Cellular Oxygen Sensing: Crystal Structure of Hypoxia-Inducible Factor Prolyl Hydroxylase (PHD2)

Journal Article · Sun Jan 01 04:00:00 EST 2006 · Proc Natl Acad Sci USA

DOI:https://doi.org/10.1073/pnas.0601283103· OSTI ID:914139

McDonough, M; Li, V; Flashman, E; Chowdhury, R; Mohr, C; Lienard, B; Zondlo, J; Oldham, N; Clifton, I

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 Angstroms 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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 914139
• Report Number(s): BNL--78707-2007-JA
• Journal Information: Proc Natl Acad Sci USA, Journal Name: Proc Natl Acad Sci USA Journal Issue: 26 Vol. 103; ISSN 0027-8424; ISSN PNASA6
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
ANEMIAS
CRYSTAL STRUCTURE
DESIGN
ENZYMES
GENES
HYDROXYLASES
HYDROXYLATION
MUTATIONS
OXIDATION
OXYGEN
REGULATIONS
RESIDUES
RESOLUTION
TRANSCRIPTION FACTORS
national synchrotron light source