5OPC

Factor Inhibiting HIF (FIH) in complex with zinc and Vadadustat

5OPC の概要

• エントリーDOI: 10.2210/pdb5opc/pdb
• 分子名称: Hypoxia-inducible factor 1-alpha inhibitor, SULFATE ION, ZINC ION, ... (6 entities in total)
• 機能のキーワード: on-heme, dioxygenase, oxygenase, dna-binding, metal-binding, transcription, helix-loop-helix-beta, dsbh, facial triad, asparaginyl/aspartyl hydroxylase, epigenetic regulation, signaling, ard, beta-hydroxylation, activator-inhibitor, oxidoreductase-peptide complex, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: Q9NWT6
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41728.25

構造登録者

Leissing, T.M.,Schofield, C.J.,Clifton, I.J.,Lu, X.,Zhang, D. (登録日: 2017-08-09, 公開日: 2017-10-18, 最終更新日: 2024-01-17)

主引用文献

Yeh, T.L.,Leissing, T.M.,Abboud, M.I.,Thinnes, C.C.,Atasoylu, O.,Holt-Martyn, J.P.,Zhang, D.,Tumber, A.,Lippl, K.,Lohans, C.T.,Leung, I.K.H.,Morcrette, H.,Clifton, I.J.,Claridge, T.D.W.,Kawamura, A.,Flashman, E.,Lu, X.,Ratcliffe, P.J.,Chowdhury, R.,Pugh, C.W.,Schofield, C.J.
Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.
Chem Sci, 8:7651-7668, 2017

PubMed Abstract: Inhibition 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 representatives of other human 2OG oxygenase subfamilies. The 'clinical' PHD inhibitors are potent inhibitors of PHD catalyzed hydroxylation of the HIF-α 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.

PubMed: 29435217
DOI: 10.1039/c7sc02103h

実験手法

X-RAY DIFFRACTION (2.3 Å)