2y34 | pdb_00002y34
S-nitrosylated PHD2 (NO exposed) in complex with Fe(II) and UN9
Structural highlights
DiseaseEGLN1_HUMAN Defects in EGLN1 are the cause of familial erythrocytosis type 3 (ECYT3) [MIM:609820. ECYT3 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels.[1] [2] FunctionEGLN1_HUMAN Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality.[3] [4] [5] [6] [7] Publication Abstract from PubMedThe hypoxic response in animals is mediated via the transcription factor hypoxia-inducible factor (HIF). An oxygen-sensing component of the HIF system is provided by Fe(II) and 2-oxoglutarate-dependent oxygenases that catalyse the posttranslational hydroxylation of the HIF-alpha subunit. It is proposed that the activity of the HIF hydroxylases can be regulated by their reaction with nitric oxide. We describe biochemical and biophysical studies on the reaction of prolyl hydroxylase domain-containing enzyme (PHD) isoform 2 (EGLN1) with nitric oxide and a nitric oxide transfer reagent. The combined results reveal the potential for the catalytic domain of PHD2 to react with nitric oxide both at its Fe(II) and at cysteine residues. Although the biological significance is unclear, the results suggest that the reaction of PHD2 with nitric oxide has the potential to be complex and are consistent with proposals based on cellular studies that nitric oxide may regulate the hypoxic response by direct reaction with the HIF hydroxylases. Studies on the Reaction of Nitric Oxide with the Hypoxia-Inducible Factor Prolyl Hydroxylase Domain 2 (EGLN1).,Chowdhury R, Flashman E, Mecinovic J, Kramer HB, Kessler BM, Frapart YM, Boucher JL, Clifton IJ, McDonough MA, Schofield CJ J Mol Biol. 2011 Jul 8;410(2):268-79. Epub 2011 May 13. PMID:21601578[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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