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- EMDB-43237: Structure of the BMAL1/HIF2A heterodimer in Complex with DNA -

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Basic information

Entry
Database: EMDB / ID: EMD-43237
TitleStructure of the BMAL1/HIF2A heterodimer in Complex with DNA
Map data
Sample
  • Complex: Ternary complex of the BMAL1/HIF2A heterodimer bound with DNA
    • Protein or peptide: Endothelial PAS domain-containing protein 1
    • Protein or peptide: Basic helix-loop-helix ARNT-like protein 1
    • DNA: Reverse strand DNA containing HRE motif
    • DNA: Forward strand DNA containing HRE motif
KeywordsTranscriptional factors / heterodimer / DNA recognition / Circadian-dependent cardioprotection / TRANSCRIPTION-DNA complex
Function / homology
Function and homology information


Cellular response to hypoxia / CLOCK-BMAL transcription complex / positive regulation of skeletal muscle cell differentiation / regulation of hair cycle / positive regulation of protein acetylation / NPAS4 regulates expression of target genes / negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway / Regulation of gene expression by Hypoxia-inducible Factor / maternal process involved in parturition / myoblast fate commitment ...Cellular response to hypoxia / CLOCK-BMAL transcription complex / positive regulation of skeletal muscle cell differentiation / regulation of hair cycle / positive regulation of protein acetylation / NPAS4 regulates expression of target genes / negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway / Regulation of gene expression by Hypoxia-inducible Factor / maternal process involved in parturition / myoblast fate commitment / regulation of type B pancreatic cell development / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / bHLH transcription factor binding / regulation of cellular senescence / regulation of protein neddylation / chromatoid body / Neddylation / norepinephrine metabolic process / positive regulation of circadian rhythm / surfactant homeostasis / oxidative stress-induced premature senescence / negative regulation of TOR signaling / epithelial cell maturation / negative regulation of cold-induced thermogenesis / response to redox state / negative regulation of fat cell differentiation / regulation of protein catabolic process / E-box binding / hemopoiesis / regulation of neurogenesis / blood vessel remodeling / embryonic placenta development / cis-regulatory region sequence-specific DNA binding / energy homeostasis / visual perception / regulation of insulin secretion / regulation of heart rate / erythrocyte differentiation / mitochondrion organization / transcription coregulator activity / lung development / circadian regulation of gene expression / mRNA transcription by RNA polymerase II / transcription coactivator binding / PML body / autophagy / multicellular organismal-level iron ion homeostasis / circadian rhythm / protein import into nucleus / positive regulation of canonical Wnt signaling pathway / positive regulation of cold-induced thermogenesis / DNA-binding transcription activator activity, RNA polymerase II-specific / gene expression / angiogenesis / spermatogenesis / cellular response to hypoxia / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / response to oxidative stress / sequence-specific DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / transcription by RNA polymerase II / cell differentiation / DNA-binding transcription factor activity, RNA polymerase II-specific / response to hypoxia / transcription cis-regulatory region binding / regulation of cell cycle / nuclear speck / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein heterodimerization activity / DNA-binding transcription factor activity / negative regulation of DNA-templated transcription / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / positive regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Hypoxia-inducible factor 1-alpha bHLH domain / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation 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) ...Hypoxia-inducible factor 1-alpha bHLH domain / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation 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
Endothelial PAS domain-containing protein 1 / Basic helix-loop-helix ARNT-like protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsLi T / Tsai KL
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) United States
CitationJournal: Nature / Year: 2025
Title: BMAL1-HIF2A heterodimer modulates circadian variations of myocardial injury.
Authors: Wei Ruan / Tao Li / In Hyuk Bang / Jaewoong Lee / Wankun Deng / Xinxin Ma / Cong Luo / Fang Du / Seung-Hee Yoo / Boyun Kim / Jiwen Li / Xiaoyi Yuan / Katherine Figarella / Yu A An / Yin-Ying ...Authors: Wei Ruan / Tao Li / In Hyuk Bang / Jaewoong Lee / Wankun Deng / Xinxin Ma / Cong Luo / Fang Du / Seung-Hee Yoo / Boyun Kim / Jiwen Li / Xiaoyi Yuan / Katherine Figarella / Yu A An / Yin-Ying Wang / Yafen Liang / Matthew DeBerge / Dongze Zhang / Zhen Zhou / Yanyu Wang / Joshua M Gorham / Jonathan G Seidman / Christine E Seidman / Sary F Aranki / Ragini Nair / Lei Li / Jagat Narula / Zhongming Zhao / Alemayehu A Gorfe / Jochen D Muehlschlegel / Kuang-Lei Tsai / Holger K Eltzschig /
Abstract: Acute myocardial infarction is a leading cause of morbidity and mortality worldwide. Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian ...Acute myocardial infarction is a leading cause of morbidity and mortality worldwide. Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian pattern, with larger infarcts and poorer outcomes in patients experiencing morning-onset events. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL1 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner-hypoxia-inducible factor 2 alpha (HIF2A)-in a diurnal manner. To substantiate this finding, we determined the cryo-EM structure of the BMAL1-HIF2A-DNA complex, revealing structural rearrangements within BMAL1 that enable cross-talk between circadian rhythms and hypoxia signalling. BMAL1 modulates the circadian hypoxic response by enhancing the transcriptional activity of HIF2A and stabilizing the HIF2A protein. We further identified amphiregulin (AREG) as a rhythmic target of the BMAL1-HIF2A complex, critical for regulating daytime variations of myocardial injury. Pharmacologically targeting the BMAL1-HIF2A-AREG pathway provides cardioprotection, with maximum efficacy when aligned with the pathway's circadian phase. These findings identify a mechanism governing circadian variations of myocardial injury and highlight the therapeutic potential of clock-based pharmacological interventions for treating ischaemic heart disease.
History
DepositionJan 1, 2024-
Header (metadata) releaseFeb 12, 2025-
Map releaseFeb 12, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43237.png

Downloads & links

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Map

FileDownload / File: emd_43237.map.gz / Format: CCP4 / Size: 134.6 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.)
1.02 Å/pix.
x 328 pix.
= 334.56 Å		1.02 Å/pix.
x 328 pix.
= 334.56 Å		1.02 Å/pix.
x 328 pix.
= 334.56 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.02 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.26
Minimum - Maximum-0.13713424 - 2.2120469
Average (Standard dev.)0.0011005269 (±0.025544828)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions328328328
Spacing328328328
CellA=B=C: 334.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_43237_msk_1.map
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Additional map: #1

Fileemd_43237_additional_1.map
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Half map: #1

Fileemd_43237_half_map_1.map
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Half map: #2

Fileemd_43237_half_map_2.map
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Sample components

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Entire : Ternary complex of the BMAL1/HIF2A heterodimer bound with DNA

EntireName: Ternary complex of the BMAL1/HIF2A heterodimer bound with DNA
Components
  • Complex: Ternary complex of the BMAL1/HIF2A heterodimer bound with DNA
    • Protein or peptide: Endothelial PAS domain-containing protein 1
    • Protein or peptide: Basic helix-loop-helix ARNT-like protein 1
    • DNA: Reverse strand DNA containing HRE motif
    • DNA: Forward strand DNA containing HRE motif

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Supramolecule #1: Ternary complex of the BMAL1/HIF2A heterodimer bound with DNA

SupramoleculeName: Ternary complex of the BMAL1/HIF2A heterodimer bound with DNA
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Endothelial PAS domain-containing protein 1

MacromoleculeName: Endothelial PAS domain-containing protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 43.372305 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSSHHHHHH SSGLVPRGSH MADKEKKRSS SELRKEKSRD AARCRRSKET EVFYELAHEL PLPHSVSSHL DKASIMRLAI SFLRTHKLL SSVCSENESE AEADQQMDNL YLKALEGFIA VVTQDGDMIF LSENISKFMG LTQVELTGHS IFDFTHPCDH E EIRENLTL ...String:
MGSSHHHHHH SSGLVPRGSH MADKEKKRSS SELRKEKSRD AARCRRSKET EVFYELAHEL PLPHSVSSHL DKASIMRLAI SFLRTHKLL SSVCSENESE AEADQQMDNL YLKALEGFIA VVTQDGDMIF LSENISKFMG LTQVELTGHS IFDFTHPCDH E EIRENLTL KNGSGFGKKS KDVSTERDFF MRMKCTVTNR GRTVNLKSAT WKVLHCTGQV RVYNNCPPHS SLCGSKEPLL SC LIIMCEP IQHPSHMDIP LDSKTFLSRH SMDMKFTYCD DRILELIGYH PEELLGRSAY EFYHALDSEN MTKSHQNLCT KGQ VVSGQY RMLAKHGGYV WLETQGTVIY NPRNLQPQCI MCVNYVLSEI EKNDVVFSMD QTES

UniProtKB: Endothelial PAS domain-containing protein 1

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Macromolecule #2: Basic helix-loop-helix ARNT-like protein 1

MacromoleculeName: Basic helix-loop-helix ARNT-like protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 49.248117 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GRIKNAREAH SQIEKRRRDK MNSFIDELAS LVPTCNAMSR KLDKLTVLRM AVQHMKTLRG ATNPYTEANY KPTFLSDDEL KHLILRAAD GFLFVVGCDR GKILFVSESV FKILNYSQND LIGQSLFDYL HPKDIAKVKE QLSSSDTAPR ERLIDAKTGL P VKTDITPG ...String:
GRIKNAREAH SQIEKRRRDK MNSFIDELAS LVPTCNAMSR KLDKLTVLRM AVQHMKTLRG ATNPYTEANY KPTFLSDDEL KHLILRAAD GFLFVVGCDR GKILFVSESV FKILNYSQND LIGQSLFDYL HPKDIAKVKE QLSSSDTAPR ERLIDAKTGL P VKTDITPG PSRLCSGARR SFFCRMKCNR PSVKVEDKDF ASTCSKKKAD RKSFCTIHST GYLKSWPPTK MGLDEDNEPD NE GCNLSCL VAIGRLHSHM VPQPANGEIR VKSMEYVSRH AIDGKFVFVD QRATAILAYL PQELLGTSCY EYFHQDDIGH LAE CHRQVL QTREKITTNC YKFKIKDGSF ITLRSRWFSF MNPWTKEVEY IVSTNTVVLA NVLEGGDPTF PQLTAPPHSM DSML PSGEG GPKRTHPTVP GIPGGTENLY FQSDYKDDDD K

UniProtKB: Basic helix-loop-helix ARNT-like protein 1

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Macromolecule #3: Reverse strand DNA containing HRE motif

MacromoleculeName: Reverse strand DNA containing HRE motif / type: dna / ID: 3 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 7.245672 KDa
SequenceString:
(DC)(DA)(DC)(DG)(DA)(DC)(DC)(DC)(DG)(DC) (DA)(DC)(DG)(DT)(DA)(DC)(DG)(DC)(DA)(DG) (DC)(DT)(DC)(DC)

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Macromolecule #4: Forward strand DNA containing HRE motif

MacromoleculeName: Forward strand DNA containing HRE motif / type: dna / ID: 4 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 7.498799 KDa
SequenceString:
(DG)(DG)(DA)(DG)(DC)(DT)(DG)(DC)(DG)(DT) (DA)(DC)(DG)(DT)(DG)(DC)(DG)(DG)(DG)(DT) (DC)(DG)(DT)(DG)

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 75.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 41991
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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