6QGV

HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with a Spiro[4.5]decanone inhibitor (JPHM-2-167)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.172 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.158 

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This is version 1.3 of the entry. See complete history. 


Literature

Studies on spiro[4.5]decanone prolyl hydroxylase domain inhibitors.

Holt-Martyn, J.P., Tumber, A., Rahman, M.Z., Lippl, K., Figg Jr., W., McDonough, M.A., Chowdhury, R., Schofield, C.J.

(2019) Medchemcomm 10: 500-504

  • DOI: https://doi.org/10.1039/c8md00548f
  • Primary Citation of Related Structures:  
    6QGV

  • PubMed Abstract: 

    The 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are targets for treatment of anaemia and other ischaemia related diseases. PHD inhibitors are in clinical trials; however, the number of reported templates for PHD inhibition is limited. We report structure-activity relationship and crystallographic studies on spiro[4.5]decanone containing PHD inhibitors. Together with other studies, our results reveal spiro[4.5]decanones as useful templates for generation of potent and selective 2OG oxygenase inhibitors.

    • Organizational Affiliation: 

    Department of Chemistry , University of Oxford , Chemistry Research Laboratory , 12 Mansfield Road , Oxford , OX1 3TA , UK . Email: christopher.schofield@chem.ox.ac.uk.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Egl nine homolog 1233Homo sapiensMutation(s): 0 
Gene Names: EGLN1, C1orf12, PNAS-118, PNAS-137
EC: 1.14.11.29
UniProt & NIH Common Fund Data Resources
Find proteins for Q9GZT9 (Homo sapiens)
Explore Q9GZT9 
Go to UniProtKB:  Q9GZT9
PHAROS:  Q9GZT9
GTEx:  ENSG00000135766 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9GZT9
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
J2H
Query on J2H
Download Ideal Coordinates CCD File 
C [auth A]8-[(3-methylpyridin-2-yl)methyl]-3-(4-phenylphenyl)-1-pyrimidin-2-yl-1,3,8-triazaspiro[4.5]decane-2,4-dione
C30 H28 N6 O2
FIMHRJKSKVXMEB-UHFFFAOYSA-N
SO4
Query on SO4
Download Ideal Coordinates CCD File 
F [auth A],
G [auth A]		SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL
Download Ideal Coordinates CCD File 
D [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
IPA
Query on IPA
Download Ideal Coordinates CCD File 
E [auth A]ISOPROPYL ALCOHOL
C3 H8 O
KFZMGEQAYNKOFK-UHFFFAOYSA-N
MN
Query on MN
Download Ideal Coordinates CCD File 
B [auth A]MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
J2H BindingDB:  6QGV IC50: 2.1 (nM) from 1 assay(s)
Binding MOAD:  6QGV IC50: 127 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.172 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.158 
  • Space Group: H 3 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 120.065α = 90
b = 120.065β = 90
c = 86.563γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
DIALSdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-02-05
    Type: Initial release
  • Version 1.1: 2021-01-20
    Changes: Database references, Refinement description
  • Version 1.2: 2021-02-24
    Changes: Database references
  • Version 1.3: 2024-01-24
    Changes: Data collection, Database references, Refinement description