PDBsum entry 1mzf

Oxidoreductase

PDB id: 1mzf

Contents

Protein chain

335 a.a. *

Ligands

AKG

Metals

FE2

Waters ×50

* Residue conservation analysis

PDB id:

1mzf

Name:

Oxidoreductase

Title:

Human factor inhibiting hif (fih1) in complex with 2-oxoglutarate

Structure:

Factor inhibiting hif1. Chain: a. Synonym: fih-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fih-1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PDB file)

Resolution:

2.40Å R-factor: 0.232 R-free: 0.244

Authors:

C.E.Dann Iii,R.K.Bruick,J.Deisenhofer

Key ref:

C.E.Dann et al. (2002). Structure of factor-inhibiting hypoxia-inducible factor 1: An asparaginyl hydroxylase involved in the hypoxic response pathway. Proc Natl Acad Sci U S A, 99, 15351-15356. PubMed id: 12432100 DOI: 10.1073/pnas.202614999

Date:

07-Oct-02 Release date: 20-Nov-02

Protein chain

Q9NWT6  (HIF1N_HUMAN) -  Hypoxia-inducible factor 1-alpha inhibitor from Homo sapiens

Seq: 349 a.a.

Struc: 335 a.a.

Enzyme reactions

• Enzyme class 1: E.C.1.14.11.30 - hypoxia-inducible factor-asparagine dioxygenase.
• Reaction: L-asparaginyl-[hypoxia-inducible factor alpha subunit] + 2-oxoglutarate + O2 = (3S)-3-hydroxy-L-asparaginyl-[hypoxia-inducible factor alpha subunit] + succinate + CO2

L-asparaginyl-[hypoxia-inducible factor alpha subunit] (Bound ligand (Het Group name = AKG) corresponds exactly) + 2-oxoglutarate + O2 = (3S)-3-hydroxy-L-asparaginyl-[hypoxia-inducible factor alpha subunit] + succinate + CO2

• Cofactor: Fe(2+); L-ascorbate
• Enzyme class 2: E.C.1.14.11.n4 - ?????

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

reference

DOI no: 10.1073/pnas.202614999

Proc Natl Acad Sci U S A 99:15351-15356 (2002)

PubMed id: 12432100

Structure of factor-inhibiting hypoxia-inducible factor 1: An asparaginyl hydroxylase involved in the hypoxic response pathway.

C.E.Dann, R.K.Bruick, J.Deisenhofer.

ABSTRACT

Precise regulation of the evolutionarily conserved hypoxia-inducible transcription factor (HIF) ensures proper adaptation to variations in oxygen availability throughout development and into adulthood. Oxygen-dependent regulation of HIF stability and activity are mediated by hydroxylation of conserved proline and asparagine residues, respectively. Because the relevant prolyl and asparginyl hydroxylases use O(2) to effect these posttranslational modifications, these enzymes are implicated as direct oxygen sensors in the mammalian hypoxic response pathway. Here we present the structure of factor-inhibiting HIF-1 (FIH-1), the pertinent asparaginyl hydroxylase involved in hypoxic signaling. Hydroxylation of the C-terminal transactivation domain (CTAD) of HIF by FIH-1 prevents CTAD association with transcriptional coactivators under normoxic conditions. Consistent with other structurally known hydroxylases, FIH-1 is comprised of a beta-strand jellyroll core with both Fe(II) and the cosubstrate 2-oxoglutarate bound in the active site. Details of the molecular contacts at the active site of FIH-1 have been elucidated and provide a platform for future drug design. Furthermore, the structure reveals the presence of a FIH-1 homodimer that forms in solution and is essential for FIH activity.

Selected figure(s)

Figure 2.
Fig 2. The primary structure of FIH-1 is labeled with secondary structure elements taken from the x-ray crystallographic model. -strands and helices are depicted as red arrows and yellow boxes, respectively. Residues responsible for Fe(II) binding are highlighted in red, whereas residues in close contact with 2-OG are highlighted in green.

Figure 3.
Fig 3. FIH-1 structure contains a -jellyroll core marked by an extension of one of the -sheets away from the core and helices dotting the periphery. (A) A ribbon model of the FIH-1 monomer is positioned looking between the -sheets comprising the jellyroll and into the active site cavity. The active site metal is shown as a red sphere. Structural elements are colored as in Fig. 2. (B) A secondary structure topology diagram shows the arrangement of the 14 -strands (triangles) and 8 helices (circles) in FIH-1. The core jellyroll motif, structurally homologous to the cupin protein family, is colored in red. (C) FIH-1 exists as a functionally relevant dimer in the crystal. The first monomer of the dimer is colored as in A, whereas the second monomer is blue. N and C termini are marked as black circles. The figure was generated by using RIBBONS (41).

Figures were selected by an automated process.