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- PDB-6pa7: The cryo-EM structure of the human DNMT3A2-DNMT3B3 complex bound ... -

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Basic information

Entry
Database: PDB / ID: 6pa7
TitleThe cryo-EM structure of the human DNMT3A2-DNMT3B3 complex bound to nucleosome.
Components
  • (DNA (167-MER)) x 2
  • (DNA (cytosine-5)-methyltransferase ...) x 2
  • Histone H2A type 1
  • Histone H2B 1.1
  • Histone H3.2
  • Histone H4
KeywordsTRANSFERASE/DNA / methyltransferase / complex / TRANSFERASE / TRANSFERASE-DNA complex
Function / homology
Function and homology information


positive regulation of cellular response to hypoxia / DNA (cytosine-5-)-methyltransferase activity, acting on CpG substrates / epigenetic programming of gene expression / cellular response to bisphenol A / DNA-methyltransferase activity / protein-cysteine methyltransferase activity / DNA (cytosine-5-)-methyltransferase / unmethylated CpG binding / DNA (cytosine-5-)-methyltransferase activity / autosome genomic imprinting ...positive regulation of cellular response to hypoxia / DNA (cytosine-5-)-methyltransferase activity, acting on CpG substrates / epigenetic programming of gene expression / cellular response to bisphenol A / DNA-methyltransferase activity / protein-cysteine methyltransferase activity / DNA (cytosine-5-)-methyltransferase / unmethylated CpG binding / DNA (cytosine-5-)-methyltransferase activity / autosome genomic imprinting / S-adenosylmethionine metabolic process / SUMOylation of DNA methylation proteins / DNA methylation-dependent heterochromatin formation / XY body / cellular response to ethanol / response to vitamin A / negative regulation of gene expression via chromosomal CpG island methylation / response to ionizing radiation / hepatocyte apoptotic process / chromosome, centromeric region / catalytic complex / heterochromatin / Transferases; Transferring one-carbon groups; Methyltransferases / DNA methylation / PRC2 methylates histones and DNA / response to cocaine / Defective pyroptosis / cellular response to amino acid stimulus / response to lead ion / euchromatin / NoRC negatively regulates rRNA expression / neuron differentiation / response to toxic substance / RMTs methylate histone arginines / nuclear matrix / structural constituent of chromatin / transcription corepressor activity / nucleosome / nucleosome assembly / response to estradiol / cellular response to hypoxia / methylation / spermatogenesis / RNA polymerase II-specific DNA-binding transcription factor binding / response to xenobiotic stimulus / protein heterodimerization activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / chromatin binding / positive regulation of gene expression / negative regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / identical protein binding / nucleus / metal ion binding / cytoplasm
Similarity search - Function
DNA (cytosine-5)-methyltransferase 3A, ADD domain / DNA (cytosine-5)-methyltransferase 3B, ADD domain / : / DNMT3, ADD PHD zinc finger / DNMT3, cysteine rich ADD domain / DNMT3, cysteine rich ADD domain, GATA1-like zinc finger / ADD domain / ADD domain profile. / DNA methylase, C-5 cytosine-specific, active site / C-5 cytosine-specific DNA methylases active site. ...DNA (cytosine-5)-methyltransferase 3A, ADD domain / DNA (cytosine-5)-methyltransferase 3B, ADD domain / : / DNMT3, ADD PHD zinc finger / DNMT3, cysteine rich ADD domain / DNMT3, cysteine rich ADD domain, GATA1-like zinc finger / ADD domain / ADD domain profile. / DNA methylase, C-5 cytosine-specific, active site / C-5 cytosine-specific DNA methylases active site. / C-5 cytosine-specific DNA methylase (Dnmt) domain profile. / C-5 cytosine methyltransferase / C-5 cytosine-specific DNA methylase / Histone, subunit A / Histone, subunit A / domain with conserved PWWP motif / PWWP domain / PWWP domain profile. / PWWP domain / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone H2A / Histone 2A / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Zinc finger, FYVE/PHD-type / Histone-fold / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
S-ADENOSYL-L-HOMOCYSTEINE / DNA / DNA (> 10) / DNA (> 100) / Histone H2B 1.1 / Histone H2A type 1 / Histone H4 / Histone H3.2 / DNA (cytosine-5)-methyltransferase 3B / DNA (cytosine-5)-methyltransferase 3A
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.94 Å
AuthorsXu, T.H. / Liu, M. / Zhou, X.E. / Liang, G. / Zhao, G. / Xu, H.E. / Melcher, K. / Jones, P.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R35CA209859 United States
CitationJournal: Nature / Year: 2020
Title: Structure of nucleosome-bound DNA methyltransferases DNMT3A and DNMT3B.
Authors: Ting-Hai Xu / Minmin Liu / X Edward Zhou / Gangning Liang / Gongpu Zhao / H Eric Xu / Karsten Melcher / Peter A Jones /
Abstract: CpG methylation by de novo DNA methyltransferases (DNMTs) 3A and 3B is essential for mammalian development and differentiation and is frequently dysregulated in cancer. These two DNMTs preferentially ...CpG methylation by de novo DNA methyltransferases (DNMTs) 3A and 3B is essential for mammalian development and differentiation and is frequently dysregulated in cancer. These two DNMTs preferentially bind to nucleosomes, yet cannot methylate the DNA wrapped around the nucleosome core, and they favour the methylation of linker DNA at positioned nucleosomes. Here we present the cryo-electron microscopy structure of a ternary complex of catalytically competent DNMT3A2, the catalytically inactive accessory subunit DNMT3B3 and a nucleosome core particle flanked by linker DNA. The catalytic-like domain of the accessory DNMT3B3 binds to the acidic patch of the nucleosome core, which orients the binding of DNMT3A2 to the linker DNA. The steric constraints of this arrangement suggest that nucleosomal DNA must be moved relative to the nucleosome core for de novo methylation to occur.
History
DepositionJun 11, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 7, 2020Group: Database references / Category: citation / citation_author
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.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 14, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Mar 20, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: Histone H3.2
B: Histone H4
C: Histone H2A type 1
D: Histone H2B 1.1
E: Histone H3.2
F: Histone H4
G: Histone H2A type 1
H: Histone H2B 1.1
I: DNA (167-MER)
J: DNA (167-MER)
K: DNA (cytosine-5)-methyltransferase 3A
N: DNA (cytosine-5)-methyltransferase 3B
P: DNA (cytosine-5)-methyltransferase 3A
S: DNA (cytosine-5)-methyltransferase 3B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)541,07319
Polymers540,19814
Non-polymers8755
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: cross-linking, chemical crosslink is needed to maintain the stability of the complex
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 4 types, 8 molecules AEBFCGDH

#1: Protein Histone H3.2


Mass: 15303.930 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P84233
#2: Protein Histone H4


Mass: 11394.426 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P62799
#3: Protein Histone H2A type 1


Mass: 13978.241 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P06897
#4: Protein Histone H2B 1.1 / H2B1.1


Mass: 13655.948 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P02281

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DNA chain , 2 types, 2 molecules IJ

#5: DNA chain DNA (167-MER)


Mass: 51327.652 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: DNA chain DNA (167-MER)


Mass: 51785.953 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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DNA (cytosine-5)-methyltransferase ... , 2 types, 4 molecules KPNS

#7: Protein DNA (cytosine-5)-methyltransferase 3A / Dnmt3a / DNA methyltransferase HsaIIIA / M.HsaIIIA


Mass: 77914.711 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DNMT3A / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9Y6K1, DNA (cytosine-5-)-methyltransferase
#8: Protein DNA (cytosine-5)-methyltransferase 3B / Dnmt3b / DNA methyltransferase HsaIIIB / M.HsaIIIB


Mass: 86294.945 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DNMT3B / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9UBC3, DNA (cytosine-5-)-methyltransferase

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Non-polymers , 2 types, 5 molecules

#9: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl / Feature type: SUBJECT OF INVESTIGATION
#10: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Type: L-peptide linking / Mass: 384.411 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H20N6O5S / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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

Component
IDNameTypeEntity IDParent-IDSource
1A ternary complex of DNMT3A/B asymmetrically binds to the nucleosomesCOMPLEX#1-#80MULTIPLE SOURCES
2HistoneCOMPLEX#1-#41RECOMBINANT
3DNA (167-MER)COMPLEX#5-#61RECOMBINANT
4DNA (cytosine-5)-methyltransferaseCOMPLEX#7-#81RECOMBINANT
Molecular weightValue: 0.52 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Xenopus laevis (African clawed frog)8355
23synthetic construct (others)32630
34Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
24Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 8
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 65 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
EM software
IDNameVersionCategory
1RELION3particle selection
4CTFFIND4.1.10CTF correction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2190114
3D reconstructionResolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 599344 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00422143
ELECTRON MICROSCOPYf_angle_d0.76931354
ELECTRON MICROSCOPYf_dihedral_angle_d20.60412092
ELECTRON MICROSCOPYf_chiral_restr0.0473478
ELECTRON MICROSCOPYf_plane_restr0.0062845

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