3HQU

PHD2:Fe:UN9:partial HIF1-alpha substrate complex

Summary for 3HQU

• Entry DOI: 10.2210/pdb3hqu/pdb
• Related: 2G1M 3HQR
• Descriptor: Egl nine homolog 1, Hypoxia-inducible factor 1 alpha, FE (II) ION, ... (5 entities in total)
• Functional Keywords: double stranded beta-helix, alternative splicing, congenital erythrocytosis, dioxygenase, disease mutation, iron, metal-binding, oxidoreductase, vitamin c, zinc, zinc-finger, activator, cytoplasm, dna-binding, hydroxylation, isopeptide bond, nucleus, phosphoprotein, polymorphism, s-nitrosylation, transcription, transcription regulation, ubl conjugation, oxidoreductase-transcription complex, oxidoreductase/transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm : Q9GZT9 Q16665
• Total number of polymer chains: 2
• Total formula weight: 29888.11

Authors

Chowdhury, R.,McDonough, M.A.,Schofield, C.J. (deposition date: 2009-06-08, release date: 2009-07-28, Last modification date: 2023-11-01)

Primary citation

Chowdhury, R.,McDonough, M.A.,Mecinovic, J.,Loenarz, C.,Flashman, E.,Hewitson, K.S.,Domene, C.,Schofield, C.J.
Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases
Structure, 17:981-989, 2009

PubMed Abstract: The oxygen-dependent hydroxylation of proline residues in the alpha subunit of hypoxia-inducible transcription factor (HIFalpha) is central to the hypoxic response in animals. Prolyl hydroxylation of HIFalpha increases its binding to the von Hippel-Lindau protein (pVHL), so signaling for degradation via the ubiquitin-proteasome system. The HIF prolyl hydroxylases (PHDs, prolyl hydroxylase domain enzymes) are related to the collagen prolyl hydroxylases, but form unusually stable complexes with their Fe(II) cofactor and 2-oxoglutarate cosubstrate. We report crystal structures of the catalytic domain of PHD2, the most important of the human PHDs, in complex with the C-terminal oxygen-dependent degradation domain of HIF-1alpha. Together with biochemical analyses, the results reveal that PHD catalysis involves a mobile region that isolates the hydroxylation site and stabilizes the PHD2.Fe(II).2OG complex. The results will be of use in the design of PHD inhibitors aimed at treating anemia and ischemic disease.

PubMed: 19604478
DOI: 10.1016/j.str.2009.06.002

Experimental method

X-RAY DIFFRACTION (2.3 Å)