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PDBsum entry 4zp4
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Protein transport/transcription
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PDB id
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4zp4
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References listed in PDB file
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Key reference
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Title
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Structural integration in hypoxia-Inducible factors.
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Authors
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D.Wu,
N.Potluri,
J.Lu,
Y.Kim,
F.Rastinejad.
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Ref.
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Nature, 2015,
524,
303-308.
[DOI no: ]
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PubMed id
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Abstract
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The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low
oxygen stress by regulating transcriptional programs in erythropoiesis,
angiogenesis and metabolism. These programs promote the growth and progression
of many tumours, making HIFs attractive anticancer targets. Transcriptionally
active HIFs consist of HIF-α and ARNT (also called HIF-1β) subunits. Here we
describe crystal structures for each of mouse HIF-2α-ARNT and HIF-1α-ARNT
heterodimers in states that include bound small molecules and their hypoxia
response element. A highly integrated quaternary architecture is shared by
HIF-2α-ARNT and HIF-1α-ARNT, wherein ARNT spirals around the outside of each
HIF-α subunit. Five distinct pockets are observed that permit small-molecule
binding, including PAS domain encapsulated sites and an interfacial cavity
formed through subunit heterodimerization. The DNA-reading head rotates, extends
and cooperates with a distal PAS domain to bind hypoxia response elements.
HIF-α mutations linked to human cancers map to sensitive sites that establish
DNA binding and the stability of PAS domains and pockets.
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