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- PDB-9v36: Human DNMT1 (aa 698-1616) bound to hemimethylated dsDNA and Inhib... -

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Basic information

Entry
Database: PDB / ID: 9v36
TitleHuman DNMT1 (aa 698-1616) bound to hemimethylated dsDNA and Inhibitor DMI26
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 Methyltransferase 1 / DNA methylation inhibitor
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
: / 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: 2.77 Å
AuthorsLi, Z.
Funding support China, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 18, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)112,2407
Polymers111,2213
Non-polymers1,0194
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 BE

#2: 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)
#3: 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)

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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-A1EQT / (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


Mass: 503.619 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H29N7O2S / Feature type: SUBJECT OF INVESTIGATION

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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 bound to hemimethylated dsDNA and DMI26 / Type: COMPLEX / Entity ID: #1-#3 / 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 softwareName: PHENIX / Version: 1.14_3260 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 394295 / Symmetry type: POINT
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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