8K72

Factor-inhibiting hypoxia-inducible factor in complex with Zn(II) and 2-(3-hydroxy-2-((3-(phenylsulfonamido)propanoyl)imino)-2,3-dihydrothiazol-4-yl)acetic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 

Starting Model: experimental
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Ligand Structure Quality Assessment 


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Literature

Structure-guided optimisation of N -hydroxythiazole-derived inhibitors of factor inhibiting hypoxia-inducible factor-alpha.

Corner, T.P.Teo, R.Z.R.Wu, Y.Salah, E.Nakashima, Y.Fiorini, G.Tumber, A.Brasnett, A.Holt-Martyn, J.P.Figg Jr., W.D.Zhang, X.Brewitz, L.Schofield, C.J.

(2023) Chem Sci 14: 12098-12120

  • DOI: https://doi.org/10.1039/d3sc04253g
  • Primary Citation of Related Structures:  
    8K71, 8K72, 8K73

  • PubMed Abstract: 

    The human 2-oxoglutarate (2OG)- and Fe(ii)-dependent oxygenases factor inhibiting hypoxia-inducible factor-α (FIH) and HIF-α prolyl residue hydroxylases 1-3 (PHD1-3) regulate the response to hypoxia in humans via catalysing hydroxylation of the α-subunits of the hypoxia-inducible factors (HIFs). Small-molecule PHD inhibitors are used for anaemia treatment; by contrast, few selective inhibitors of FIH have been reported, despite their potential to regulate the hypoxic response, either alone or in combination with PHD inhibition. We report molecular, biophysical, and cellular evidence that the N -hydroxythiazole scaffold, reported to inhibit PHD2, is a useful broad spectrum 2OG oxygenase inhibitor scaffold, the inhibition potential of which can be tuned to achieve selective FIH inhibition. Structure-guided optimisation resulted in the discovery of N -hydroxythiazole derivatives that manifest substantially improved selectivity for FIH inhibition over PHD2 and other 2OG oxygenases, including Jumonji-C domain-containing protein 5 (∼25-fold), aspartate/asparagine-β-hydroxylase (>100-fold) and histone N ε -lysine demethylase 4A (>300-fold). The optimised N -hydroxythiazole-based FIH inhibitors modulate the expression of FIH-dependent HIF target genes and, consistent with reports that FIH regulates cellular metabolism, suppressed lipid accumulation in adipocytes. Crystallographic studies reveal that the N -hydroxythiazole derivatives compete with both 2OG and the substrate for binding to the FIH active site. Derivatisation of the N -hydroxythiazole scaffold has the potential to afford selective inhibitors for 2OG oxygenases other than FIH.


  • Organizational Affiliation

    Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road OX1 3TA Oxford United Kingdom [email protected] [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hypoxia-inducible factor 1-alpha inhibitor349Homo sapiensMutation(s): 0 
Gene Names: HIF1ANFIH1
EC: 1.14.11.30 (PDB Primary Data), 1.14.11 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NWT6 (Homo sapiens)
Explore Q9NWT6 
Go to UniProtKB:  Q9NWT6
PHAROS:  Q9NWT6
GTEx:  ENSG00000166135 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NWT6
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
VJF (Subject of Investigation/LOI)
Query on VJF

Download Ideal Coordinates CCD File 
K [auth A]2-[(2~{Z})-3-oxidanyl-2-[3-(phenylsulfonylamino)propanoylimino]-1,3-thiazol-4-yl]ethanoic acid
C14 H15 N3 O6 S2
MHACTLSRQSKDHU-PEZBUJJGSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A]
C [auth A]
D [auth A]
E [auth A]
F [auth A]
B [auth A],
C [auth A],
D [auth A],
E [auth A],
F [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A],
I [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
J [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.45 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.202 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.61α = 90
b = 86.61β = 90
c = 145.05γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
xia2data reduction
xia2data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Biotechnology and Biological Sciences Research Council (BBSRC)United KingdomBB/J003018/1
Biotechnology and Biological Sciences Research Council (BBSRC)United KingdomBB/R000344/1

Revision History  (Full details and data files)

  • Version 1.0: 2023-12-13
    Type: Initial release