Publication Date:
2015-08-08
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-1beta) subunits. Here we describe crystal structures for each of mouse HIF-2alpha-ARNT and HIF-1alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2alpha-ARNT and HIF-1alpha-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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Dalei -- Potluri, Nalini -- Lu, Jingping -- Kim, Youngchang -- Rastinejad, Fraydoon -- England -- Nature. 2015 Aug 20;524(7565):303-8. doi: 10.1038/nature14883. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Metabolic Disease Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, USA. ; Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245371" target="_blank"〉PubMed〈/a〉
Keywords:
ARNTL Transcription Factors/chemistry/metabolism
;
Animals
;
Aryl Hydrocarbon Receptor Nuclear Translocator/*chemistry/metabolism
;
Basic Helix-Loop-Helix Transcription Factors/*chemistry/metabolism
;
Binding Sites
;
CLOCK Proteins/chemistry/metabolism
;
Cell Hypoxia/genetics
;
Crystallography, X-Ray
;
DNA/chemistry/metabolism
;
Hypoxia-Inducible Factor 1, alpha Subunit/*chemistry/metabolism
;
Mice
;
Models, Molecular
;
Mutation/genetics
;
Neoplasms/genetics
;
Phosphorylation
;
Protein Multimerization
;
Protein Structure, Quaternary
;
Protein Structure, Tertiary
;
Response Elements/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
