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- PDB-9lq1: Structure of human DNMT3A-TCL1A complex -

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Basic information

Entry
Database: PDB / ID: 9lq1
TitleStructure of human DNMT3A-TCL1A complex
Components
  • Isoform 1 of DNA (cytosine-5)-methyltransferase 3A
  • T-cell leukemia/lymphoma protein 1A
KeywordsTRANSFERASE / complex
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsLiu, Q.T. / Li, J.H.
Funding support China, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Nov 5, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform 1 of DNA (cytosine-5)-methyltransferase 3A
B: T-cell leukemia/lymphoma protein 1A
E: T-cell leukemia/lymphoma protein 1A
F: Isoform 1 of DNA (cytosine-5)-methyltransferase 3A
D: T-cell leukemia/lymphoma protein 1A
C: T-cell leukemia/lymphoma protein 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)258,29012
Polymers257,8976
Non-polymers3926
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 Isoform 1 of DNA (cytosine-5)-methyltransferase 3A / Dnmt3a / Cysteine methyltransferase DNMT3A / DNA methyltransferase HsaIIIA / DNA MTase HsaIIIA / M.HsaIIIA


Mass: 101997.477 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, Transferases; Transferring one-carbon groups; Methyltransferases
#2: Protein
T-cell leukemia/lymphoma protein 1A / Oncogene TCL-1 / Oncogene TCL1 / Protein p14 TCL1


Mass: 13475.537 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TCL1A, TCL1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P56279
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn / 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: Structure of human DNMT3A-TCL1A complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8 / Details: 25mM Tris pH 8.0, 150mM NaCl,5 mM DTT
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
225 mMTris(hydroxymethyl)aminomethaneTris1
35 mMDithiothreitolDTT1
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample was monodisperse
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 / Details: Vitrification carried out in argon atmosphere

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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: 1800 nm / Nominal defocus min: 1100 nm
Image recordingElectron dose: 51.36 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
8PHENIXmodel refinement
13Coot0.9.8.13D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2226401 / Symmetry type: POINT
RefinementHighest resolution: 3.36 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00410916
ELECTRON MICROSCOPYf_angle_d0.5614797
ELECTRON MICROSCOPYf_dihedral_angle_d5.1911457
ELECTRON MICROSCOPYf_chiral_restr0.0411573
ELECTRON MICROSCOPYf_plane_restr0.0051922

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