auth A]N-(3-fluorophenyl)-4-nitro-2,1,3-benzoxadiazol-5-amine
C12 H7 F N4 O3
QMETXUTZEYHEJB-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0XB PDBBind:  4GS9 Kd: 2200 (nM) from 1 assay(s)
BindingDB:  4GS9 Kd: 2200 (nM) from 1 assay(s)
Binding MOAD:  4GS9 Kd: 2200 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.745α = 90
b = 83.054β = 105.78
c = 41.075γ = 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: 2013-04-03
    Type: Initial release
  • Version 1.1: 2018-05-30
    Changes: Advisory, Data collection, Derived calculations
  • Version 1.2: 2023-09-13
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description