5op6
From Proteopedia
Factor Inhibiting HIF (FIH) in complex with zinc and GSK128863
Structural highlights
Function[HIF1N_HUMAN] Hydroxylates HIF-1 alpha at 'Asp-803' in the C-terminal transactivation domain (CAD). Functions as an oxygen sensor and, under normoxic conditions, the hydroxylation prevents interaction of HIF-1 with transcriptional coactivators including Cbp/p300-interacting transactivator. Involved in transcriptional repression through interaction with HIF1A, VHL and histone deacetylases. Hydroxylates specific Asn residues within ankyrin repeat domains (ARD) of NFKB1, NFKBIA, NOTCH1, ASB4, PPP1R12A and several other ARD-containing proteins. Also hydroxylates Asp and His residues within ARDs of ANK1 and TNKS2, respectively. Negatively regulates NOTCH1 activity, accelerating myogenic differentiation. Positively regulates ASB4 activity, promoting vascular differentiation.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedInhibition of the human 2-oxoglutarate (2OG) dependent hypoxia inducible factor (HIF) prolyl hydroxylases (human PHD1-3) causes upregulation of HIF, thus promoting erythropoiesis and is therefore of therapeutic interest. We describe cellular, biophysical, and biochemical studies comparing four PHD inhibitors currently in clinical trials for anaemia treatment, that describe their mechanisms of action, potency against isolated enzymes and in cells, and selectivities versus representatives of other human 2OG oxygenase subfamilies. The 'clinical' PHD inhibitors are potent inhibitors of PHD catalyzed hydroxylation of the HIF-alpha oxygen dependent degradation domains (ODDs), and selective against most, but not all, representatives of other human 2OG dependent dioxygenase subfamilies. Crystallographic and NMR studies provide insights into the different active site binding modes of the inhibitors. Cell-based results reveal the inhibitors have similar effects on the upregulation of HIF target genes, but differ in the kinetics of their effects and in extent of inhibition of hydroxylation of the N- and C-terminal ODDs; the latter differences correlate with the biophysical observations. Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.,Yeh TL, Leissing TM, Abboud MI, Thinnes CC, Atasoylu O, Holt-Martyn JP, Zhang D, Tumber A, Lippl K, Lohans CT, Leung IKH, Morcrette H, Clifton IJ, Claridge TDW, Kawamura A, Flashman E, Lu X, Ratcliffe PJ, Chowdhury R, Pugh CW, Schofield CJ Chem Sci. 2017 Nov 1;8(11):7651-7668. doi: 10.1039/c7sc02103h. Epub 2017 Sep 11. PMID:29435217[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Clifton, I J | Leissing, T M | Lu, X | Schofield, C J | Thinnes, C C | Activator-inhibitor | Ard | Asparaginyl/aspartyl hydroxylase | Beta-hydroxylation | Dioxygenase | Dna-binding | Dsbh | Epigenetic regulation | Facial triad | Helix-loop-helix-beta | Metal-binding | On-heme | Oxidoreductase | Oxidoreductase-peptide complex | Oxygenase | Signaling | Transcription
