5OX5

HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with CCT6, a GSK1278863-related compound

Summary for 5OX5

• Entry DOI: 10.2210/pdb5ox5/pdb
• Descriptor: Egl nine homolog 1, MANGANESE (II) ION, (6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl)glycine, ... (5 entities in total)
• Functional Keywords: oxidoreductase, non-heme dioxygenase, iron, 2-oxoglutarate, hypoxia-inducible factor, hif, hif prolyl hydroxylase domain 2, phd2, egln1, oxygenase, hypoxia, dna-binding, metal-binding, transcription, helix-loop-helix-beta, dsbh, facial triad, cytoplasm, transcription/epigenetic regulation, signaling, development, cell structure, beta-hydroxylation, transcription activator/inhibitor, ubl conjugation, polymorphism, vitamin c, zinc-finger, familial erythrocytosis, breast cancer, transcription complex
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q9GZT9
• Total number of polymer chains: 1
• Total formula weight: 28470.10

Authors

Chowdhury, R.,Thinnes, C.C.,Schofield, C.J. (deposition date: 2017-09-06, release date: 2017-10-18, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.251 Å)