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- EMDB-64750: CryoEM structure of human DNMT1 (aa 698-1616) bound to hemimethyl... -

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Entry
Database: EMDB / ID: EMD-64750
TitleCryoEM structure of human DNMT1 (aa 698-1616) bound to hemimethylated dsDNA and Inhibitor DMI26
Map data
Sample
  • Complex: human DNMT1 bound to hemimethylated dsDNA and DMI26
    • 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-phenyl-ethanamide
KeywordsDNA Methyltransferase 1 / DNA methylation inhibitor / TRANSFERASE
Function / homology
Function and homology information


histone H3K23ub reader activity / negative regulation of phenotypic switching / histone H3K18ub reader activity / histone H3K14ub reader activity / negative regulation of vascular associated smooth muscle cell differentiation / chromosomal DNA methylation maintenance following DNA replication / negative regulation of vascular associated smooth muscle cell apoptotic process / DNA-methyltransferase activity / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity ...histone H3K23ub reader activity / negative regulation of phenotypic switching / histone H3K18ub reader activity / histone H3K14ub reader activity / negative regulation of vascular associated smooth muscle cell differentiation / chromosomal DNA methylation maintenance following DNA replication / negative regulation of vascular associated smooth muscle cell apoptotic process / DNA-methyltransferase activity / DNA (cytosine-5-)-methyltransferase / DNA (cytosine-5-)-methyltransferase activity / STAT3 nuclear events downstream of ALK signaling / SUMOylation of DNA methylation proteins / methyl-CpG binding / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression via chromosomal CpG island methylation / lncRNA binding / positive regulation of vascular associated smooth muscle cell proliferation / pericentric heterochromatin / heterochromatin / Nuclear events stimulated by ALK signaling in cancer / DNA methylation / PRC2 methylates histones and DNA / Defective pyroptosis / replication fork / promoter-specific chromatin binding / NoRC negatively regulates rRNA expression / chromosome / negative regulation of gene expression / positive regulation of gene expression / 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: 2.77 Å
AuthorsLi Z
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82473951 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2026
Title: Structure-guided design of 7-azaindole DNMT1 inhibitors active against hypomethylating agent-resistant acute myeloid leukemia.
Authors: Shibing Tang / Liangyi Zong / Shuyuan Ma / Yini Shang / Jiale Wei / Jianguang Liu / Ying Cui / Huahui Guo / Kang Zou / Kezhi Wang / Hongkun Li / Fei Ye / Jing Huang / Cheng Luo / Zhihai Li / ...Authors: Shibing Tang / Liangyi Zong / Shuyuan Ma / Yini Shang / Jiale Wei / Jianguang Liu / Ying Cui / Huahui Guo / Kang Zou / Kezhi Wang / Hongkun Li / Fei Ye / Jing Huang / Cheng Luo / Zhihai Li / Stephen B Baylin / Xiangqian Kong /
Abstract: Pharmacological reversal of abnormal promoter DNA hypermethylation at tumor suppressor genes (TSGs) is a key therapeutic paradigm for cancer management. However, the clinical efficacy of currently ...Pharmacological reversal of abnormal promoter DNA hypermethylation at tumor suppressor genes (TSGs) is a key therapeutic paradigm for cancer management. However, the clinical efficacy of currently approved nucleoside analog hypomethylating agents (HMAs) is limited by dose-dependent toxicity and high resistance rates. Nonnucleoside, DNA methyltransferase 1 (DNMT1)-selective inhibitors offer a promising alternative. To date, only limited chemotypes, exemplified by the dicyanopyridine derivative GSK3685032 (GSK5032), have demonstrated translatable DNMT1 inhibition, with resistance emerging upon prolonged exposure. To address these limitations, we employ structure-guided scaffold hopping and chemical optimization to develop a series of DNMT1 inhibitors (DNMT1i) featuring a bicyclic 7-azaindole scaffold. We identify DMI46, a potent enzymatic DNMT1i capable of reversing cancer-specific DNA methylation abnormalities and TSG silencing, leading to robust antileukemic effects and favorable tolerability. Cryoelectron microscopy (cryo-EM) studies reveal that the 7-azaindole inhibitor exhibits enhanced intercalation into hemi-methylated CpG dyads and increased minor-groove contacts within the DNMT1/hemimethylated DNA complex compared to GSK5032. These structural features enable sustained DNMT1 targeting and significant antiproliferative activity of DMI46 in GSK5032-resistant acute myeloid leukemia (AML) cells. We also demonstrate DMI46's capacity to overcome AML resistance to nucleoside-based HMAs both in vitro and in vivo. These findings introduce a distinct DNMT1i chemotype with enhanced on-target engagement and broad applicability against HMA-resistant AML.
History
DepositionMay 21, 2025-
Header (metadata) releaseMar 18, 2026-
Map releaseMar 18, 2026-
UpdateSep 30, 2026-
Current statusSep 30, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_64750.png

Downloads & links

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Map

FileDownload / File: emd_64750.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: 0.25
Minimum - Maximum-0.0016970779 - 1.9619055
Average (Standard dev.)0.0007797566 (±0.020943116)
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: #1

Fileemd_64750_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_64750_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : human DNMT1 bound to hemimethylated dsDNA and DMI26

EntireName: human DNMT1 bound to hemimethylated dsDNA and DMI26
Components
  • Complex: human DNMT1 bound to hemimethylated dsDNA and DMI26
    • 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-phenyl-ethanamide

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Supramolecule #1: human DNMT1 bound to hemimethylated dsDNA and DMI26

SupramoleculeName: human DNMT1 bound to hemimethylated dsDNA and DMI26 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
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(*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: 2 / 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 #3: 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: 3 / 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 #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-phenyl-ethanamide
type: ligand / ID: 6 / Number of copies: 1 / Formula: A1EQT
Molecular weightTheoretical: 503.619 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: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 394295
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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