Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2009-7-16
pubmed:databankReference
pubmed:abstractText
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:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1878-4186
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
17
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
981-9
pubmed:meshHeading
pubmed-meshheading:19604478-Anoxia, pubmed-meshheading:19604478-Binding Sites, pubmed-meshheading:19604478-Catalysis, pubmed-meshheading:19604478-Catalytic Domain, pubmed-meshheading:19604478-Crystallography, X-Ray, pubmed-meshheading:19604478-Humans, pubmed-meshheading:19604478-Hydroxylation, pubmed-meshheading:19604478-Hydroxyproline, pubmed-meshheading:19604478-Hypoxia-Inducible Factor 1, pubmed-meshheading:19604478-Ketoglutaric Acids, pubmed-meshheading:19604478-Models, Molecular, pubmed-meshheading:19604478-Oxygen, pubmed-meshheading:19604478-Procollagen-Proline Dioxygenase, pubmed-meshheading:19604478-Proline, pubmed-meshheading:19604478-Proteasome Endopeptidase Complex, pubmed-meshheading:19604478-Protein Binding, pubmed-meshheading:19604478-Protein Conformation, pubmed-meshheading:19604478-Protein Structure, Secondary, pubmed-meshheading:19604478-Protein Structure, Tertiary, pubmed-meshheading:19604478-Signal Transduction, pubmed-meshheading:19604478-Ubiquitin-Protein Ligases, pubmed-meshheading:19604478-Von Hippel-Lindau Tumor Suppressor Protein
pubmed:year
2009
pubmed:articleTitle
Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases.
pubmed:affiliation
Department of Chemistry and Oxford Centre for Integrative Systems Biology, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't