PDBsum entry: 1iz3

Transcription

PDB id: 1iz3

Contents

Protein chain

338 a.a. *

Ligands

SO4

* Residue conservation analysis

PDB id:

1iz3

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)

Resolution:

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

Date:

19-Sep-02 Release date: 10-Jun-03

Protein chain

Q9NWT6  (HIF1N_HUMAN) -  Hypoxia-inducible factor 1-alpha inhibitor

Seq: 349 a.a.

Struc: 338 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.1.14.11.16 - Peptide-aspartate beta-dioxygenase.
• Reaction: Peptide L-aspartate + 2-oxoglutarate + O₂ = peptide 3-hydroxy-L- aspartate + succinate + CO₂
• Cofactor: Iron

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: nucleus (1 term)
• Biological process: oxidation-reduction process (3 terms)
• Biochemical function: protein binding (5 terms)

reference

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.

ABSTRACT

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.