PDBsum entry: 2g1m

Oxidoreductase

PDB id: 2g1m

Contents

Protein chain

211 a.a. *

Ligands

4HG

Metals

FE2

Waters ×127

* Residue conservation analysis

PDB id:

2g1m

Name:

Oxidoreductase

Title:

Cellular oxygen sensing: crystal structure of hypoxia- inducible factor prolyl hydroxylase (phd2)

Structure:

Egl nine homolog 1. Chain: a. Fragment: catalytic domain. Synonym: hypoxia-inducible factor prolyl hydroxylase 2, hif-prolyl hydroxylase 2, hif-ph2, hph-2, prolyl hydroxylase domain-containing protein 2, phd2, sm-20. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egln1, c1orf12. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.20Å R-factor: 0.216 R-free: 0.289

Authors:

M.A.Mcdonough,C.J.Schofield

Key ref:

M.A.McDonough et al. (2006). Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc Natl Acad Sci U S A, 103, 9814-9819. PubMed id: 16782814 DOI: 10.1073/pnas.0601283103

Date:

14-Feb-06 Release date: 13-Jun-06

Protein chain

Q9GZT9  (EGLN1_HUMAN) -  Egl nine homolog 1

Seq: 426 a.a.

Struc: 211 a.a.

Enzyme reactions

• Enzyme class: E.C.1.14.11.29 - Hypoxia-inducible factor-proline dioxygenase.
• Reaction: Hypoxia-inducible factor-L-proline + 2-oxoglutarate + O₂ = hypoxia- inducible factor-trans-4-hydroxy-L-proline + succinate + CO₂
• Cofactor: Iron; L-ascorbate

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

 Gene Ontology (GO) functional annotation 

• Biological process: oxidation-reduction process (1 term)
• Biochemical function: oxidoreductase activity (5 terms)

reference

DOI no: 10.1073/pnas.0601283103

Proc Natl Acad Sci U S A 103:9814-9819 (2006)

PubMed id: 16782814

Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2).

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, C.J.Schofield.

ABSTRACT

Cellular and physiological responses to changes in dioxygen levels in metazoans are mediated via the posttranslational oxidation of hypoxia-inducible transcription factor (HIF). Hydroxylation of conserved prolyl residues in the HIF-alpha subunit, catalyzed by HIF prolyl-hydroxylases (PHDs), signals for its proteasomal degradation. The requirement of the PHDs for dioxygen links changes in dioxygen levels with the transcriptional regulation of the gene array that enables the cellular response to chronic hypoxia; the PHDs thus act as an oxygen-sensing component of the HIF system, and their inhibition mimics the hypoxic response. We describe crystal structures of the catalytic domain of human PHD2, an important prolyl-4-hydroxylase in the human hypoxic response in normal cells, in complex with Fe(II) and an inhibitor to 1.7 A resolution. PHD2 crystallizes as a homotrimer and contains a double-stranded beta-helix core fold common to the Fe(II) and 2-oxoglutarate-dependant dioxygenase family, the residues of which are well conserved in the three human PHD enzymes (PHD 1-3). The structure provides insights into the hypoxic response, helps to rationalize a clinically observed mutation leading to familial erythrocytosis, and will aid in the design of PHD selective inhibitors for the treatment of anemia and ischemic disease.

Selected figure(s)

Figure 1.
Fig. 1. The PHD reaction and an inhibitor. (a) PHD catalyzed prolyl-4-hydroxylation of HIF- ; one of the oxygens (red) from the dioxygen cosubstrate is incorporated into proline to form trans-4-hydroxyproline, and the other is incorporated into succinate. (b) The structure of compound A.

Figure 4.
Fig. 4. Surface representations of PHD2[cat] (a) and phytanoyl CoA hydroxylase (b) (21) comparing the entrances to the active site cavities. The surfaces are colored by depth with a gradient from blue (outermost) to orange (innermost).

Figures were selected by an automated process.