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- EMDB-70418: Dimer of HIF-2a-ARNT Heterodimers Complexed on 51-bp HRE/HAS -

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Basic information

Entry
Database: EMDB / ID: EMD-70418
TitleDimer of HIF-2a-ARNT Heterodimers Complexed on 51-bp HRE/HAS
Map data
Sample
  • Complex: Dimer of two HIF-2a-ARNT heterodimers complexed on 51-bp HRE
    • DNA: 51-nt Hypoxia Response Element (Forward)
    • DNA: 51-nt Hypoxia Response Element (Reverse)
    • Protein or peptide: Endothelial PAS domain-containing protein 1
    • Protein or peptide: Aryl hydrocarbon receptor nuclear translocator
KeywordsComplex / Hypoxia / Transcription / Cancer / Dimer / Higher-ordered / DNA BINDING PROTEIN
Function / homology
Function and homology information


myoblast fate commitment / nuclear aryl hydrocarbon receptor complex / positive regulation of hormone biosynthetic process / Aryl hydrocarbon receptor signalling / aryl hydrocarbon receptor complex / Cellular response to hypoxia / Transcriptional regulation of pluripotent stem cells / regulation of protein neddylation / PTK6 Expression / positive regulation of protein sumoylation ...myoblast fate commitment / nuclear aryl hydrocarbon receptor complex / positive regulation of hormone biosynthetic process / Aryl hydrocarbon receptor signalling / aryl hydrocarbon receptor complex / Cellular response to hypoxia / Transcriptional regulation of pluripotent stem cells / regulation of protein neddylation / PTK6 Expression / positive regulation of protein sumoylation / norepinephrine metabolic process / Xenobiotics / surfactant homeostasis / Phase I - Functionalization of compounds / epithelial cell maturation / positive regulation of vascular endothelial growth factor receptor signaling pathway / Regulation of gene expression by Hypoxia-inducible Factor / aryl hydrocarbon receptor binding / positive regulation of vascular endothelial growth factor production / blood vessel remodeling / Endogenous sterols / embryonic placenta development / cis-regulatory region sequence-specific DNA binding / NPAS4 regulates expression of target genes / positive regulation of endothelial cell proliferation / visual perception / regulation of heart rate / Pexophagy / lung development / positive regulation of erythrocyte differentiation / positive regulation of glycolytic process / erythrocyte differentiation / RNA polymerase II transcription regulatory region sequence-specific DNA binding / mitochondrion organization / mRNA transcription by RNA polymerase II / PPARA activates gene expression / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / multicellular organismal-level iron ion homeostasis / negative regulation of inflammatory response / RNA polymerase II transcription regulator complex / transcription coactivator binding / nuclear receptor activity / sequence-specific double-stranded DNA binding / positive regulation of cold-induced thermogenesis / Neddylation / cellular response to oxidative stress / response to oxidative stress / DNA-binding transcription activator activity, RNA polymerase II-specific / angiogenesis / transcription regulator complex / cellular response to hypoxia / sequence-specific DNA binding / RNA polymerase II-specific DNA-binding transcription factor binding / DNA-binding transcription factor activity, RNA polymerase II-specific / cell differentiation / response to hypoxia / nuclear speck / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein heterodimerization activity / regulation of transcription by RNA polymerase II / chromatin / signal transduction / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
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 / Helix-loop-helix DNA-binding domain / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain) ...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 / 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 / Endothelial PAS domain-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsClosson JD / 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 29, 2025-
Header (metadata) releaseJun 11, 2025-
Map releaseJun 11, 2025-
UpdateJun 25, 2025-
Current statusJun 25, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70418.png

Downloads & links

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Map

FileDownload / File: emd_70418.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 400 pix.
= 337.6 Å		0.84 Å/pix.
x 400 pix.
= 337.6 Å		0.84 Å/pix.
x 400 pix.
= 337.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.844 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-1.4034662 - 2.1493194
Average (Standard dev.)0.0017521584 (±0.037548907)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 337.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_70418_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_70418_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Dimer of two HIF-2a-ARNT heterodimers complexed on 51-bp HRE

EntireName: Dimer of two HIF-2a-ARNT heterodimers complexed on 51-bp HRE
Components
  • Complex: Dimer of two HIF-2a-ARNT heterodimers complexed on 51-bp HRE
    • DNA: 51-nt Hypoxia Response Element (Forward)
    • DNA: 51-nt Hypoxia Response Element (Reverse)
    • Protein or peptide: Endothelial PAS domain-containing protein 1
    • Protein or peptide: Aryl hydrocarbon receptor nuclear translocator

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Supramolecule #1: Dimer of two HIF-2a-ARNT heterodimers complexed on 51-bp HRE

SupramoleculeName: Dimer of two HIF-2a-ARNT heterodimers complexed on 51-bp HRE
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 202 KDa

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Macromolecule #1: 51-nt Hypoxia Response Element (Forward)

MacromoleculeName: 51-nt Hypoxia Response Element (Forward) / type: dna / ID: 1 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.82208 KDa
SequenceString:
(DA)(DG)(DG)(DG)(DG)(DT)(DG)(DG)(DA)(DG) (DG)(DG)(DG)(DG)(DC)(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)

GENBANK: GENBANK: M11319.1

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Macromolecule #2: 51-nt Hypoxia Response Element (Reverse)

MacromoleculeName: 51-nt Hypoxia Response Element (Reverse) / type: dna / ID: 2 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.608979 KDa
SequenceString:
(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)(DG)(DC)(DC) (DC) (DC)(DC)(DT)(DC)(DC)(DA)(DC)(DC) (DC)(DC)(DT)

GENBANK: GENBANK: M11319.1

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Macromolecule #3: Endothelial PAS domain-containing protein 1

MacromoleculeName: Endothelial PAS domain-containing protein 1 / type: protein_or_peptide / ID: 3
Details: N-terminal 21 residues (MGSSHHHHHHSQDPGKEKKRS) are vector-derived
Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.684453 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGSSHHHHHH SQDPGKEKKR SSSERRKEKS RDAARCRRSK ETEVFYELAH ELPLPHSVSS HLDKASIMRL AISFLRTHKL LSSVCSENE SEAEADQQMD NLYLKALEGF IAVVTQDGDM IFLSENISKF MGLTQVELTG HSIFDFTHPC DHEEIRENLS L KNGSGFGK ...String:
MGSSHHHHHH SQDPGKEKKR SSSERRKEKS RDAARCRRSK ETEVFYELAH ELPLPHSVSS HLDKASIMRL AISFLRTHKL LSSVCSENE SEAEADQQMD NLYLKALEGF IAVVTQDGDM IFLSENISKF MGLTQVELTG HSIFDFTHPC DHEEIRENLS L KNGSGFGK KSKDMSTERD FFMRMKCTVT NRGRTVNLKS ATWKVLHCTG QVKVYNNCPP HNSLCGYKEP LLSCLIIMCE PI QHPSHMD IPLDSKTFLS RHSMDMKFTY CDDRITELIG YHPEELLGRS AYEFYHALDS ENMTKSHQNL CTKGQVVSGQ YRM LAKHGG YVWLETQGTV IYNPRNLQPQ CIMCVNYVLS EIEKNDVVFS MDQTES

UniProtKB: Endothelial PAS domain-containing protein 1

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Macromolecule #4: Aryl hydrocarbon receptor nuclear translocator

MacromoleculeName: Aryl hydrocarbon receptor nuclear translocator / type: protein_or_peptide / ID: 4 / 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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4.2 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 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 2 / 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: 3 / Number real images: 10910 / Average electron dose: 58.94 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: 656778
CTF correctionSoftware - Name: Warp (ver. 1.0.9) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionAlgorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.7.0) / Number images used: 164352
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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