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- EMDB-70443: Dimer of HIF-1a-ARNT Heterodimers Complexed on 52-bp HRE/HAS -

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Basic information

Entry
Database: EMDB / ID: EMD-70443
TitleDimer of HIF-1a-ARNT Heterodimers Complexed on 52-bp HRE/HAS
Map data
Sample
  • Complex: Dimer of two HIF-1a-ARNT heterodimers complexed on 52-bp HRE
    • DNA: 52-nt Hypoxia Response Element (Forward)
    • DNA: 52-nt Hypoxia Response Element (Reverse)
    • Protein or peptide: Hypoxia-inducible factor 1-alpha
    • Protein or peptide: Aryl hydrocarbon receptor nuclear translocator
KeywordsComplex / Hypoxia / Transcription / Cancer / Dimer / Higher-ordered / DNA BINDING PROTEIN
Function / homology
Function and homology information


epithelial cell differentiation involved in mammary gland alveolus development / neural fold elevation formation / iris morphogenesis / intestinal epithelial cell maturation / : / hypoxia-inducible factor-1alpha signaling pathway / positive regulation of chemokine-mediated signaling pathway / elastin metabolic process / regulation of transforming growth factor beta2 production / glandular epithelial cell maturation ...epithelial cell differentiation involved in mammary gland alveolus development / neural fold elevation formation / iris morphogenesis / intestinal epithelial cell maturation / : / hypoxia-inducible factor-1alpha signaling pathway / positive regulation of chemokine-mediated signaling pathway / elastin metabolic process / regulation of transforming growth factor beta2 production / glandular epithelial cell maturation / nuclear aryl hydrocarbon receptor complex / hemoglobin biosynthetic process / negative regulation of mesenchymal cell apoptotic process / cardiac ventricle morphogenesis / connective tissue replacement involved in inflammatory response wound healing / positive regulation of hormone biosynthetic process / negative regulation of growth / Aryl hydrocarbon receptor signalling / aryl hydrocarbon receptor complex / Cellular response to hypoxia / retina vasculature development in camera-type eye / mesenchymal cell apoptotic process / PTK6 Expression / negative regulation of bone mineralization / intracellular oxygen homeostasis / regulation of protein neddylation / B-1 B cell homeostasis / collagen metabolic process / vascular endothelial growth factor production / positive regulation of protein sumoylation / dopaminergic neuron differentiation / Xenobiotics / transcription regulator activator activity / STAT3 nuclear events downstream of ALK signaling / negative regulation of thymocyte apoptotic process / lactate metabolic process / Phase I - Functionalization of compounds / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / positive regulation of cytokine production involved in inflammatory response / negative regulation of TOR signaling / insulin secretion involved in cellular response to glucose stimulus / positive regulation of vascular endothelial growth factor receptor signaling pathway / response to iron ion / Regulation of gene expression by Hypoxia-inducible Factor / neural crest cell migration / embryonic hemopoiesis / regulation of glycolytic process / DNA-binding transcription repressor activity / motile cilium / PTK6 promotes HIF1A stabilization / DNA-binding transcription activator activity / muscle cell cellular homeostasis / positive regulation of neuroblast proliferation / digestive tract morphogenesis / axonal transport of mitochondrion / response to muscle activity / heart looping / bone mineralization / intracellular glucose homeostasis / E-box binding / aryl hydrocarbon receptor binding / outflow tract morphogenesis / TOR signaling / positive regulation of vascular endothelial growth factor production / positive regulation of epithelial cell migration / positive regulation of macroautophagy / epithelial to mesenchymal transition / neuroblast proliferation / cellular response to interleukin-1 / positive regulation of blood vessel endothelial cell migration / chondrocyte differentiation / Endogenous sterols / embryonic placenta development / positive regulation of insulin secretion involved in cellular response to glucose stimulus / cis-regulatory region sequence-specific DNA binding / positive regulation of chemokine production / lactation / positive regulation of endothelial cell proliferation / NPAS4 regulates expression of target genes / axon cytoplasm / negative regulation of miRNA transcription / positive regulation of erythrocyte differentiation / positive regulation of glycolytic process / response to reactive oxygen species / nuclear receptor binding / transcription corepressor binding / RNA polymerase II transcription regulatory region sequence-specific DNA binding / Hsp90 protein binding / euchromatin / PPARA activates gene expression / cerebral cortex development / visual learning / cellular response to virus / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / positive regulation of miRNA transcription / NOTCH1 Intracellular Domain Regulates Transcription / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / histone deacetylase binding / transcription coactivator binding
Similarity search - Function
Hypoxia-inducible factor-1 alpha / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / : / Hypoxia-inducible factor 1-alpha bHLH domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / Nuclear translocator / PAS fold-3 / PAS fold ...Hypoxia-inducible factor-1 alpha / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / : / Hypoxia-inducible factor 1-alpha bHLH domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / Nuclear translocator / PAS fold-3 / PAS fold / Helix-loop-helix DNA-binding domain / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain) / PAS domain / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily / PAS fold / PAS fold / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily
Similarity search - Domain/homology
Aryl hydrocarbon receptor nuclear translocator / Hypoxia-inducible factor 1-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsClosson JD / Tiyani TT / Xu X / Gardner KH
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)U54 CA132378 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)U54 C137788 United States
The G. Harold and Leila Y. Mathers FoundationMF-2112-02288 United States
CitationJournal: bioRxiv / Year: 2025
Title: CONTEXT-DEPENDENT VARIABILITY OF HIF HETERODIMERS INFLUENCES INTERACTIONS WITH MACROMOLECULAR AND SMALL MOLECULE PARTNERS.
Authors: Joseph D Closson / Xingjian Xu / Meiling Zhang / Tarsisius T Tiyani / Leandro Pimentel Marcelino / Eta A Isiorho / Jason S Nagati / Joseph A Garcia / Kevin H Gardner /
Abstract: Hypoxia inducible factors (HIFs) are transcription factors that coordinate cellular responses to low oxygen levels, functioning as an α/β heterodimer which binds a short hypoxia response element ...Hypoxia inducible factors (HIFs) are transcription factors that coordinate cellular responses to low oxygen levels, functioning as an α/β heterodimer which binds a short hypoxia response element (HRE) DNA sequence. Prior studies suggest HIF/HRE complexes are augmented by the binding of additional factors nearby, but those interactions are not well understood. Here, we integrated structural and biochemical approaches to investigate several functionally relevant HIF assemblies with other protein, small molecule, and DNA partners. First, we used cryo-electron microscopy (cryo-EM) to establish HIF-1 and HIF-2 form novel "dimer-of-heterodimers" (DoHD) complexes on extended human EPO enhancer sequences, showing that one heterodimer bound at a canonical HRE site with the second binding in an inverted fashion to an HRE-adjacent sequence (HAS) 8 bp away. Consistent with ARNT PAS-B domains predominating interactions within a DoHD, we found HIF-1 and HIF-2 assemble mixed DoHD complexes on the same DNA. Second, we saw substantial variability among ligands for isolated ARNT or HIF-2α PAS-B domains to bind larger complexes: for example, the ARNT PAS-B binding KG-548 and KG-279 ligands both bound the simpler HIF-2 heterodimer but exhibited differential binding to a HIF-2 DoHD. Finally, we combined cryo-EM and hydrogen-deuterium exchange by mass spectrometry (HDX-MS) to show how HIF-1 and HIF-2 heterodimers engage the transforming acidic coiled-coil containing protein 3 (TACC3) coactivator via both ARNT and HIF-α subunits, though this was unseen in the larger DoHD. Our findings highlight the importance of both molecular context and dynamics in biomolecular complex formation, adding to the complexities of potential regulation.
History
DepositionApr 30, 2025-
Header (metadata) releaseJun 11, 2025-
Map releaseJun 11, 2025-
UpdateAug 27, 2025-
Current statusAug 27, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70443.png

Downloads & links

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Map

FileDownload / File: emd_70443.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 400 pix.
= 332. Å		0.83 Å/pix.
x 400 pix.
= 332. Å		0.83 Å/pix.
x 400 pix.
= 332. Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 7.77
Minimum - Maximum-54.40746 - 70.050899999999999
Average (Standard dev.)-0.000000000003842 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 332.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_70443_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_70443_half_map_2.map
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Sample components

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Entire : Dimer of two HIF-1a-ARNT heterodimers complexed on 52-bp HRE

EntireName: Dimer of two HIF-1a-ARNT heterodimers complexed on 52-bp HRE
Components
  • Complex: Dimer of two HIF-1a-ARNT heterodimers complexed on 52-bp HRE
    • DNA: 52-nt Hypoxia Response Element (Forward)
    • DNA: 52-nt Hypoxia Response Element (Reverse)
    • Protein or peptide: Hypoxia-inducible factor 1-alpha
    • Protein or peptide: Aryl hydrocarbon receptor nuclear translocator

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Supramolecule #1: Dimer of two HIF-1a-ARNT heterodimers complexed on 52-bp HRE

SupramoleculeName: Dimer of two HIF-1a-ARNT heterodimers complexed on 52-bp HRE
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #3-#4, #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 205 KDa

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Macromolecule #1: Hypoxia-inducible factor 1-alpha

MacromoleculeName: Hypoxia-inducible factor 1-alpha / type: protein_or_peptide / ID: 1
Details: N-terminal 14 residues (MGSSHHHHHHSQDP) are vector-derived
Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.962926 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGSSHHHHHH SQDPGAGGAN DKKKISSERR KEKSRDAARS RRSKESEVFY ELAHQLPLPH NVSSHLDKAS VMRLTISYLR VRKLLDAGD LDIEDDMKAQ MNCFYLKALD GFVMVLTDDG DMIYISDNVN KYMGLTQFEL TGHSVFDFTH PCDHEEMREM L THRNGLVK ...String:
MGSSHHHHHH SQDPGAGGAN DKKKISSERR KEKSRDAARS RRSKESEVFY ELAHQLPLPH NVSSHLDKAS VMRLTISYLR VRKLLDAGD LDIEDDMKAQ MNCFYLKALD GFVMVLTDDG DMIYISDNVN KYMGLTQFEL TGHSVFDFTH PCDHEEMREM L THRNGLVK KGKEQNTQRS FFLRMKCTLT SRGRTMNIKS ATWKVLHCTG HIHVYDTNSN QPQCGYKKPP MTCLVLICEP IP HPSNIEI PLDSKTFLSR HSLDMKFSYC DERITELMGY EPEELLGRSI YEYYHALDSD HLTKTHHDMF TKGQVTTGQY RML AKRGGY VWVETQATVI YNTKNSQPQC IVCVNYVVSG IIQHDLIFSL QQTECVL

UniProtKB: Hypoxia-inducible factor 1-alpha

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Macromolecule #2: Aryl hydrocarbon receptor nuclear translocator

MacromoleculeName: Aryl hydrocarbon receptor nuclear translocator / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.06182 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MRENHSEIER RRRNKMTAYI TELSDMVPTC SALARKPDKL TILRMAVSHM KSLRGTGNTS TDGSYKPSFL TDQELKHLIL EAADGFLFI VSCETGRVVY VSDSVTPVLN QPQSEWFGST LYDQVHPDDV DKLREQLSTS ENALTGRILD LKTGTVKKEG Q QSSMRMCM ...String:
MRENHSEIER RRRNKMTAYI TELSDMVPTC SALARKPDKL TILRMAVSHM KSLRGTGNTS TDGSYKPSFL TDQELKHLIL EAADGFLFI VSCETGRVVY VSDSVTPVLN QPQSEWFGST LYDQVHPDDV DKLREQLSTS ENALTGRILD LKTGTVKKEG Q QSSMRMCM GSRRSFICRM RCGSSSVDPV SVNRLSFVRN RCRNGLGSVK DGEPHFVVVH CTGYIKAWPP AGVSLPDDDP EA GQGSKFC LVAIGRLQVT SSPNCTDMSN VCQPTEFISR HNIEGIFTFV DHRCVATVGY QPQELLGKNI VEFCHPEDQQ LLR DSFQQV VKLKGQVLSV MFRFRSKNQE WLWMRTSSFT FQNPYSDEIE YIICTNTNVK NSSQE

UniProtKB: Aryl hydrocarbon receptor nuclear translocator

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Macromolecule #3: 52-nt Hypoxia Response Element (Forward)

MacromoleculeName: 52-nt Hypoxia Response Element (Forward) / type: dna / ID: 3 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.821092 KDa
SequenceString: (DT)(DG)(DG)(DG)(DC)(DC)(DC)(DT)(DA)(DC) (DG)(DT)(DG)(DC)(DT)(DG)(DT)(DC)(DT)(DC) (DA)(DC)(DA)(DC)(DA)(DG)(DC)(DC)(DT) (DG)(DT)(DC)(DT)(DG)(DA)(DC)(DC)(DT)(DC) (DT) (DC)(DG)(DA)(DC)(DC)(DC) ...String:
(DT)(DG)(DG)(DG)(DC)(DC)(DC)(DT)(DA)(DC) (DG)(DT)(DG)(DC)(DT)(DG)(DT)(DC)(DT)(DC) (DA)(DC)(DA)(DC)(DA)(DG)(DC)(DC)(DT) (DG)(DT)(DC)(DT)(DG)(DA)(DC)(DC)(DT)(DC) (DT) (DC)(DG)(DA)(DC)(DC)(DC)(DT)(DA) (DC)(DC)(DG)(DG)

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Macromolecule #4: 52-nt Hypoxia Response Element (Reverse)

MacromoleculeName: 52-nt Hypoxia Response Element (Reverse) / type: dna / ID: 4 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.226375 KDa
SequenceString: (DC)(DC)(DG)(DG)(DT)(DA)(DG)(DG)(DG)(DT) (DC)(DG)(DA)(DG)(DA)(DG)(DG)(DT)(DC)(DA) (DG)(DA)(DC)(DA)(DG)(DG)(DC)(DT)(DG) (DT)(DG)(DT)(DG)(DA)(DG)(DA)(DC)(DA)(DG) (DC) (DA)(DC)(DG)(DT)(DA)(DG) ...String:
(DC)(DC)(DG)(DG)(DT)(DA)(DG)(DG)(DG)(DT) (DC)(DG)(DA)(DG)(DA)(DG)(DG)(DT)(DC)(DA) (DG)(DA)(DC)(DA)(DG)(DG)(DC)(DT)(DG) (DT)(DG)(DT)(DG)(DA)(DG)(DA)(DC)(DA)(DG) (DC) (DA)(DC)(DG)(DT)(DA)(DG)(DG)(DG) (DC)(DC)(DC)(DA)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.2 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
50.0 mMC8H18N2O4S2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid
150.0 mMNaClSodium Chloride
5.0 mMMgCl2Magnesium Chloride

Details: 50mM HEPES, 150mM NaCl, 5mM MgCl2
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK II

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 2 / Number real images: 4098 / Average electron dose: 58.19 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 4.0 µm / Nominal defocus min: 0.3 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 262568
CTF correctionSoftware - Name: Warp (ver. 1.0.9) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: AlphaFold2 model of human HIF-1
Final reconstructionNumber classes used: 1 / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.7.0) / Number images used: 71802
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final 3D classificationNumber classes: 1 / Software - Name: cryoSPARC (ver. 4.7.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
SoftwareName: UCSF ChimeraX (ver. 1.9)
Output model

PDB-9ofu:
Dimer of HIF-1a-ARNT Heterodimers Complexed on 52-bp HRE/HAS

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