4XT2

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2.

Scheuermann, T.H.Stroud, D.Sleet, C.E.Bayeh, L.Shokri, C.Wang, H.Caldwell, C.G.Longgood, J.MacMillan, J.B.Bruick, R.K.Gardner, K.H.Tambar, U.K.

(2015) J Med Chem 58: 5930-5941

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00529
  • Primary Citation of Related Structures:  
    4XT2

  • PubMed Abstract: 

    Hypoxia inducible factor (HIF) transcription factors reside at the center of signaling pathways used by mammalian cells to sense and respond to low oxygen levels. While essential to maintain oxygen homeostasis, misregulation of HIF protein activity correlates with tumor development and metastasis. To provide artificial routes to target misregulated HIF activity, we identified small molecule antagonists of the HIF-2 transcription factor that bind an internal cavity within the C-terminal PAS domain of the HIF-2α subunit. Here we describe a new class of chiral small molecule ligands that provide the highest affinity binding, the most effective, isoform-selective inhibition of HIF-2 in cells, and trigger the largest protein conformation changes reported to date. The current results further illuminate the molecular mechanism of HIF-2 antagonism and suggest additional routes to develop higher affinity and potency HIF-2 antagonists.


  • Organizational Affiliation

    †Department of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aryl hydrocarbon receptor nuclear translocatorA [auth B],
B [auth D]
121Homo 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
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Endothelial PAS domain-containing protein 1C [auth A],
D [auth C]
117Homo sapiensMutation(s): 1 
Gene Names: EPAS1BHLHE73HIF2AMOP2PASD2
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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
43L
Query on 43L

Download Ideal Coordinates CCD File 
E [auth A],
F [auth C]
(5S,7R)-5,7-bis(3-bromophenyl)-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine
C16 H13 Br2 N5
JHRYBPMSBXHLJL-LSDHHAIUSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
43L BindingDB:  4XT2 Kd: min: 63, max: 70 (nM) from 2 assay(s)
IC50: min: 112, max: 3.00e+4 (nM) from 2 assay(s)
Binding MOAD:  4XT2 Kd: 63 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.253α = 90
b = 84.39β = 104.39
c = 82.784γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Cancer Prevention and Research Institute of Texas (CPRIT)United StatesRP130513
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesP01 CA95471
Cancer Prevention and Research Institute of Texas (CPRIT)United StatesRP100846

Revision History  (Full details and data files)

  • Version 1.0: 2015-12-09
    Type: Initial release
  • Version 1.1: 2015-12-23
    Changes: Refinement description
  • Version 1.2: 2017-09-06
    Changes: Advisory, Author supporting evidence, Derived calculations
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2023-09-27
    Changes: Advisory, Data collection, Database references, Refinement description