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- PDB-8qzm: Structure of DNMT3A1 UDR region bound to H2AK119ub nucleosome -

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Basic information

Entry
Database: PDB / ID: 8qzm
TitleStructure of DNMT3A1 UDR region bound to H2AK119ub nucleosome
Components
  • (DNA (145-MER)) x 2
  • DNA (cytosine-5)-methyltransferase 3A
  • Histone H2A type 1
  • Histone H2B type 1-C/E/F/G/I
  • Histone H3 (Fragment)
  • Histone H4
KeywordsDNA BINDING PROTEIN / Chromatin / Nucleosome / methyltransferase / Ubiquitin
Function / homology
Function and homology information


positive regulation of cellular response to hypoxia / transposable element silencing by piRNA-mediated DNA methylation / protein-cysteine methyltransferase activity / regulatory ncRNA-mediated heterochromatin formation / DNA (cytosine-5-)-methyltransferase activity / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase activity, acting on CpN substrates / DNA (cytosine-5-)-methyltransferase activity, acting on CpNpG substrates / unmethylated CpG binding / DNA (cytosine-5-)-methyltransferase ...positive regulation of cellular response to hypoxia / transposable element silencing by piRNA-mediated DNA methylation / protein-cysteine methyltransferase activity / regulatory ncRNA-mediated heterochromatin formation / DNA (cytosine-5-)-methyltransferase activity / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase activity, acting on CpN substrates / DNA (cytosine-5-)-methyltransferase activity, acting on CpNpG substrates / unmethylated CpG binding / DNA (cytosine-5-)-methyltransferase / autosome genomic imprinting / SUMOylation of DNA methylation proteins / XY body / cellular response to ethanol / response to vitamin A / response to ionizing radiation / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression via chromosomal CpG island methylation / lncRNA binding / hepatocyte apoptotic process / chromosome, centromeric region / catalytic complex / negative regulation of megakaryocyte differentiation / protein localization to CENP-A containing chromatin / heterochromatin / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / Packaging Of Telomere Ends / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Deposition of new CENPA-containing nucleosomes at the centromere / telomere organization / Inhibition of DNA recombination at telomere / Meiotic synapsis / RNA Polymerase I Promoter Opening / Assembly of the ORC complex at the origin of replication / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / innate immune response in mucosa / SUMOylation of chromatin organization proteins / DNA methylation / Condensation of Prophase Chromosomes / Transferases; Transferring one-carbon groups; Methyltransferases / Chromatin modifications during the maternal to zygotic transition (MZT) / HCMV Late Events / SIRT1 negatively regulates rRNA expression / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / PRC2 methylates histones and DNA / post-embryonic development / Regulation of endogenous retroelements by KRAB-ZFP proteins / Defective pyroptosis / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / HDACs deacetylate histones / Nonhomologous End-Joining (NHEJ) / RNA Polymerase I Promoter Escape / cellular response to amino acid stimulus / Transcriptional regulation by small RNAs / response to cocaine / Formation of the beta-catenin:TCF transactivating complex / response to lead ion / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / euchromatin / G2/M DNA damage checkpoint / HDMs demethylate histones / NoRC negatively regulates rRNA expression / DNA Damage/Telomere Stress Induced Senescence / B-WICH complex positively regulates rRNA expression / PKMTs methylate histone lysines / Meiotic recombination / Pre-NOTCH Transcription and Translation / Metalloprotease DUBs / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / nuclear matrix / Transcriptional regulation of granulopoiesis / response to toxic substance / HCMV Early Events / antimicrobial humoral immune response mediated by antimicrobial peptide / neuron differentiation / transcription corepressor activity / structural constituent of chromatin / antibacterial humoral response / UCH proteinases / nucleosome / heterochromatin formation / E3 ubiquitin ligases ubiquitinate target proteins / response to estradiol / nucleosome assembly / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / chromatin organization / HATs acetylate histones / RUNX1 regulates transcription of genes involved in differentiation of HSCs / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / Processing of DNA double-strand break ends / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / spermatogenesis / methylation
Similarity search - Function
DNA (cytosine-5)-methyltransferase 3A, ADD domain / : / DNA (cytosine-5-)-methyltransferase, N-terminal / DNMT3, cysteine rich ADD domain / : / DNMT3, cysteine rich ADD domain, GATA1-like zinc finger / DNMT3, ADD PHD zinc finger / ADD domain / ADD domain profile. / DNA methylase, C-5 cytosine-specific, active site ...DNA (cytosine-5)-methyltransferase 3A, ADD domain / : / DNA (cytosine-5-)-methyltransferase, N-terminal / DNMT3, cysteine rich ADD domain / : / DNMT3, cysteine rich ADD domain, GATA1-like zinc finger / DNMT3, ADD PHD 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 / 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 / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / 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 / Histone-fold / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
DNA / DNA (> 10) / DNA (> 100) / Histone H3 / Histone H2A type 1 / Histone H4 / Histone H2B type 1-C/E/F/G/I / DNA (cytosine-5)-methyltransferase 3A
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsBurdett, H. / Wapenaar, H. / Wilson, M.D.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Wellcome Trust210493/Z/18/Z United Kingdom
Medical Research Council (MRC, United Kingdom)T029471/1 United Kingdom
CitationJournal: EMBO Rep / Year: 2024
Title: The N-terminal region of DNMT3A engages the nucleosome surface to aid chromatin recruitment.
Authors: Hannah Wapenaar / Gillian Clifford / Willow Rolls / Moira Pasquier / Hayden Burdett / Yujie Zhang / Gauri Deák / Juan Zou / Christos Spanos / Mark R D Taylor / Jacquie Mills / James A ...Authors: Hannah Wapenaar / Gillian Clifford / Willow Rolls / Moira Pasquier / Hayden Burdett / Yujie Zhang / Gauri Deák / Juan Zou / Christos Spanos / Mark R D Taylor / Jacquie Mills / James A Watson / Dhananjay Kumar / Richard Clark / Alakta Das / Devisree Valsakumar / Janice Bramham / Philipp Voigt / Duncan Sproul / Marcus D Wilson /
Abstract: DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns in vertebrates. Here we structurally and biochemically explore the interaction of ...DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns in vertebrates. Here we structurally and biochemically explore the interaction of DNMT3A1 with diverse modified nucleosomes indicative of different chromatin environments. A cryo-EM structure of the full-length DNMT3A1-DNMT3L complex with a H2AK119ub nucleosome reveals that the DNMT3A1 ubiquitin-dependent recruitment (UDR) motif interacts specifically with H2AK119ub and makes extensive contacts with the core nucleosome histone surface. This interaction facilitates robust DNMT3A1 binding to nucleosomes, and previously unexplained DNMT3A disease-associated mutations disrupt this interface. Furthermore, the UDR-nucleosome interaction synergises with other DNMT3A chromatin reading elements in the absence of histone ubiquitylation. H2AK119ub does not stimulate DNMT3A DNA methylation activity, as observed for the previously described H3K36me2 mark, which may explain low levels of DNA methylation on H2AK119ub marked facultative heterochromatin. This study highlights the importance of multivalent binding of DNMT3A to histone modifications and the nucleosome surface and increases our understanding of how DNMT3A1 chromatin recruitment occurs.
History
DepositionOct 27, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 23, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Dec 18, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone H3 (Fragment)
B: Histone H4
C: Histone H2A type 1
D: Histone H2B type 1-C/E/F/G/I
E: Histone H3 (Fragment)
F: Histone H4
G: Histone H2A type 1
H: Histone H2B type 1-C/E/F/G/I
I: DNA (145-MER)
J: DNA (145-MER)
K: DNA (cytosine-5)-methyltransferase 3A


Theoretical massNumber of molelcules
Total (without water)331,26611
Polymers331,26611
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

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Protein , 5 types, 9 molecules AEBFCGDHK

#1: Protein Histone H3 (Fragment)


Mass: 15257.838 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: H3_0 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A7K7T3V7
#2: Protein Histone H4


Mass: 11263.231 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: HIST1H4A, H4/A, H4FA, HIST1H4B, H4/I, H4FI, HIST1H4C, H4/G, H4FG, HIST1H4D, H4/B, H4FB, HIST1H4E, H4/J, H4FJ, HIST1H4F, H4/C, H4FC, HIST1H4H, H4/H, H4FH, HIST1H4I, H4/M, H4FM, HIST1H4J, H4/E, ...Gene: HIST1H4A, H4/A, H4FA, HIST1H4B, H4/I, H4FI, HIST1H4C, H4/G, H4FG, HIST1H4D, H4/B, H4FB, HIST1H4E, H4/J, H4FJ, HIST1H4F, H4/C, H4FC, HIST1H4H, H4/H, H4FH, HIST1H4I, H4/M, H4FM, HIST1H4J, H4/E, H4FE, HIST1H4K, H4/D, H4FD, HIST1H4L, H4/K, H4FK, HIST2H4A, H4/N, H4F2, H4FN, HIST2H4, HIST2H4B, H4/O, H4FO, HIST4H4
Production host: Escherichia coli (E. coli) / References: UniProt: P62805
#3: Protein Histone H2A type 1 / H2A.1 / Histone H2A/ptl


Mass: 13964.305 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: H2A crosslinked at K119C with acetone linker to ubiquitin G76C
Source: (gene. exp.) Homo sapiens (human)
Gene: H2AC11, H2AFP, HIST1H2AG, H2AC13, H2AFC, HIST1H2AI, H2AC15, H2AFD, HIST1H2AK, H2AC16, H2AFI, HIST1H2AL, H2AC17, H2AFN, HIST1H2AM
Production host: Escherichia coli (E. coli) / References: UniProt: P0C0S8
#4: Protein Histone H2B type 1-C/E/F/G/I / Histone H2B.1 A / Histone H2B.a / H2B/a / Histone H2B.g / H2B/g / Histone H2B.h / H2B/h / Histone ...Histone H2B.1 A / Histone H2B.a / H2B/a / Histone H2B.g / H2B/g / Histone H2B.h / H2B/h / Histone H2B.k / H2B/k / Histone H2B.l / H2B/l


Mass: 13806.018 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: HIST1H2BC, H2BFL, HIST1H2BE, H2BFH, HIST1H2BF, H2BFG, HIST1H2BG, H2BFA, HIST1H2BI, H2BFK
Production host: Escherichia coli (E. coli) / References: UniProt: P62807
#7: Protein DNA (cytosine-5)-methyltransferase 3A


Mass: 102269.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: copurified with DNMT3L / Source: (gene. exp.) Homo sapiens (human) / Gene: DNMT3A / Production host: Escherichia coli (E. coli) / References: UniProt: Q9Y6K1

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DNA chain , 2 types, 2 molecules IJ

#5: DNA chain DNA (145-MER)


Mass: 60642.590 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: DNA chain DNA (145-MER)


Mass: 59771.035 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Details

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

Component
IDNameTypeEntity IDParent-IDSource
1DNMT3A1-DNMT3L in complex with a human H2AKc119ub nucleosome wrapped with 195bp of Widom-601 positioning DNACOMPLEXall0MULTIPLE SOURCES
2H2AKc119ub Nucleosome wrapped with 195 bp Widom601 DNACOMPLEX#1-#61RECOMBINANT
3DNMT3A1-DNMT3L complexCOMPLEX#71RECOMBINANT
4UbiquitinCOMPLEX1RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.397 MDaNO
210.250 MDaNO
310.147 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
54Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Escherichia coli (E. coli)562
32Escherichia coli (E. coli)562
43Escherichia coli (E. coli)562
54Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
Details: 15 mM HEPES pH 7.5, 65 mM NaCl, 1 mM DTT, 0.1 mM S-Adenosyl methionine
Buffer component
IDConc.NameFormulaBuffer-ID
115 mMHEPESC8H18N2O4S1
265 mMsodium chlorideNaCl1
31 mMDithiothreitolC4H10O2S21
40.1 mMS-Adenosyl methionineC15H22N6O5S1
SpecimenConc.: 0.13 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 / Nominal magnification: 105000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 61 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 15491
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.3.1particle selection
2EPUimage acquisition
4cryoSPARC4.3.1CTF correction
7ISOLDE1.6.0model fitting
8UCSF ChimeraX1.6.1model fitting
10PHENIX1.20.1-4487model refinement
11Coot0.9.8.8model refinement
12cryoSPARC4.3.1initial Euler assignment
13cryoSPARC4.3.1final Euler assignment
14cryoSPARC4.3.1classification
15cryoSPARC4.3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 7826521
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 191397 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingB value: 50 / Protocol: RIGID BODY FIT / Space: REAL
Atomic model building

3D fitting-ID: 1

IDPDB-IDChain-IDDetailsSource nameTypeAccession codeInitial refinement model-ID
1KModel AngeloOtherin silico model
27XD1

7xd1

PDBexperimental model7XD12

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