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Transcription regulator, oxidoreductase PDB id
1yci
Jmol
Contents
Protein chain
336 a.a. *
Ligands
SO4 ×3
NDF ×2
Metals
FE2
Waters ×90
* Residue conservation analysis
PDB id:
1yci
Name: Transcription regulator, oxidoreductase
Title: Factor inhibiting hif-1 alpha in complex with n-(carboxycarb phenylalanine
Structure: Hypoxia-inducible factor 1 alpha inhibitor. Chain: a. Synonym: hypoxia- inducible factor asparagine hydroxylase, inhibiting hif-1, fih-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hif1an. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PDB file)
Resolution:
2.70Å     R-factor:   0.210     R-free:   0.244
Authors: M.A.Mcdonough,C.J.Schofield
Key ref: M.A.McDonough et al. (2005). Selective inhibition of factor inhibiting hypoxia-inducible factor. J Am Chem Soc, 127, 7680-7681. PubMed id: 15913349 DOI: 10.1021/ja050841b
Date:
22-Dec-04     Release date:   31-May-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9NWT6  (HIF1N_HUMAN) -  Hypoxia-inducible factor 1-alpha inhibitor
Seq:
Struc: 		349 a.a.
336 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.14.11.16  - Peptide-aspartate beta-dioxygenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Peptide L-aspartate + 2-oxoglutarate + O2 = peptide 3-hydroxy-L- aspartate + succinate + CO2
Peptide L-aspartate
 + 2-oxoglutarate
 + O(2)
 = peptide 3-hydroxy-L- aspartate
 + succinate
 + CO(2)
      Cofactor: Iron


Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     oxidation-reduction process   3 terms 
  Biochemical function     protein binding     5 terms  

 

 
    reference    
 
 
DOI no: 10.1021/ja050841b J Am Chem Soc 127:7680-7681 (2005)
PubMed id: 15913349  
 
 
Selective inhibition of factor inhibiting hypoxia-inducible factor.
M.A.McDonough, L.A.McNeill, M.Tilliet, C.A.Papamicaël, Q.Y.Chen, B.Banerji, K.S.Hewitson, C.J.Schofield.
 
  ABSTRACT  
 
A set of four non-heme iron(II) and 2-oxoglutarate-dependent enzymes catalyze the post-translational modification of a transcription factor, hypoxia inducible factor (HIF), that mediates the hypoxic response in animals. Hydroxylation of HIF both causes its degradation and limits its activity. We describe how the use of structural data coupled to solid-phase synthesis led to the discovery of a selective inhibitor of one of the HIF hydroxylases. The inhibitor N-oxalyl-d-phenylalanine was shown to inhibit the HIF asparaginyl hydroxylase (FIH) but not a HIF prolyl hydroxylase. A crystal structure of the inhibitor complexed to FIH reveals that it binds in the 2OG and, likely, in the dioxygen binding site. The results will help to enable the modulation of the hypoxic response for the up-regulation of specific genes of biomedical importance, such as erythropoietin and vascular endothelial growth factor.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21406036 E.Muchnik, and J.Kaplan (2011).
HIF prolyl hydroxylase inhibitors for anemia.
  Expert Opin Investig Drugs, 20, 645-656.  
21449664 H.Heli, S.Mirtorabi, and K.Karimian (2011).
Advances in iron chelation: an update.
  Expert Opin Ther Pat, 21, 819-856.  
21386837 M.N.Khan, T.Bhattacharyya, P.Andrikopoulos, M.A.Esteban, R.Barod, T.Connor, M.Ashcroft, P.H.Maxwell, and S.Kiriakidis (2011).
Factor inhibiting HIF (FIH-1) promotes renal cancer cell survival by protecting cells from HIF-1α-mediated apoptosis.
  Br J Cancer, 104, 1151-1159.  
21421125 Z.Geng, J.Zhu, J.Cao, J.Geng, X.Song, Z.Zhang, N.Bian, and Z.Wang (2011).
Effects of polynitrogen compounds on the activity of recombinant human HIF-1α prolyl hydroxylase 3 in E. coli.
  J Inorg Biochem, 105, 391-399.  
20396966 H.Moon, S.Han, H.Park, and J.Choe (2010).
Crystal structures of human FIH-1 in complex with quinol family inhibitors.
  Mol Cells, 29, 471-474.
PDB codes: 3kcx 3kcy
20625934 L.Donovan, S.M.Welford, J.Haaga, J.LaManna, and K.P.Strohl (2010).
Hypoxia--implications for pharmaceutical developments.
  Sleep Breath, 14, 291-298.  
20094655 M.Sakurai, N.R.Rose, L.Schultz, A.M.Quinn, A.Jadhav, S.S.Ng, U.Oppermann, C.J.Schofield, and A.Simeonov (2010).
A miniaturized screen for inhibitors of Jumonji histone demethylases.
  Mol Biosyst, 6, 357-364.  
20088513 N.R.Rose, E.C.Woon, G.L.Kingham, O.N.King, J.Mecinović, I.J.Clifton, S.S.Ng, J.Talib-Hardy, U.Oppermann, M.A.McDonough, and C.J.Schofield (2010).
Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches.
  J Med Chem, 53, 1810-1818.
PDB code: 2wwj
19754349 S.Nagel, N.P.Talbot, J.Mecinović, T.G.Smith, A.M.Buchan, and C.J.Schofield (2010).
Therapeutic manipulation of the HIF hydroxylases.
  Antioxid Redox Signal, 12, 481-501.  
20010896 T.Miyata, and C.Y.de Strihou (2010).
Diabetic nephropathy: a disorder of oxygen metabolism?
  Nat Rev Nephrol, 6, 83-95.  
19222864 B.Muz, M.N.Khan, S.Kiriakidis, and E.M.Paleolog (2009).
The role of hypoxia and HIF-dependent signalling events in rheumatoid arthritis.
  Arthritis Res Ther, 11, 201.  
18568157 R.Chowdhury, A.Hardy, and C.J.Schofield (2008).
The human oxygen sensing machinery and its manipulation.
  Chem Soc Rev, 37, 1308-1319.  
17429948 G.M.Montero-Morán, M.Li, E.Rendòn-Huerta, F.Jourdan, D.J.Lowe, A.W.Stumpff-Kane, M.Feig, C.Scazzocchio, and R.P.Hausinger (2007).
Purification and characterization of the FeII- and alpha-ketoglutarate-dependent xanthine hydroxylase from Aspergillus nidulans.
  Biochemistry, 46, 5293-5304.  
17135241 K.S.Hewitson, B.M.Liénard, M.A.McDonough, I.J.Clifton, D.Butler, A.S.Soares, N.J.Oldham, L.A.McNeill, and C.J.Schofield (2007).
Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates.
  J Biol Chem, 282, 3293-3301.
PDB codes: 2cgn 2cgo
16782814 M.A.McDonough, V.Li, E.Flashman, R.Chowdhury, C.Mohr, B.M.Liénard, J.Zondlo, N.J.Oldham, I.J.Clifton, J.Lewis, L.A.McNeill, R.J.Kurzeja, K.S.Hewitson, E.Yang, S.Jordan, R.S.Syed, and C.J.Schofield (2006).
Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2).
  Proc Natl Acad Sci U S A, 103, 9814-9819.
PDB codes: 2g19 2g1m
16261239 B.Banerji, A.Conejo-Garcia, L.A.McNeill, M.A.McDonough, M.R.Buck, K.S.Hewitson, N.J.Oldham, and C.J.Schofield (2005).
The inhibition of factor inhibiting hypoxia-inducible factor (FIH) by beta-oxocarboxylic acids.
  Chem Commun (Camb), 0, 5438-5440.  
16186124 M.A.McDonough, K.L.Kavanagh, D.Butler, T.Searls, U.Oppermann, and C.J.Schofield (2005).
Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease.
  J Biol Chem, 280, 41101-41110.
PDB code: 2a1x
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.