3hqu

PHD2:Fe:UN9:partial HIF1-alpha substrate complex

spinqualitylabelsall models 3hqu, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3hqu is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: FE2, UN9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease EGLN1_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. Function EGLN1_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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed The oxygen-dependent hydroxylation of proline residues in the alpha subunit of hypoxia-inducible transcription factor (HIFalpha) is central to the hypoxic response in animals. Prolyl hydroxylation of HIFalpha increases its binding to the von Hippel-Lindau protein (pVHL), so signaling for degradation via the ubiquitin-proteasome system. The HIF prolyl hydroxylases (PHDs, prolyl hydroxylase domain enzymes) are related to the collagen prolyl hydroxylases, but form unusually stable complexes with their Fe(II) cofactor and 2-oxoglutarate cosubstrate. We report crystal structures of the catalytic domain of PHD2, the most important of the human PHDs, in complex with the C-terminal oxygen-dependent degradation domain of HIF-1alpha. Together with biochemical analyses, the results reveal that PHD catalysis involves a mobile region that isolates the hydroxylation site and stabilizes the PHD2.Fe(II).2OG complex. The results will be of use in the design of PHD inhibitors aimed at treating anemia and ischemic disease. Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases.,Chowdhury R, McDonough MA, Mecinovic J, Loenarz C, Flashman E, Hewitson KS, Domene C, Schofield CJ Structure. 2009 Jul 15;17(7):981-9. PMID:19604478 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Factor inhibiting HIF Polyl hydroxylase domain 3D structures

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