6zbo

HIF Prolyl Hydroxylase 2 (PHD2/EGLN1) in Complex with 1-(6-morpholinopyrimidin-4-yl)-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-ol (Molidustat)

spinqualitylabelsall models 6zbo, resolution 1.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6zbo is a 6 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 1.79Å Ligands: CL, MN, QEQ 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 Human prolyl-hydroxylases (PHDs) are hypoxia-sensing 2-oxoglutarate (2OG) oxygenases, catalysis by which suppresses the transcription of hypoxia-inducible factor target genes. PHD inhibition enables the treatment of anaemia/ischaemia-related disease. The PHD inhibitor Molidustat is approved for the treatment of renal anaemia; it differs from other approved/late-stage PHD inhibitors in lacking a glycinamide side chain. The first reported crystal structures of Molidustat and IOX4 (a brain-penetrating derivative) complexed with PHD2 reveal how their contiguous triazole, pyrazolone and pyrimidine/pyridine rings bind at the active site. The inhibitors bind to the active-site metal in a bidentate manner through their pyrazolone and pyrimidine nitrogens, with the triazole pi-pi-stacking with Tyr303 in the 2OG binding pocket. Comparison of the new structures with other PHD inhibitor complexes reveals differences in the conformations of Tyr303, Tyr310, and a mobile loop linking beta2-beta3, which are involved in dynamic substrate binding/product release. Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat.,Figg WD Jr, McDonough MA, Chowdhury R, Nakashima Y, Zhang Z, Holt-Martyn JP, Krajnc A, Schofield CJ ChemMedChem. 2021 Jul 6;16(13):2082-2088. doi: 10.1002/cmdc.202100133. Epub 2021 , Apr 9. PMID:33792169 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Polyl hydroxylase domain 3D structures

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