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- PDB-9v5p: Human DNMT1 (aa 698-1616) in complex with hemimethylated dsDNA an... -

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Basic information

Entry
Database: PDB / ID: 9v5p
TitleHuman DNMT1 (aa 698-1616) in complex with hemimethylated dsDNA and inhibitor DMT207
Components
  • DNA (5'-D(*AP*CP*TP*TP*AP*(5CM)P*GP*GP*AP*AP*GP*G)-3')
  • DNA (5'-D(*CP*CP*TP*TP*CP*CP*GP*TP*AP*AP*GP*T)-3')
  • DNA (cytosine-5)-methyltransferase 1
KeywordsTRANSFERASE / DNA methyltransferas 1 / inhibitor
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
: / S-ADENOSYL-L-HOMOCYSTEINE / DNA / DNA (> 10) / DNA (cytosine-5)-methyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.85 Å
AuthorsLi, Z.
Funding support China, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Apr 8, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: DNA (cytosine-5)-methyltransferase 1
E: DNA (5'-D(*CP*CP*TP*TP*CP*CP*GP*TP*AP*AP*GP*T)-3')
B: DNA (5'-D(*AP*CP*TP*TP*AP*(5CM)P*GP*GP*AP*AP*GP*G)-3')
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,2707
Polymers111,2213
Non-polymers1,0494
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 1 molecules A

#1: Protein DNA (cytosine-5)-methyltransferase 1 / Dnmt1 / CXXC-type zinc finger protein 9 / DNA methyltransferase HsaI / DNA MTase HsaI / M.HsaI / MCMT


Mass: 103882.148 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DNMT1, AIM, CXXC9, DNMT / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P26358, DNA (cytosine-5-)-methyltransferase

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DNA chain , 2 types, 2 molecules EB

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


Mass: 3613.366 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: DNA chain DNA (5'-D(*AP*CP*TP*TP*AP*(5CM)P*GP*GP*AP*AP*GP*G)-3')


Mass: 3725.469 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Non-polymers , 3 types, 4 molecules

#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Mass: 384.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N6O5S
#6: Chemical ChemComp-A1EQ2 / (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


Mass: 533.645 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H31N7O3S

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Details

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: human DNMT1 in complex with hemimethylated dsDNA and inhibitor DMT207
Type: COMPLEX / Entity ID: #1, #3, #2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
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: 3000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 72 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.14_3260model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 338318 / Symmetry type: POINT
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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