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- EMDB-63290: Structure of human DNMT3A-TCL1A complex -

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Basic information

Entry
Database: EMDB / ID: EMD-63290
TitleStructure of human DNMT3A-TCL1A complex
Map data
Sample
  • Complex: Structure of human DNMT3A-TCL1A complex
    • Protein or peptide: Isoform 1 of DNA (cytosine-5)-methyltransferase 3A
    • Protein or peptide: T-cell leukemia/lymphoma protein 1A
  • Ligand: ZINC ION
Keywordscomplex / 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 / cellular response to bisphenol A / unmethylated CpG binding / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / autosome genomic imprinting / SUMOylation of DNA methylation proteins ...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 / DNA (cytosine-5-)-methyltransferase activity / 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 / hepatocyte apoptotic process / negative regulation of gene expression via chromosomal CpG island methylation / lncRNA binding / cellular response to ethanol / chromosome, centromeric region / catalytic complex / heterochromatin / Transferases; Transferring one-carbon groups; Methyltransferases / DNA methylation / protein serine/threonine kinase activator activity / 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 / 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 / intracellular signal transduction / RNA polymerase II cis-regulatory region sequence-specific DNA binding / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / chromatin binding / protein kinase binding / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / DNA binding / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
TCL1/MTCP1 / TCL1/MTCP1 superfamily / TCL1/MTCP1 family / 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 ...TCL1/MTCP1 / TCL1/MTCP1 superfamily / TCL1/MTCP1 family / 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
T-cell leukemia/lymphoma protein 1A / DNA (cytosine-5)-methyltransferase 3A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsLiu QT / Li JH
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2026
Title: Molecular basis for the inhibition of de novo DNA methylation by TCL1A.
Authors: Qingting Liu / Jinhong Li / Xiaoxiao Wang / Yaozong Li / Yu Wu / Zhuo Han / Zixin Guo / Li Guo / Xiang Wang / Gang Yuan / Zheng Gao / Lei Li / Dong Deng /
Abstract: DNA methyltransferases DNMT3A/B mediate de novo DNA methylation, essential for embryonic development and cell fate determination. Dysregulation of DNMT3A/B causes developmental defects and ...DNA methyltransferases DNMT3A/B mediate de novo DNA methylation, essential for embryonic development and cell fate determination. Dysregulation of DNMT3A/B causes developmental defects and tumorigenesis. TCL1A is critical for embryogenesis but promotes lymphomagenesis when deregulated. Previous studies suggested TCL1A binds DNMT3A/B and inhibits their activity, but the mechanism remained unclear. Here, we report the cryo-EM structure of the DNMT3A-TCL1A complex, which comprises a DNMT3A dimer bound by two TCL1A dimers. TCL1A interacts with the catalytic domain of DNMT3A, overlapping with the DNMT3L-binding site, and induces extended conformational rearrangements. The target recognition domain and catalytic loop shift markedly, reducing DNA accessibility, while the catalytic loop occupies the SAM-binding pocket, thereby blocking methyltransferase activity. Supported by biochemical assays and molecular dynamics simulations, we propose a dynamic inhibition mechanism in which TCL1A exploits DNMT3A conformational plasticity to suppress de novo DNA methylation.
History
DepositionJan 27, 2025-
Header (metadata) releaseNov 5, 2025-
Map releaseNov 5, 2025-
UpdateApr 15, 2026-
Current statusApr 15, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63290.png

Downloads & links

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Map

FileDownload / File: emd_63290.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 300 pix.
= 330. Å		1.1 Å/pix.
x 300 pix.
= 330. Å		1.1 Å/pix.
x 300 pix.
= 330. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-1.564861 - 2.0969105
Average (Standard dev.)-0.0002915931 (±0.03242038)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 330.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_63290_additional_1.map
Projections & Slices
AxesZYX

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Half map: #2

Fileemd_63290_half_map_1.map
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Histogram

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Half map: #1

Fileemd_63290_half_map_2.map
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Sample components

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Entire : Structure of human DNMT3A-TCL1A complex

EntireName: Structure of human DNMT3A-TCL1A complex
Components
  • Complex: Structure of human DNMT3A-TCL1A complex
    • Protein or peptide: Isoform 1 of DNA (cytosine-5)-methyltransferase 3A
    • Protein or peptide: T-cell leukemia/lymphoma protein 1A
  • Ligand: ZINC ION

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Supramolecule #1: Structure of human DNMT3A-TCL1A complex

SupramoleculeName: Structure of human DNMT3A-TCL1A complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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

MacromoleculeName: Isoform 1 of 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: 101.997477 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MPAMPSSGPG DTSSSAAERE EDRKDGEEQE EPRGKEERQE PSTTARKVGR PGRKRKHPPV ESGDTPKDPA VISKSPSMAQ DSGASELLP NGDLEKRSEP QPEEGSPAGG QKGGAPAEGE GAAETLPEAS RAVENGCCTP KEGRGAPAEA GKEQKETNIE S MKMEGSRG ...String:
MPAMPSSGPG DTSSSAAERE EDRKDGEEQE EPRGKEERQE PSTTARKVGR PGRKRKHPPV ESGDTPKDPA VISKSPSMAQ DSGASELLP NGDLEKRSEP QPEEGSPAGG QKGGAPAEGE GAAETLPEAS RAVENGCCTP KEGRGAPAEA GKEQKETNIE S MKMEGSRG RLRGGLGWES SLRQRPMPRL TFQAGDPYYI SKRKRDEWLA RWKREAEKKA KVIAGMNAVE ENQGPGESQK VE EASPPAV QQPTDPASPT VATTPEPVGS DAGDKNATKA GDDEPEYEDG RGFGIGELVW GKLRGFSWWP GRIVSWWMTG RSR AAEGTR WVMWFGDGKF SVVCVEKLMP LSSFCSAFHQ ATYNKQPMYR KAIYEVLQVA SSRAGKLFPV CHDSDESDTA KAVE VQNKP MIEWALGGFQ PSGPKGLEPP EEEKNPYKEV YTDMWVEPEA AAYAPPPPAK KPRKSTAEKP KVKEIIDERT RERLV YEVR QKCRNIEDIC ISCGSLNVTL EHPLFVGGMC QNCKNCFLEC AYQYDDDGYQ SYCTICCGGR EVLMCGNNNC CRCFCV ECV DLLVGPGAAQ AAIKEDPWNC YMCGHKGTYG LLRRREDWPS RLQMFFANNH DQEFDPPKVY PPVPAEKRKP IRVLSLF DG IATGLLVLKD LGIQVDRYIA SEVCEDSITV GMVRHQGKIM YVGDVRSVTQ KHIQEWGPFD LVIGGSPCND LSIVNPAR K GLYEGTGRLF FEFYRLLHDA RPKEGDDRPF FWLFENVVAM GVSDKRDISR FLESNPVMID AKEVSAAHRA RYFWGNLPG MNRPLASTVN DKLELQECLE HGRIAKFSKV RTITTRSNSI KQGKDQHFPV FMNEKEDILW CTEMERVFGF PVHYTDVSNM SRLARQRLL GRSWSVPVIR HLFAPLKEYF ACV

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

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Macromolecule #2: T-cell leukemia/lymphoma protein 1A

MacromoleculeName: T-cell leukemia/lymphoma protein 1A / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.475537 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MAECPTLGEA VTDHPDRLWA WEKFVYLDEK QHAWLPLTIE IKDRLQLRVL LRREDVVLGR PMTPTQIGPS LLPIMWQLYP DGRYRSSDS SFWRLVYHIK IDGVEDMLLE LLPDD

UniProtKB: T-cell leukemia/lymphoma protein 1A

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 6 / 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

Concentration2.0 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
25.0 mMTrisTris(hydroxymethyl)aminomethane
5.0 mMDTTDithiothreitol

Details: 25mM Tris pH 8.0, 150mM NaCl,5 mM DTT
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: Vitrification carried out in argon atmosphere.
DetailsThis sample was monodisperse

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 51.36 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.1 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: Coot (ver. 0.9.8.1) / Number images used: 2226401
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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