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- PDB-9mpp: The cryo-EM structure of nucleosome-bound DNA methyltransferases ... -

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Basic information

Entry
Database: PDB / ID: 9mpp
TitleThe cryo-EM structure of nucleosome-bound DNA methyltransferases DNMT3A2 and DNMT3L
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
KeywordsDNA BINDING PROTEIN / methyltransferase / DNMT-nucleosome complex / TRANSFERASE / TRANSFERASE-DNA complex
Function / homology
Function and homology information


negative regulation of DNA methylation-dependent heterochromatin formation / transposable element silencing by heterochromatin formation / genomic imprinting / 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 ...negative regulation of DNA methylation-dependent heterochromatin formation / transposable element silencing by heterochromatin formation / genomic imprinting / 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 / ESC/E(Z) complex / male meiosis I / SUMOylation of DNA methylation proteins / XY body / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression via chromosomal CpG island methylation / response to ionizing radiation / negative regulation of gene expression, epigenetic / lncRNA binding / cellular response to ethanol / chromosome, centromeric region / stem cell differentiation / heterochromatin / Transferases; Transferring one-carbon groups; Methyltransferases / condensed nuclear chromosome / DNA methylation / PRC2 methylates histones and DNA / response to cocaine / Defective pyroptosis / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / euchromatin / response to toxic substance / response to lead ion / enzyme activator activity / nucleosomal DNA binding / nuclear matrix / RMTs methylate histone arginines / innate immune response in mucosa / structural constituent of chromatin / transcription corepressor activity / response to estradiol / nucleosome / neuron differentiation / nucleosome assembly / methylation / antimicrobial humoral immune response mediated by antimicrobial peptide / heterochromatin formation / spermatogenesis / cellular response to hypoxia / antibacterial humoral response / chromatin organization / RNA polymerase II-specific DNA-binding transcription factor binding / response to xenobiotic stimulus / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein heterodimerization activity / negative regulation of DNA-templated transcription / chromatin binding / negative regulation of transcription by RNA polymerase II / enzyme binding / DNA binding / : / nucleoplasm / zinc ion binding / nucleus / cytosol / 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 / : / Histone H2A conserved site / Histone H2A signature. / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone 2A / Histone H2A / Zinc finger, FYVE/PHD-type / 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 domain / Histone-fold / Zinc finger, RING/FYVE/PHD-type / S-adenosyl-L-methionine-dependent methyltransferase superfamily
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 3-like / DNA (cytosine-5)-methyltransferase 3A
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
synthetic construct (others)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 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: 2026
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 31, 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: Image / Data content type: Image / 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
Revision 1.3Feb 4, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.2Feb 11, 2026Data content type: EM metadata / Data content type: EM metadata / Group: Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_author_list / Data content type: EM metadata / Item: _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 H3.2
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)
M: DNA (cytosine-5)-methyltransferase 3A
N: DNA (cytosine-5)-methyltransferase 3-like
K: DNA (cytosine-5)-methyltransferase 3A
L: DNA (cytosine-5)-methyltransferase 3-like
hetero molecules


Theoretical massNumber of molelcules
Total (without water)455,83922
Polymers454,67714
Non-polymers1,1618
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

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Protein , 4 types, 8 molecules AEBFCGDH

#1: Protein Histone H3.2 / Histone H3


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: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#6: DNA chain DNA (167-MER)


Mass: 51785.953 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)

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

#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 3-like


Mass: 43534.633 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

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Non-polymers , 2 types, 8 molecules

#9: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#10: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


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
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
1Nucleosome-bound DNA methyltransferases DNMT3A2 and DNMT3LCOMPLEX#1-#80MULTIPLE SOURCES
2NucleosomeCOMPLEX#1-#61RECOMBINANT
3human DNA methyltransferase 3A2 and 3L complexCOMPLEX#7-#81RECOMBINANT
Molecular weightValue: 0.454 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Xenopus laevis (African clawed frog)8355
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Escherichia coli (E. coli)562
33Spodoptera 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 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: 3000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 60 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 3 / Num. of real images: 31987

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.6particle selection
2SerialEMimage acquisition
4cryoSPARC4.6CTF correction
7UCSF Chimerav1.18model 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: 10464848
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 625915 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeSource nameType
16pa7

6pa7

16pa7PDBexperimental model
24u7p

4u7p

14u7pPDBexperimental model
31AlphaFoldin silico model
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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