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- PDB-8vhg: Structure of the BMAL1/HIF2A heterodimer in Complex with DNA -

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Basic information

Entry
Database: PDB / ID: 8vhg
TitleStructure of the BMAL1/HIF2A heterodimer in Complex with DNA
Components
  • Basic helix-loop-helix ARNT-like protein 1
  • Endothelial PAS domain-containing protein 1
  • Forward strand DNA containing HRE motif
  • Reverse strand DNA containing HRE motif
KeywordsTRANSCRIPTION/DNA / Transcriptional 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 / Regulation of gene expression by Hypoxia-inducible Factor / maternal process involved in parturition / myoblast fate commitment / negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway ...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 / Regulation of gene expression by Hypoxia-inducible Factor / maternal process involved in parturition / myoblast fate commitment / negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway / norepinephrine biosynthetic process / regulation of type B pancreatic cell development / bHLH transcription factor binding / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / positive regulation of dopamine biosynthetic process / regulation of cellular senescence / aryl hydrocarbon receptor complex / regulation of protein neddylation / chromatoid body / intracellular oxygen homeostasis / Neddylation / norepinephrine metabolic process / positive regulation of circadian rhythm / surfactant homeostasis / oxidative stress-induced premature senescence / epithelial cell maturation / negative regulation of TOR signaling / negative regulation of cold-induced thermogenesis / cobalt ion binding / response to redox state / negative regulation of fat cell differentiation / E-box binding / aryl hydrocarbon receptor binding / regulation of insulin secretion / regulation of protein catabolic process / hemopoiesis / regulation of neurogenesis / blood vessel remodeling / embryonic placenta development / cis-regulatory region sequence-specific DNA binding / energy homeostasis / cell maturation / visual perception / lung development / regulation of heart rate / erythrocyte differentiation / RNA polymerase II transcription regulatory region sequence-specific DNA binding / transcription coregulator activity / circadian regulation of gene expression / mitochondrion organization / circadian rhythm / Hsp90 protein binding / PML body / multicellular organismal-level iron ion homeostasis / mRNA transcription by RNA polymerase II / autophagy / transcription coactivator binding / protein import into nucleus / sequence-specific double-stranded DNA binding / positive regulation of canonical Wnt signaling pathway / positive regulation of cold-induced thermogenesis / response to oxidative stress / angiogenesis / DNA-binding transcription activator activity, RNA polymerase II-specific / spermatogenesis / transcription regulator complex / cellular response to hypoxia / sequence-specific DNA binding / gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA-binding transcription factor activity, RNA polymerase II-specific / response to hypoxia / cell differentiation / regulation of cell cycle / transcription cis-regulatory region binding / nuclear speck / nuclear body / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein heterodimerization activity / negative regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / DNA binding / 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
DNA / DNA (> 10) / Endothelial PAS domain-containing protein 1 / Basic helix-loop-helix ARNT-like protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsLi, T. / Tsai, K.L.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 23, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2May 7, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.3Jun 4, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Endothelial PAS domain-containing protein 1
B: Basic helix-loop-helix ARNT-like protein 1
C: Reverse strand DNA containing HRE motif
D: Forward strand DNA containing HRE motif


Theoretical massNumber of molelcules
Total (without water)107,3654
Polymers107,3654
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Endothelial PAS domain-containing protein 1 / EPAS-1 / HIF-1-alpha-like factor / HLF / mHLF / HIF-related factor / HRF / Hypoxia-inducible factor ...EPAS-1 / HIF-1-alpha-like factor / HLF / mHLF / HIF-related factor / HRF / Hypoxia-inducible factor 2-alpha / HIF-2-alpha / HIF2-alpha


Mass: 43372.305 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Epas1, Hif2a / Production host: Escherichia coli (E. coli) / References: UniProt: P97481
#2: Protein Basic helix-loop-helix ARNT-like protein 1 / Arnt3 / Aryl hydrocarbon receptor nuclear translocator-like protein 1 / Brain and muscle ARNT-like 1


Mass: 49248.117 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Bmal1, Arntl / Production host: Escherichia coli (E. coli) / References: UniProt: Q9WTL8
#3: DNA chain Reverse strand DNA containing HRE motif


Mass: 7245.672 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Mus musculus (house mouse)
#4: DNA chain Forward strand DNA containing HRE motif


Mass: 7498.799 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Mus musculus (house mouse)
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Ternary complex of the BMAL1/HIF2A heterodimer bound with DNA
Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 75 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 41991 / Symmetry type: POINT
RefinementHighest resolution: 3.6 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0044878
ELECTRON MICROSCOPYf_angle_d0.7166727
ELECTRON MICROSCOPYf_dihedral_angle_d20.3811820
ELECTRON MICROSCOPYf_chiral_restr0.043770
ELECTRON MICROSCOPYf_plane_restr0.007720

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