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- EMDB-75886: Cryo-EM structure of human DNMT3A homo-hexamer -

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Basic information

Entry
Database: EMDB / ID: EMD-75886
TitleCryo-EM structure of human DNMT3A homo-hexamer
Map dataComposite map
Sample
  • Complex: DNMT3A
    • Protein or peptide: DNA (cytosine-5)-methyltransferase 3A
  • Ligand: S-ADENOSYL-L-HOMOCYSTEINE
  • Ligand: ZINC ION
KeywordsDNA (cytosine-5)-methyltransferase / TRANSFERASE
Function / homology
Function and homology information


transposable element silencing by piRNA-mediated DNA methylation / protein-cysteine methyltransferase activity / positive regulation of cellular response to hypoxia / regulatory ncRNA-mediated heterochromatin formation / unmethylated CpG binding / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / hepatocyte apoptotic process / response to vitamin A / XY body ...transposable element silencing by piRNA-mediated DNA methylation / protein-cysteine methyltransferase activity / positive regulation of cellular response to hypoxia / regulatory ncRNA-mediated heterochromatin formation / unmethylated CpG binding / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / hepatocyte apoptotic process / response to vitamin A / XY body / SUMOylation of DNA methylation proteins / DNA methylation-dependent constitutive heterochromatin formation / cellular response to ethanol / negative regulation of gene expression via chromosomal CpG island methylation / response to ionizing radiation / lncRNA binding / chromosome, centromeric region / catalytic complex / heterochromatin / Transferases; Transferring one-carbon groups; Methyltransferases / response to cocaine / DNA methylation / PRC2 methylates histones and DNA / Defective pyroptosis / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / euchromatin / response to toxic substance / response to lead ion / nuclear matrix / RMTs methylate histone arginines / transcription corepressor activity / response to estradiol / neuron differentiation / cellular response to hypoxia / RNA polymerase II-specific DNA-binding transcription factor binding / response to xenobiotic stimulus / RNA polymerase II cis-regulatory region sequence-specific DNA binding / chromosome / negative regulation of DNA-templated transcription / chromatin binding / negative regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / identical protein binding / nucleus / cytoplasm
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 (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 / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
DNA (cytosine-5)-methyltransferase 3A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.66 Å
AuthorsSong J / Lu J / Chen J
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2026
Title: Multidomain interaction governs the filamentous assembly of the dominant-negative DNMT3A R882H mutant.
Authors: Jianbin Chen / Jiuwei Lu / Zhixu Long / Sol Yoon / Megan Fukunaga / Jikui Song /
Abstract: DNA methyltransferase DNMT3A-mediated de novo DNA methylation is important for proper regulation of gene expression and genomic stability in development. The DNMT3A R882H (DNMT3A) mutation, a hot- ...DNA methyltransferase DNMT3A-mediated de novo DNA methylation is important for proper regulation of gene expression and genomic stability in development. The DNMT3A R882H (DNMT3A) mutation, a hot-spot mutation in acute myeloid leukemia and developmental disorders, exerts a dominant-negative effect in DNMT3A-mediated DNA methylation through promoting high-order protein assembly. However, due to the lack of structural knowledge on DNMT3A homo-oligomers, the mechanism behind wild-type DNMT3A (DNMT3A) and DNMT3A polymerization remains unclear. Here, we report the single-particle cryo-EM structures of homo-oligomeric DNMT3A and filamentous DNMT3A, revealing the role of the regulatory Pro-Trp-Trp-Pro (PWWP) and ATRX-DNMT3-DNMT3L (ADD) domains of DNMT3A in their dynamic assembly. While the oligomeric assembly of DNMT3A is mainly driven by the well-characterized oligomer interfaces in the methyltransferase domain, the autoinhibitory interaction of the PWWP and ADD domains in DNMT3A places them in a position for intermolecular contact, thereby contributing to the filamentous assembly of DNMT3A. Disrupting the autoinhibitory interaction facilitates the transition of DNMT3A polymer toward the low-order oligomeric assembly, reinforcing the aggregation-attenuation effect of the previously characterized oligomer-interface mutation R676K. Together, this study uncovers a multidomain cooperated assembly mechanism for DNMT3A, with important implication in development of effective therapeutic strategies against DNMT3A-associated diseases.
History
DepositionMar 6, 2026-
Header (metadata) releaseAug 19, 2026-
Map releaseAug 19, 2026-
UpdateSep 2, 2026-
Current statusSep 2, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75886.png

Downloads & links

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Map

FileDownload / File: emd_75886.map.gz / Format: CCP4 / Size: 87.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.3 Å/pix.
x 284 pix.
= 370.109 Å		1.3 Å/pix.
x 284 pix.
= 370.109 Å		1.3 Å/pix.
x 284 pix.
= 370.109 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.3032 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 2.0
Minimum - Maximum-31.615220000000001 - 71.812709999999996
Average (Standard dev.)0.003396239 (±0.9831312)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions284284284
Spacing284284284
CellA=B=C: 370.1088 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : DNMT3A

EntireName: DNMT3A
Components
  • Complex: DNMT3A
    • Protein or peptide: DNA (cytosine-5)-methyltransferase 3A
  • Ligand: S-ADENOSYL-L-HOMOCYSTEINE
  • Ligand: ZINC ION

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Supramolecule #1: DNMT3A

SupramoleculeName: DNMT3A / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: DNA (cytosine-5)-methyltransferase 3A

MacromoleculeName: DNA (cytosine-5)-methyltransferase 3A / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO / EC number: DNA (cytosine-5-)-methyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 72.297797 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: SEPEYEDGRG FGIGELVWGK LRGFSWWPGR IVSWWMTGRS RAAEGTRWVM WFGDGKFSVV CVEKLMPLSS FCSAFHQATY NKQPMYRKA IYEVLQVASS RAGKLFPVCH DSDESDTAKA VEVQNKPMIE WALGGFQPSG PKGLEPPEEE KNPYKEVYTD M WVEPEAAA ...String:
SEPEYEDGRG FGIGELVWGK LRGFSWWPGR IVSWWMTGRS RAAEGTRWVM WFGDGKFSVV CVEKLMPLSS FCSAFHQATY NKQPMYRKA IYEVLQVASS RAGKLFPVCH DSDESDTAKA VEVQNKPMIE WALGGFQPSG PKGLEPPEEE KNPYKEVYTD M WVEPEAAA YAPPPPAKKP RKSTAEKPKV KEIIDERTRE RLVYEVRQKC RNIEDICISC GSLNVTLEHP LFVGGMCQNC KN CFLECAY QYDDDGYQSY CTICCGGREV LMCGNNNCCR CFCVECVDLL VGPGAAQAAI KEDPWNCYMC GHKGTYGLLR RRE DWPSRL QMFFANNHDQ EFDPPKVYPP VPAEKRKPIR VLSLFDGIAT GLLVLKDLGI QVDRYIASEV CEDSITVGMV RHQG KIMYV GDVRSVTQKH IQEWGPFDLV IGGSPCNDLS IVNPARKGLY EGTGRLFFEF YRLLHDARPK EGDDRPFFWL FENVV AMGV SDKRDISRFL ESNPVMIDAK EVSAAHRARY FWGNLPGMNR PLASTVNDKL ELQECLEHGR IAKFSKVRTI TTRSNS IKQ GKDQHFPVFM NEKEDILWCT EMERVFGFPV HYTDVSNMSR LARQRLLGRS WSVPVIRHLF APLKEYFACV

UniProtKB: DNA (cytosine-5)-methyltransferase 3A

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Macromolecule #2: S-ADENOSYL-L-HOMOCYSTEINE

MacromoleculeName: S-ADENOSYL-L-HOMOCYSTEINE / type: ligand / ID: 2 / Number of copies: 4 / Formula: SAH
Molecular weightTheoretical: 384.411 Da
Chemical component information

ChemComp-SAH:
S-ADENOSYL-L-HOMOCYSTEINE

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 12 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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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: 7.2
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 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: 3.66 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.7.1) / Number images used: 197622
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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