2g19
Cellular Oxygen Sensing: Crystal Structure of Hypoxia-Inducible Factor Prolyl Hydroxylase (PHD2)
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OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Erythrocytosis, familial, 3 OMIM:[606425]
About this StructureAbout this Structure
2G19 is a Single protein structure of sequence from Homo sapiens with FE2 and 4HG as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2)., McDonough MA, Li V, Flashman E, Chowdhury R, Mohr C, Lienard BM, Zondlo J, Oldham NJ, Clifton IJ, Lewis J, McNeill LA, Kurzeja RJ, Hewitson KS, Yang E, Jordan S, Syed RS, Schofield CJ, Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9814-9. Epub 2006 Jun 16. PMID:16782814
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