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Structural integration in hypoxia-inducible factors.(Report)

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. Transcription... Full description

Journal Title: Nature August 20, 2015, Vol.524(7565), p.303(17)
Main Author: Wu, Dalei
Other Authors: Potluri, Nalini , Lu, Jingping , Kim, Youngchang , Rastinejad, Fraydoon
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0028-0836 ; DOI: 10.1038/nature14883
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recordid: gale_ofg426445082
title: Structural integration in hypoxia-inducible factors.(Report)
format: Article
creator:
  • Wu, Dalei
  • Potluri, Nalini
  • Lu, Jingping
  • Kim, Youngchang
  • Rastinejad, Fraydoon
subjects:
  • Anoxia – Health Aspects
  • DNA Binding Proteins – Analysis
ispartof: Nature, August 20, 2015, Vol.524(7565), p.303(17)
description: 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-alpha and ARNT (also called HIF-1 beta) subunits. Here we describe crystal structures for each of mouse HIF-2 alpha-ARNT and HIF-1 alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2 alpha-ARNT and HIF-1 alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha 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-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.
language: eng
source:
identifier: ISSN: 0028-0836 ; DOI: 10.1038/nature14883
fulltext: fulltext
issn:
  • 0028-0836
  • 00280836
url: Link


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titleStructural integration in hypoxia-inducible factors.(Report)
creatorWu, Dalei ; Potluri, Nalini ; Lu, Jingping ; Kim, Youngchang ; Rastinejad, Fraydoon
ispartofNature, August 20, 2015, Vol.524(7565), p.303(17)
identifierISSN: 0028-0836 ; DOI: 10.1038/nature14883
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descriptionThe 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-alpha and ARNT (also called HIF-1 beta) subunits. Here we describe crystal structures for each of mouse HIF-2 alpha-ARNT and HIF-1 alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2 alpha-ARNT and HIF-1 alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha 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-alpha 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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