5LBE

HIF prolyl hydroxylase 2 (PHD2/EGLN1) G294E variant in complex with Mn(II) and N-[(1-chloro-4-hydroxyisoquinolin-3-yl)carbonyl]glycine (IOX3/FG2216)

Summary for 5LBE

• Entry DOI: 10.2210/pdb5lbe/pdb
• Related: 3HQR 4BQX 5L9B 5L9R 5L9V 5LA9 5LAS 5LAT 5LB6 5LBB 5LBC
• Descriptor: Egl nine homolog 1, MANGANESE (II) ION, N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)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: 28565.62

Authors

Chowdhury, R.,Schofield, C.J. (deposition date: 2016-06-15, release date: 2016-08-31, Last modification date: 2024-10-16)

Primary citation

Chowdhury, R.,Leung, I.K.,Tian, Y.M.,Abboud, M.I.,Ge, W.,Domene, C.,Cantrelle, F.X.,Landrieu, I.,Hardy, A.P.,Pugh, C.W.,Ratcliffe, P.J.,Claridge, T.D.,Schofield, C.J.
Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases.
Nat Commun, 7:12673-12673, 2016

PubMed Abstract: The response to hypoxia in animals involves the expression of multiple genes regulated by the αβ-hypoxia-inducible transcription factors (HIFs). The hypoxia-sensing mechanism involves oxygen limited hydroxylation of prolyl residues in the N- and C-terminal oxygen-dependent degradation domains (NODD and CODD) of HIFα isoforms, as catalysed by prolyl hydroxylases (PHD 1-3). Prolyl hydroxylation promotes binding of HIFα to the von Hippel-Lindau protein (VHL)-elongin B/C complex, thus signalling for proteosomal degradation of HIFα. We reveal that certain PHD2 variants linked to familial erythrocytosis and cancer are highly selective for CODD or NODD. Crystalline and solution state studies coupled to kinetic and cellular analyses reveal how wild-type and variant PHDs achieve ODD selectivity via different dynamic interactions involving loop and C-terminal regions. The results inform on how HIF target gene selectivity is achieved and will be of use in developing selective PHD inhibitors.

PubMed: 27561929
DOI: 10.1038/ncomms12673

Experimental method

X-RAY DIFFRACTION (1.749 Å)