PDBsum entry 1iz3

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Transcription PDB id
Protein chain
338 a.a. *
* Residue conservation analysis
PDB id:
Name: Transcription
Title: Dimeric structure of fih (factor inhibiting hif)
Structure: Fih. Chain: a. Synonym: factor inhibiting hif1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PDB file)
2.80Å     R-factor:   0.230     R-free:   0.277
Authors: C.Lee,S.-J.Kim,D.-G.Jeong,S.M.Lee,S.-E.Ryu
Key ref:
C.Lee et al. (2003). Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and von Hippel-Lindau. J Biol Chem, 278, 7558-7563. PubMed id: 12482756 DOI: 10.1074/jbc.M210385200
19-Sep-02     Release date:   10-Jun-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q9NWT6  (HIF1N_HUMAN) -  Hypoxia-inducible factor 1-alpha inhibitor
349 a.a.
338 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class 1: E.C.1.14.11  - Gamma-butyrobetaine dioxygenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 4-trimethylammoniobutanoate + 2-oxoglutarate + O2 = 3-hydroxy-4- trimethylammoniobutanoate + succinate + CO2
+ 2-oxoglutarate
+ O(2)
= 3-hydroxy-4- trimethylammoniobutanoate
+ succinate
+ CO(2)
      Cofactor: Fe(2+); L-ascorbate
   Enzyme class 2: E.C.  - Hypoxia-inducible factor-asparagine dioxygenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2 = hypoxia- inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2
Hypoxia-inducible factor-L-asparagine
+ 2-oxoglutarate
+ O(2)
= hypoxia- inducible factor-(3S)-3-hydroxy-L-asparagine
+ succinate
+ CO(2)
      Cofactor: Fe(2+); L-ascorbate
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   4 terms 
  Biological process     peptidyl-histidine hydroxylation   12 terms 
  Biochemical function     peptidyl-histidine dioxygenase activity     16 terms  


DOI no: 10.1074/jbc.M210385200 J Biol Chem 278:7558-7563 (2003)
PubMed id: 12482756  
Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and von Hippel-Lindau.
C.Lee, S.J.Kim, D.G.Jeong, S.M.Lee, S.E.Ryu.
The master switch of cellular hypoxia responses, hypoxia-inducible factor 1 (HIF-1), is hydroxylated by factor inhibiting HIF-1 (FIH-1) at a conserved asparagine residue under normoxia, which suppresses transcriptional activity of HIF-1 by abrogating its interaction with transcription coactivators. Here we report the crystal structure of human FIH-1 at 2.8-A resolution. The structural core of FIH-1 consists of a jellyroll-like beta-barrel containing the conserved ferrous-binding triad residues, confirming that FIH-1 is a member of the 2-oxoglutarate-dependent dioxygenase family. Except for the core structure and triad residues, FIH-1 has many structural deviations from other family members including N- and C-terminal insertions and various deletions in the middle of the structure. The ferrous-binding triad region is highly exposed to the solvent, which is connected to a prominent groove that may bind to a helix near the hydroxylation site of HIF-1. The structure, which is in a dimeric state, also reveals the putative von Hippel-Lindau-binding site that is distinctive to the putative HIF-1-binding site, supporting the formation of the ternary complex by FIH-1, HIF-1, and von Hippel-Lindau. The unique environment of the active site and cofactor-binding region revealed in the structure should allow design of selective drugs that can be used in ischemic diseases to promote hypoxia responses.
  Selected figure(s)  
Figure 3.
Fig. 3. The active site conformation. a, the active site residues in FIH-1 are presented as superimposed with the corresponding residues of CAS in complex with 2OG and ferrous ion. The two structures were superposed as in Fig. 2. In the figure, facial triad residues (His-199, Asp-201, and His-279 of FIH-1; His-144, Glu-146, and His-279 of CAS) and the residue implicated in the 2OG binding (Lys-214 of FIH-1; Arg-293 of CAS) are presented. Side chains of FIH-1 and CAS are drawn in blue and yellow sticks, and labeled black and red, respectively. One of the facial triad residues (His-279) is common in both proteins (labeled magenta). Main chains near the presented residues are drawn as tubes of C -carbon trace (FIH-1, purple; CAS, gray). b, the 2F[o] F[c] electron density map around the facial triad residues (His-199, Asp-201, and His-279) is presented in stereo. The map is contoured at 1.0 level.
Figure 4.
Fig. 4. The putative binding sites for HIF-1 and VHL. a, the electrostatic potential surface of FIH-1 is presented with the docked peptide representing the region near the hydroxylation site of HIF-1 CAD. Positive and negative potentials are colored blue and red, respectively. In the figure, an ideal -helical polyalanine model (13 residues) was manually docked on the prominent groove near the active site of FIH-1. The facial triad residues (His-199, Asp-201, and His-279) in the active site also are shown in the figure. b, the putative HIF-1 CAD- and VHL-binding sites are represented on a ribbon diagram of FIH-1 with the same orientation as a. Two parts of the N-terminal 126 residues were colored differently (residues 12-88, pink; residues 89-126, orange). The rest of the molecule is colored gray. The -helical polyalanine model docked in the putative substrate-binding groove and the facial triad residues are shown as in a.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 7558-7563) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
20015196 J.Chiche, M.C.Brahimi-Horn, and J.Pouysségur (2010).
Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer.
  J Cell Mol Med, 14, 771-794.  
20101266 L.Yu, Y.Wang, S.Huang, J.Wang, Z.Deng, Q.Zhang, W.Wu, X.Zhang, Z.Liu, W.Gong, and Z.Chen (2010).
Structural insights into a novel histone demethylase PHF8.
  Cell Res, 20, 166-173.
PDB codes: 3k3n 3k3o
19947658 M.A.Culpepper, E.E.Scott, and J.Limburg (2010).
Crystal structure of prolyl 4-hydroxylase from Bacillus anthracis.
  Biochemistry, 49, 124-133.
PDB code: 3itq
19845827 S.C.Correia, and P.I.Moreira (2010).
Hypoxia-inducible factor 1: a new hope to counteract neurodegeneration?
  J Neurochem, 112, 1.  
19308685 F.Dayan, N.M.Mazure, M.C.Brahimi-Horn, and J.Pouysségur (2008).
A Dialogue between the Hypoxia-Inducible Factor and the Tumor Microenvironment.
  Cancer Microenviron, 1, 53-68.  
18813363 J.M.Simmons, T.A.Müller, and R.P.Hausinger (2008).
Fe(II)/alpha-ketoglutarate hydroxylases involved in nucleobase, nucleoside, nucleotide, and chromatin metabolism.
  Dalton Trans, (), 5132-5142.  
18440561 R.Tal, A.Shaish, L.Bangio, M.Peled, E.Breitbart, and D.Harats (2008).
Activation of C-transactivation domain is essential for optimal HIF-1 alpha-mediated transcriptional and angiogenic effects.
  Microvasc Res, 76, 1-6.  
18805587 Y.H.Chen, L.M.Comeaux, R.W.Herbst, E.Saban, D.C.Kennedy, M.J.Maroney, and M.J.Knapp (2008).
Coordination changes and auto-hydroxylation of FIH-1: uncoupled O2-activation in a human hypoxia sensor.
  J Inorg Biochem, 102, 2120-2129.  
17301803 A.Ozer, and R.K.Bruick (2007).
Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one?
  Nat Chem Biol, 3, 144-153.  
17471263 A.Wolf, C.Schmitz, and A.Böttger (2007).
Changing story of the receptor for phosphatidylserine-dependent clearance of apoptotic cells.
  EMBO Rep, 8, 465-469.  
18096060 E.Y.Tan, L.Campo, C.Han, H.Turley, F.Pezzella, K.C.Gatter, A.L.Harris, and S.B.Fox (2007).
Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer.
  Breast Cancer Res, 9, R89.  
17682059 J.Li, E.Wang, S.Dutta, J.S.Lau, S.W.Jiang, K.Datta, and D.Mukhopadhyay (2007).
Protein kinase C-mediated modulation of FIH-1 expression by the homeodomain protein CDP/Cut/Cux.
  Mol Cell Biol, 27, 7345-7353.  
17320759 M.C.Vissers, S.P.Gunningham, M.J.Morrison, G.U.Dachs, and M.J.Currie (2007).
Modulation of hypoxia-inducible factor-1 alpha in cultured primary cells by intracellular ascorbate.
  Free Radic Biol Med, 42, 765-772.  
17220275 Q.Yan, S.Bartz, M.Mao, L.Li, and W.G.Kaelin (2007).
The hypoxia-inducible factor 2alpha N-terminal and C-terminal transactivation domains cooperate to promote renal tumorigenesis in vivo.
  Mol Cell Biol, 27, 2092-2102.  
17431691 V.Purpero, and G.R.Moran (2007).
The diverse and pervasive chemistries of the alpha-keto acid dependent enzymes.
  J Biol Inorg Chem, 12, 587-601.  
18039096 W.G.Kaelin (2007).
Von hippel-lindau disease.
  Annu Rev Pathol, 2, 145-173.  
16603238 J.R.Whetstine, A.Nottke, F.Lan, M.Huarte, S.Smolikov, Z.Chen, E.Spooner, E.Li, G.Zhang, M.Colaiacovo, and Y.Shi (2006).
Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases.
  Cell, 125, 467-481.  
16716598 K.Hirota, and G.L.Semenza (2006).
Regulation of angiogenesis by hypoxia-inducible factor 1.
  Crit Rev Oncol Hematol, 59, 15-26.  
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
16732293 P.A.Cloos, J.Christensen, K.Agger, A.Maiolica, J.Rappsilber, T.Antal, K.H.Hansen, and K.Helin (2006).
The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3.
  Nature, 442, 307-311.  
16983801 R.J.Klose, E.M.Kallin, and Y.Zhang (2006).
JmjC-domain-containing proteins and histone demethylation.
  Nat Rev Genet, 7, 715-727.  
16321790 H.Acker (2005).
The oxygen sensing signal cascade under the influence of reactive oxygen species.
  Philos Trans R Soc Lond B Biol Sci, 360, 2201-2210.  
15738986 H.J.Dyson, and P.E.Wright (2005).
Intrinsically unstructured proteins and their functions.
  Nat Rev Mol Cell Biol, 6, 197-208.  
16311632 R.H.Baltz, V.Miao, and S.K.Wrigley (2005).
Natural products to drugs: daptomycin and related lipopeptide antibiotics.
  Nat Prod Rep, 22, 717-741.  
15905109 T.Kietzmann, and A.Görlach (2005).
Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression.
  Semin Cell Dev Biol, 16, 474-486.  
16094605 V.N.Uversky, C.J.Oldfield, and A.K.Dunker (2005).
Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling.
  J Mol Recognit, 18, 343-384.  
15122348 C.J.Schofield, and P.J.Ratcliffe (2004).
Oxygen sensing by HIF hydroxylases.
  Nat Rev Mol Cell Biol, 5, 343-354.  
15134335 E.Metzen, and P.J.Ratcliffe (2004).
HIF hydroxylation and cellular oxygen sensing.
  Biol Chem, 385, 223-230.  
15341671 H.Cangul (2004).
Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers.
  BMC Genet, 5, 27.  
15341784 K.S.Hewitson, and C.J.Schofield (2004).
The HIF pathway as a therapeutic target.
  Drug Discov Today, 9, 704-711.  
14718929 K.Valegård, A.C.Terwisscha van Scheltinga, A.Dubus, G.Ranghino, L.M.Oster, J.Hajdu, and I.Andersson (2004).
The structural basis of cephalosporin formation in a mononuclear ferrous enzyme.
  Nat Struct Mol Biol, 11, 95.
PDB codes: 1unb 1uo9 1uob 1uof 1uog
15193161 M.Cikala, O.Alexandrova, C.N.David, M.Pröschel, B.Stiening, P.Cramer, and A.Böttger (2004).
The phosphatidylserine receptor from Hydra is a nuclear protein with potential Fe(II) dependent oxygenase activity.
  BMC Cell Biol, 5, 26.  
15162797 M.F.Czyzyk-Krzeska, and J.Meller (2004).
von Hippel-Lindau tumor suppressor: not only HIF's executioner.
  Trends Mol Med, 10, 146-149.  
15220362 M.R.Morris, E.Maina, N.V.Morgan, D.Gentle, D.Astuti, H.Moch, T.Kishida, M.Yao, P.Schraml, F.M.Richards, F.Latif, and E.R.Maher (2004).
Molecular genetic analysis of FIH-1, FH, and SDHB candidate tumour suppressor genes in renal cell carcinoma.
  J Clin Pathol, 57, 706-711.  
15489165 Z.Zhang, J.S.Ren, I.J.Clifton, and C.J.Schofield (2004).
Crystal structure and mechanistic implications of 1-aminocyclopropane-1-carboxylic acid oxidase--the ethylene-forming enzyme.
  Chem Biol, 11, 1383-1394.
PDB codes: 1w9y 1wa6
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.