5OPC

Factor Inhibiting HIF (FIH) in complex with zinc and Vadadustat


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.

Yeh, T.L.Leissing, T.M.Abboud, M.I.Thinnes, C.C.Atasoylu, O.Holt-Martyn, J.P.Zhang, D.Tumber, A.Lippl, K.Lohans, C.T.Leung, I.K.H.Morcrette, H.Clifton, I.J.Claridge, T.D.W.Kawamura, A.Flashman, E.Lu, X.Ratcliffe, P.J.Chowdhury, R.Pugh, C.W.Schofield, C.J.

(2017) Chem Sci 8: 7651-7668

  • DOI: https://doi.org/10.1039/c7sc02103h
  • Primary Citation of Related Structures:  
    5OP6, 5OP8, 5OPC, 5OX5, 5OX6

  • PubMed Abstract: 

    Inhibition of the human 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (human PHD1-3) causes upregulation of HIF, thus promoting erythropoiesis and is therefore of therapeutic interest. We describe cellular, biophysical, and biochemical studies comparing four PHD inhibitors currently in clinical trials for anaemia treatment, that describe their mechanisms of action, potency against isolated enzymes and in cells, and selectivities versus representatives of other human 2OG oxygenase subfamilies. The 'clinical' PHD inhibitors are potent inhibitors of PHD catalyzed hydroxylation of the HIF-α oxygen dependent degradation domains (ODDs), and selective against most, but not all, representatives of other human 2OG dependent dioxygenase subfamilies. Crystallographic and NMR studies provide insights into the different active site binding modes of the inhibitors. Cell-based results reveal the inhibitors have similar effects on the upregulation of HIF target genes, but differ in the kinetics of their effects and in extent of inhibition of hydroxylation of the N- and C-terminal ODDs; the latter differences correlate with the biophysical observations.


  • Organizational Affiliation

    Chemistry Research Laboratory , Department of Chemistry , University of Oxford , 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
Hypoxia-inducible factor 1-alpha inhibitor350Homo 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
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
A1Z (Subject of Investigation/LOI)
Query on A1Z

Download Ideal Coordinates CCD File 
M [auth A]Vadadustat
C14 H11 Cl N2 O4
JGRXMPYUTJLTKT-UHFFFAOYSA-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]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

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

Download Ideal Coordinates CCD File 
G [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
A1Z Binding MOAD:  5OPC IC50: 2.90e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.799α = 90
b = 86.799β = 90
c = 149.52γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Engineering and Physical Sciences Research CouncilUnited KingdomG03706X/1

Revision History  (Full details and data files)

  • Version 1.0: 2017-10-18
    Type: Initial release
  • Version 1.1: 2018-02-21
    Changes: Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description