6st3

HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with 4-hydroxy-N-(4-phenoxybenzyl)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxamide

spinqualitylabelsall models 6st3, resolution 2.43Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6st3 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 2.426Å Ligands: FMT, LUW, MN 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. Publication Abstract from PubMed The 2-oxoglutarate-dependent hypoxia inducible factor prolyl hydroxylases (PHDs) are targets for treatment of a variety of disease states including anemia. One PHD inhibitor is approved for use in the treatment of renal anemia and others are in late stage clinical trials. However, the number of reported templates for PHD inhibition is limited. We report structure-activity relationship and crystallographic studies on a promising class of 4-hydroxypyrimidine-containing PHD inhibitors. Structure-Activity Relationship and Crystallographic Studies On 4-Hydroxypyrimidine HIF Prolyl Hydroxylase Domain Inhibitors.,Holt-Martyn J, Chowdhury R, Tumber A, Yeh TL, Abboud MI, Lippl K, Lohans C, Langley G, McDonough M, Pugh C, Ratcliffe P, Schofield C ChemMedChem. 2019 Nov 21. doi: 10.1002/cmdc.201900557. PMID:31751494 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Polyl hydroxylase domain 3D structures

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