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- EMDB-71814: Cryo-EM structure of human DNMT3A/3L -

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Basic information

Entry
Database: EMDB / ID: EMD-71814
TitleCryo-EM structure of human DNMT3A/3L
Map datasharpened map
Sample
  • Complex: DNMT3A/3L
    • Protein or peptide: DNA (cytosine-5)-methyltransferase 3A
    • Protein or peptide: DNA (cytosine-5)-methyltransferase 3-like
  • Ligand: S-ADENOSYL-L-HOMOCYSTEINE
  • Ligand: ZINC ION
KeywordsDNA (cytosine-5)-methyltransferase / TRANSFERASE
Function / homology
Function and homology information


epigenetic programing of female pronucleus / chorionic trophoblast cell differentiation / negative regulation of DNA methylation-dependent heterochromatin formation / transposable element silencing by heterochromatin formation / transposable element silencing by piRNA-mediated DNA methylation / protein-cysteine methyltransferase activity / positive regulation of cellular response to hypoxia / regulatory ncRNA-mediated heterochromatin formation / cellular response to bisphenol A / unmethylated CpG binding ...epigenetic programing of female pronucleus / chorionic trophoblast cell differentiation / negative regulation of DNA methylation-dependent heterochromatin formation / transposable element silencing by heterochromatin formation / transposable element silencing by piRNA-mediated DNA methylation / protein-cysteine methyltransferase activity / positive regulation of cellular response to hypoxia / regulatory ncRNA-mediated heterochromatin formation / cellular response to bisphenol A / unmethylated CpG binding / DNA (cytosine-5-)-methyltransferase / genomic imprinting / DNA (cytosine-5-)-methyltransferase activity / ESC/E(Z) complex / autosome genomic imprinting / SUMOylation of DNA methylation proteins / XY body / oocyte development / response to vitamin A / DNA methylation-dependent constitutive heterochromatin formation / response to ionizing radiation / negative regulation of gene expression, epigenetic / hepatocyte apoptotic process / negative regulation of gene expression via chromosomal CpG island methylation / lncRNA binding / male meiosis I / chromosome, centromeric region / cellular response to ethanol / catalytic complex / heterochromatin / Transferases; Transferring one-carbon groups; Methyltransferases / placenta development / DNA methylation / stem cell differentiation / condensed nuclear chromosome / PRC2 methylates histones and DNA / post-embryonic development / Defective pyroptosis / response to cocaine / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / cellular response to amino acid stimulus / euchromatin / response to lead ion / response to toxic substance / enzyme activator activity / RMTs methylate histone arginines / neuron differentiation / nuclear matrix / transcription corepressor activity / response to estradiol / methylation / spermatogenesis / cellular response to hypoxia / RNA polymerase II-specific DNA-binding transcription factor binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / chromatin binding / enzyme binding / negative regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol
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 / Zinc finger, FYVE/PHD-type / Zinc finger, RING/FYVE/PHD-type / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
DNA (cytosine-5)-methyltransferase 3-like / DNA (cytosine-5)-methyltransferase 3A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.66 Å
AuthorsLu J / Song J
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Nat Commun / Year: 2026
Title: Structural insight into hierarchical DNMT3A autoinhibition and its dysregulation in disease.
Authors: Jiuwei Lu / Emily Vig / Jianbin Chen / Kristjan H Gretarsson / Nelli Khudaverdyan / Zengyu Shao / Chao Lu / Chia-En A Chang / Jikui Song /
Abstract: DNA methyltransferase DNMT3A-mediated DNA methylation is important for genomic imprinting and transcriptional regulation. However, how the regulatory domains of DNMT3A cooperate with its ...DNA methyltransferase DNMT3A-mediated DNA methylation is important for genomic imprinting and transcriptional regulation. However, how the regulatory domains of DNMT3A cooperate with its methyltransferase domain and histone marks to orchestrate genomic methylation remains unclear. Here we report the cryo-EM structure of DNMT3A2 with regulatory factor DNMT3L, revealing an intricate domain interaction underlying multilayered autoinhibition. The PWWP domain interacts with the ADD and methyltransferase domains to block the target recognition domain and the H3K36me2-binding pocket, thereby coupling the H3K36me2 binding with DNMT3A activation, adding a layer of allosteric regulation distinct from the previously characterized ADD-H3K4me0 regulation. Molecular dynamics simulations of the DNMT3A-DNMT3L complex further reveals that relief of DNMT3A autoinhibition involves disengagement of the CpG-recognition loop of the target recognition domain from autoinhibitory interaction, leading to enhanced accessibility of the target recognition domain loop for DNA binding and DNMT3A activation. Importantly, our combined structural, biochemical and genomic methylation analysis demonstrates that disrupting the PWWP-ADD interaction by disease-associated DNMT3A mutations leads to impaired DNMT3A autoinhibition and substrate specificity, providing a potential explanation to aberrant DNA methylation in disease.
History
DepositionJul 24, 2025-
Header (metadata) releaseDec 31, 2025-
Map releaseDec 31, 2025-
UpdateMay 6, 2026-
Current statusMay 6, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71814.png

Downloads & links

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Map

FileDownload / File: emd_71814.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.24 Å/pix.
x 256 pix.
= 317.44 Å		1.24 Å/pix.
x 256 pix.
= 317.44 Å		1.24 Å/pix.
x 256 pix.
= 317.44 Å

Surface

Projections

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Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.24 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.205
Minimum - Maximum-2.4632654 - 3.1281655
Average (Standard dev.)0.00017676073 (±0.055954345)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 317.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: unsharpened map

Fileemd_71814_additional_1.map
Annotationunsharpened map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_71814_half_map_1.map
AnnotationHalf map A
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_71814_half_map_2.map
AnnotationHalf map B
Projections & Slices
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Sample components

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Entire : DNMT3A/3L

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

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Supramolecule #1: DNMT3A/3L

SupramoleculeName: DNMT3A/3L / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
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: 2 / 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: DNA (cytosine-5)-methyltransferase 3-like

MacromoleculeName: DNA (cytosine-5)-methyltransferase 3-like / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.630789 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MAAIPALDPE AEPSMDVILV GSSELSSSVS PGTGRDLIAY EVKANQRNIE DICICCGSLQ VHTQHPLFEG GICAPCKDKF LDALFLYDD DGYQSYCSIC CSGETLLICG NPDCTRCYCF ECVDSLVGPG TSGKVHAMSN WVCYLCLPSS RSGLLQRRRK W RSQLKAFY ...String:
MAAIPALDPE AEPSMDVILV GSSELSSSVS PGTGRDLIAY EVKANQRNIE DICICCGSLQ VHTQHPLFEG GICAPCKDKF LDALFLYDD DGYQSYCSIC CSGETLLICG NPDCTRCYCF ECVDSLVGPG TSGKVHAMSN WVCYLCLPSS RSGLLQRRRK W RSQLKAFY DRESENPLEM FETVPVWRRQ PVRVLSLFED IKKELTSLGF LESGSDPGQL KHVVDVTDTV RKDVEEWGPF DL VYGATPP LGHTCDRPPS WYLFQFHRLL QYARPKPGSP RPFFWMFVDN LVLNKEDLDV ASRFLEMEPV TIPDVHGGSL QNA VRVWSN IPAIRSRHWA LVSEEELSLL AQNKQSSKLA AKWPTKLVKN CFLPLREYFK YFSTELTSSL

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

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Macromolecule #3: S-ADENOSYL-L-HOMOCYSTEINE

MacromoleculeName: S-ADENOSYL-L-HOMOCYSTEINE / type: ligand / ID: 3 / Number of copies: 2 / Formula: SAH
Molecular weightTheoretical: 384.411 Da
Chemical component information

ChemComp-SAH:
S-ADENOSYL-L-HOMOCYSTEINE

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / 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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k 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: 2.3000000000000003 µm / Nominal defocus min: 0.8 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 / Number images used: 65578
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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