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- PDB-9mp0: The cryo-EM structure of the human DNA methyltransferases DNMT3A2... -

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Basic information

Entry
Database: PDB / ID: 9mp0
TitleThe cryo-EM structure of the human DNA methyltransferases DNMT3A2 and DNMT3L dodecamer
Components
  • DNA (cytosine-5)-methyltransferase 3-like
  • DNA (cytosine-5)-methyltransferase 3A
KeywordsDNA BINDING PROTEIN / methyltransferase / dodecamer / TRANSFERASE / TRANSFERASE-DNA complex
Function / homology
Function and homology information


epigenetic programing of female pronucleus / chorionic trophoblast cell differentiation / positive regulation of cellular response to hypoxia / transposable element silencing by piRNA-mediated DNA methylation / negative regulation of DNA methylation-dependent heterochromatin formation / transposable element silencing by heterochromatin formation / protein-cysteine methyltransferase activity / regulatory ncRNA-mediated heterochromatin formation / unmethylated CpG binding / cellular response to bisphenol A ...epigenetic programing of female pronucleus / chorionic trophoblast cell differentiation / positive regulation of cellular response to hypoxia / transposable element silencing by piRNA-mediated DNA methylation / negative regulation of DNA methylation-dependent heterochromatin formation / transposable element silencing by heterochromatin formation / protein-cysteine methyltransferase activity / regulatory ncRNA-mediated heterochromatin formation / unmethylated CpG binding / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / autosome genomic imprinting / genomic imprinting / SUMOylation of DNA methylation proteins / ESC/E(Z) complex / XY body / response to vitamin A / DNA methylation-dependent constitutive heterochromatin formation / response to ionizing radiation / negative regulation of gene expression via chromosomal CpG island methylation / hepatocyte apoptotic process / lncRNA binding / negative regulation of gene expression, epigenetic / male meiosis I / cellular response to ethanol / chromosome, centromeric region / catalytic complex / heterochromatin / Transferases; Transferring one-carbon groups; Methyltransferases / DNA methylation / placenta development / condensed nuclear chromosome / PRC2 methylates histones and DNA / post-embryonic development / Defective pyroptosis / response to cocaine / stem cell differentiation / cellular response to amino acid stimulus / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / enzyme activator activity / euchromatin / response to lead ion / response to toxic substance / RMTs methylate histone arginines / nuclear matrix / neuron differentiation / transcription corepressor activity / response to estradiol / spermatogenesis / methylation / 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 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 / Zinc finger, FYVE/PHD-type / Zinc finger, RING/FYVE/PHD-type / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
S-ADENOSYL-L-HOMOCYSTEINE / DNA (cytosine-5)-methyltransferase 3-like / DNA (cytosine-5)-methyltransferase 3A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.66 Å
AuthorsYan, Y. / Zhou, X.E. / Xu, T.H.
Funding support United States, 2items
OrganizationGrant numberCountry
Other privateStartup funds
National Institutes of Health/National Cancer Institute (NIH/NCI)R35CA209859 United States
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Mechanisms of DNMT3A-3L-mediated de novo DNA methylation on chromatin.
Authors: Yan Yan / X Edward Zhou / Stacey L Thomas / Minmin Liu / Gan-Qiang Lai / Evan J Worden / Peter A Jones / Ting-Hai Xu /
Abstract: De novo DNA methylation is mediated by DNA methyltransferases DNMT3A and DNMT3B, in cooperation with the catalytically inactive paralogs DNMT3L and DNMT3B3. DNMT3L is predominantly expressed in ...De novo DNA methylation is mediated by DNA methyltransferases DNMT3A and DNMT3B, in cooperation with the catalytically inactive paralogs DNMT3L and DNMT3B3. DNMT3L is predominantly expressed in embryonic stem cells to establish methylation patterns and is silenced upon differentiation, with DNMT3B3 substituting in somatic cells. Here we present high-resolution cryo-electron microscopy structures of nucleosome-bound, full-length DNMT3A2-3L and its oligomeric assemblies in the nucleosome-free state. We identified the critical role of DNMT3L as a histone modification sensor, guiding chromatin engagement through a mechanism distinct from DNMT3B3. The structures show a 180° rotated 'switching helix' in DNMT3L that prevents direct interaction with the nucleosome acidic patch. Instead, nucleosome binding is mediated by the DNMT3L ADD domain, while the DNMT3A PWWP domain exhibits reduced engagement in the absence of H3K36 methylation. The oligomeric arrangement of DNMT3A2-3L in nucleosome-free states highlights its dynamic assembly and potential allosteric regulation. We further capture dynamic structural movements of DNMT3A2-3L on nucleosomes. These findings uncover a previously unknown mechanism by which DNMT3A-3L mediates de novo DNA methylation on chromatin through complex assembly, histone tail sensing, dynamic DNA search and regulated nucleosome engagement, providing insights into epigenetic regulation.
History
DepositionDec 29, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 8, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 8, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 8, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 8, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Oct 8, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 8, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Oct 8, 2025Data content type: Mask / Part number: 2 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Oct 8, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 12, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.2Nov 19, 2025Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: DNA (cytosine-5)-methyltransferase 3A
M: DNA (cytosine-5)-methyltransferase 3A
N: DNA (cytosine-5)-methyltransferase 3A
O: DNA (cytosine-5)-methyltransferase 3A
R: DNA (cytosine-5)-methyltransferase 3A
S: DNA (cytosine-5)-methyltransferase 3A
T: DNA (cytosine-5)-methyltransferase 3A
U: DNA (cytosine-5)-methyltransferase 3A
P: DNA (cytosine-5)-methyltransferase 3-like
Q: DNA (cytosine-5)-methyltransferase 3-like
hetero molecules


Theoretical massNumber of molelcules
Total (without water)715,41748
Polymers710,37910
Non-polymers5,03838
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 77914.711 Da / Num. of mol.: 8
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
#2: Protein DNA (cytosine-5)-methyltransferase 3-like


Mass: 43530.645 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DNMT3L / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UJW3
#3: Chemical...
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 30 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Mass: 384.411 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C14H20N6O5S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: human DNA (cytosine-5)-methyltransferases DNMT3A2 and DNMT3L dodecamer
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.709 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 16686

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.6particle selection
2SerialEMimage acquisition
4cryoSPARC4.6CTF correction
7UCSF Chimera1.18model fitting
8PHENIXmodel fitting
10cryoSPARC4.6initial Euler assignment
11cryoSPARC4.6final Euler assignment
13cryoSPARC4.63D reconstruction
14PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2308537
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.66 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 185119 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
14u7p

4u7p

14u7p1PDBexperimental model
21AlphaFoldin silico model
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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