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- EMDB-64791: CryoEM structure of human DNMT1 (aa 698-1616) in complex with hem... -

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Basic information

Entry
Database: EMDB / ID: EMD-64791
TitleCryoEM structure of human DNMT1 (aa 698-1616) in complex with hemimethylated dsDNA and inhibitor DMT207
Map data
Sample
  • Complex: human DNMT1 in complex with hemimethylated dsDNA and inhibitor DMT207
    • Protein or peptide: DNA (cytosine-5)-methyltransferase 1
    • DNA: DNA (5'-D(*AP*CP*TP*TP*AP*(5CM)P*GP*GP*AP*AP*GP*G)-3')
    • DNA: DNA (5'-D(*CP*CP*TP*TP*CP*CP*GP*TP*AP*AP*GP*T)-3')
  • Ligand: ZINC ION
  • Ligand: S-ADENOSYL-L-HOMOCYSTEINE
  • Ligand: (2~{R})-2-[3,5-dicyano-1-[2-[2-(dimethylamino)ethyl-methyl-amino]-2-oxidanylidene-ethyl]-4-ethyl-pyrrolo[2,3-b]pyridin-6-yl]sulfanyl-2-(4-methoxyphenyl)ethanamide
KeywordsDNA methyltransferas 1 / inhibitor / TRANSFERASE
Function / homology
Function and homology information


histone H3K23ub reader activity / histone H3K18ub reader activity / histone H3K14ub reader activity / : / epigenetic programming of gene expression / chromosomal DNA methylation maintenance following DNA replication / negative regulation of vascular associated smooth muscle cell apoptotic process / DNA-methyltransferase activity / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase ...histone H3K23ub reader activity / histone H3K18ub reader activity / histone H3K14ub reader activity / : / epigenetic programming of gene expression / chromosomal DNA methylation maintenance following DNA replication / negative regulation of vascular associated smooth muscle cell apoptotic process / DNA-methyltransferase activity / cellular response to bisphenol A / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / female germ cell nucleus / SUMOylation of DNA methylation proteins / STAT3 nuclear events downstream of ALK signaling / methyl-CpG binding / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression via chromosomal CpG island methylation / lncRNA binding / pericentric heterochromatin / positive regulation of vascular associated smooth muscle cell proliferation / Nuclear events stimulated by ALK signaling in cancer / heterochromatin / replication fork / DNA methylation / PRC2 methylates histones and DNA / Defective pyroptosis / cellular response to amino acid stimulus / promoter-specific chromatin binding / NoRC negatively regulates rRNA expression / methylation / negative regulation of gene expression / positive regulation of gene expression / DNA-templated transcription / negative regulation of transcription by RNA polymerase II / mitochondrion / DNA binding / zinc ion binding / nucleoplasm / nucleus
Similarity search - Function
DMAP1-binding Domain / DMAP1-binding Domain / DMAP1-binding domain / DMAP1-binding domain profile. / DNA (cytosine-5)-methyltransferase 1, replication foci domain / Cytosine specific DNA methyltransferase replication foci domain / DNA methylase, C-5 cytosine-specific, conserved site / C-5 cytosine-specific DNA methylases C-terminal signature. / CXXC zinc finger domain / Zinc finger, CXXC-type ...DMAP1-binding Domain / DMAP1-binding Domain / DMAP1-binding domain / DMAP1-binding domain profile. / DNA (cytosine-5)-methyltransferase 1, replication foci domain / Cytosine specific DNA methyltransferase replication foci domain / DNA methylase, C-5 cytosine-specific, conserved site / C-5 cytosine-specific DNA methylases C-terminal signature. / CXXC zinc finger domain / Zinc finger, CXXC-type / Zinc finger CXXC-type 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 / Bromo adjacent homology domain / BAH domain / Bromo adjacent homology (BAH) domain / Bromo adjacent homology (BAH) domain superfamily / BAH domain profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
DNA (cytosine-5)-methyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.85 Å
AuthorsLi Z
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82473951 China
CitationJournal: Adv Sci (Weinh) / Year: 2026
Title: Discovery of a Novel DNMT1 Inhibitor with Improved Efficacy in Treating β-Thalassemia.
Authors: Yijie Shen / Jiale Wei / Shibing Tang / Dongliang Wu / Liangyi Zong / Shuyuan Ma / Qing Xiong / Ruijie Gong / Siyuan Xu / Chuxuan Peng / Qin Feng / Songchen Liu / Qitong Liu / Yuhua Ye / ...Authors: Yijie Shen / Jiale Wei / Shibing Tang / Dongliang Wu / Liangyi Zong / Shuyuan Ma / Qing Xiong / Ruijie Gong / Siyuan Xu / Chuxuan Peng / Qin Feng / Songchen Liu / Qitong Liu / Yuhua Ye / Quan Zhao / Cheng Luo / Peng Huang / Zhihai Li / Xiangqian Kong / Xianjiang Lan /
Abstract: β-thalassemia is a recessively inherited blood disorder affecting millions worldwide. Pharmacological induction of fetal hemoglobin (HbF) is an effective therapeutic strategy, yet existing DNA ...β-thalassemia is a recessively inherited blood disorder affecting millions worldwide. Pharmacological induction of fetal hemoglobin (HbF) is an effective therapeutic strategy, yet existing DNA methyltransferase (DNMT) inhibitors, although effective HbF inducers, currently are not approved for β-thalassemia treatment. Here, we report that DMT207, a novel non-nucleoside DNMT1 inhibitor, robustly reactivates HbF in HUDEP-2 cells and adult primary erythroblasts with minimal toxicity. In a mouse model of β-thalassemia, DMT207 effectively elevates the levels of mouse fetal- and embryonic-type hemoglobin, promotes the maturation of erythroid cells, and alleviates the splenomegaly. Further multi-omics analyses expose γ-globin as one of the most sensitive genes with promoter demethylation and transcriptional activation following DMT207 treatment. Mechanistically, DMT207 traps DNMT1 into a catalytically inactive conformation and concurrently enhances its interaction with UHRF1, which partially contributes to DNMT1 degradation. These findings highlight the therapeutic potential of DMT207 for β-thalassemia and support its further preclinical development.
History
DepositionMay 26, 2025-
Header (metadata) releaseApr 8, 2026-
Map releaseApr 8, 2026-
UpdateApr 8, 2026-
Current statusApr 8, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_64791.png

Downloads & links

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Map

FileDownload / File: emd_64791.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 274.176 Å		1.07 Å/pix.
x 256 pix.
= 274.176 Å		1.07 Å/pix.
x 256 pix.
= 274.176 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.071 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.0017425407 - 1.6795522
Average (Standard dev.)0.00073802855 (±0.020566678)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 274.176 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_64791_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_64791_half_map_2.map
Projections & Slices
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Sample components

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Entire : human DNMT1 in complex with hemimethylated dsDNA and inhibitor DMT207

EntireName: human DNMT1 in complex with hemimethylated dsDNA and inhibitor DMT207
Components
  • Complex: human DNMT1 in complex with hemimethylated dsDNA and inhibitor DMT207
    • Protein or peptide: DNA (cytosine-5)-methyltransferase 1
    • DNA: DNA (5'-D(*AP*CP*TP*TP*AP*(5CM)P*GP*GP*AP*AP*GP*G)-3')
    • DNA: DNA (5'-D(*CP*CP*TP*TP*CP*CP*GP*TP*AP*AP*GP*T)-3')
  • Ligand: ZINC ION
  • Ligand: S-ADENOSYL-L-HOMOCYSTEINE
  • Ligand: (2~{R})-2-[3,5-dicyano-1-[2-[2-(dimethylamino)ethyl-methyl-amino]-2-oxidanylidene-ethyl]-4-ethyl-pyrrolo[2,3-b]pyridin-6-yl]sulfanyl-2-(4-methoxyphenyl)ethanamide

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Supramolecule #1: human DNMT1 in complex with hemimethylated dsDNA and inhibitor DMT207

SupramoleculeName: human DNMT1 in complex with hemimethylated dsDNA and inhibitor DMT207
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1, #3, #2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: DNA (cytosine-5)-methyltransferase 1

MacromoleculeName: DNA (cytosine-5)-methyltransferase 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: DNA (cytosine-5-)-methyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 103.882148 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: EADDDEEVDD NIPEMPSPKK MHQGKKKKQN KNRISWVGEA VKTDGKKSYY KKVCIDAETL EVGDCVSVIP DDSSKPLYLA RVTALWEDS SNGQMFHAHW FCAGTDTVLG ATSDPLELFL VDECEDMQLS YIHSKVKVIY KAPSENWAME GGMDPESLLE G DDGKTYFY ...String:
EADDDEEVDD NIPEMPSPKK MHQGKKKKQN KNRISWVGEA VKTDGKKSYY KKVCIDAETL EVGDCVSVIP DDSSKPLYLA RVTALWEDS SNGQMFHAHW FCAGTDTVLG ATSDPLELFL VDECEDMQLS YIHSKVKVIY KAPSENWAME GGMDPESLLE G DDGKTYFY QLWYDQDYAR FESPPKTQPT EDNKFKFCVS CARLAEMRQK EIPRVLEQLE DLDSRVLYYS ATKNGILYRV GD GVYLPPE AFTFNIKLSS PVKRPRKEPV DEDLYPEHYR KYSDYIKGSN LDAPEPYRIG RIKEIFCPKK SNGRPNETDI KIR VNKFYR PENTHKSTPA SYHADINLLY WSDEEAVVDF KAVQGRCTVE YGEDLPECVQ VYSMGGPNRF YFLEAYNAKS KSFE DPPNH ARSPGNKGKG KGKGKGKPKS QACEPSEPEI EIKLPKLRTL DVFSGCGGLS EGFHQAGISD TLWAIEMWDP AAQAF RLNN PGSTVFTEDC NILLKLVMAG ETTNSRGQRL PQKGDVEMLC GGPPCQGFSG MNRFNSRTYS KFKNSLVVSF LSYCDY YRP RFFLLENVRN FVSFKRSMVL KLTLRCLVRM GYQCTFGVLQ AGQYGVAQTR RRAIILAAAP GEKLPLFPEP LHVFAPR AC QLSVVVDDKK FVSNITRLSS GPFRTITVRD TMSDLPEVRN GASALEISYN GEPQSWFQRQ LRGAQYQPIL RDHICKDM S ALVAARMRHI PLAPGSDWRD LPNIEVRLSD GTMARKLRYT HHDRKNGRSS SGALRGVCSC VEAGKACDPA ARQFNTLIP WCLPHTGNRH NHWAGLYGRL EWDGFFSTTV TNPEPMGKQG RVLHPEQHRV VSVRECARSQ GFPDTYRLFG NILDKHRQVG NAVPPPLAK AIGLEIKLCM LAKARESASA KIKEEEAAKD

UniProtKB: DNA (cytosine-5)-methyltransferase 1

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Macromolecule #2: DNA (5'-D(*CP*CP*TP*TP*CP*CP*GP*TP*AP*AP*GP*T)-3')

MacromoleculeName: DNA (5'-D(*CP*CP*TP*TP*CP*CP*GP*TP*AP*AP*GP*T)-3') / type: dna / ID: 2 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.613366 KDa
SequenceString:
(DC)(DC)(DT)(DT)(DC)(DC)(DG)(DT)(DA)(DA) (DG)(DT)

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Macromolecule #3: DNA (5'-D(*AP*CP*TP*TP*AP*(5CM)P*GP*GP*AP*AP*GP*G)-3')

MacromoleculeName: DNA (5'-D(*AP*CP*TP*TP*AP*(5CM)P*GP*GP*AP*AP*GP*G)-3')
type: dna / ID: 3 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.725469 KDa
SequenceString:
(DA)(DC)(DT)(DT)(DA)(5CM)(DG)(DG)(DA)(DA) (DG)(DG)

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Macromolecule #4: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #5: S-ADENOSYL-L-HOMOCYSTEINE

MacromoleculeName: S-ADENOSYL-L-HOMOCYSTEINE / type: ligand / ID: 5 / Number of copies: 1 / Formula: SAH
Molecular weightTheoretical: 384.411 Da
Chemical component information

ChemComp-SAH:
S-ADENOSYL-L-HOMOCYSTEINE

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Macromolecule #6: (2~{R})-2-[3,5-dicyano-1-[2-[2-(dimethylamino)ethyl-methyl-amino]...

MacromoleculeName: (2~{R})-2-[3,5-dicyano-1-[2-[2-(dimethylamino)ethyl-methyl-amino]-2-oxidanylidene-ethyl]-4-ethyl-pyrrolo[2,3-b]pyridin-6-yl]sulfanyl-2-(4-methoxyphenyl)ethanamide
type: ligand / ID: 6 / Number of copies: 1 / Formula: A1EQ2
Molecular weightTheoretical: 533.645 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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 72.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 338318
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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