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- PDB-11oi: Cryo-EM structure of human DNMT3A homo-hexamer -

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Basic information

Entry
Database: PDB / ID: 11oi
TitleCryo-EM structure of human DNMT3A homo-hexamer
ComponentsDNA (cytosine-5)-methyltransferase 3A
KeywordsTRANSFERASE / DNA (cytosine-5)-methyltransferase
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
S-ADENOSYL-L-HOMOCYSTEINE / DNA (cytosine-5)-methyltransferase 3A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.66 Å
AuthorsSong, J. / Lu, J. / Chen, J.
Funding support United States, 1items
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, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 19, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.1Sep 2, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Sep 2, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: DNA (cytosine-5)-methyltransferase 3A
E: DNA (cytosine-5)-methyltransferase 3A
F: DNA (cytosine-5)-methyltransferase 3A
D: DNA (cytosine-5)-methyltransferase 3A
A: DNA (cytosine-5)-methyltransferase 3A
B: DNA (cytosine-5)-methyltransferase 3A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)436,10922
Polymers433,7876
Non-polymers2,32316
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 / Cysteine methyltransferase DNMT3A / DNA methyltransferase HsaIIIA / DNA MTase HsaIIIA / M.HsaIIIA


Mass: 72297.797 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DNMT3A / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9Y6K1, DNA (cytosine-5-)-methyltransferase, Transferases; Transferring one-carbon groups; Methyltransferases
#2: Chemical
ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Mass: 384.411 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H20N6O5S
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestN
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: DNMT3A / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.2
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.7.1particle selection
2PHENIX1.21.2_5419model refinement
13cryoSPARC3.7.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.66 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 197622 / Symmetry type: POINT
RefinementHighest resolution: 3.66 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00617894
ELECTRON MICROSCOPYf_angle_d0.63824259
ELECTRON MICROSCOPYf_dihedral_angle_d5.6822553
ELECTRON MICROSCOPYf_chiral_restr0.0432626
ELECTRON MICROSCOPYf_plane_restr0.0053186

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