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- EMDB-62000: Cryo-EM structure of USP7:DNMT1 complex; open conformation -

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Basic information

Entry
Database: EMDB / ID: EMD-62000
TitleCryo-EM structure of USP7:DNMT1 complex; open conformation
Map data
Sample
  • Complex: DNMT1:USP7
    • Protein or peptide: Ubiquitin carboxyl-terminal hydrolase 7
    • Protein or peptide: DNA (cytosine-5)-methyltransferase 1
KeywordsDNA methylation / deubiquitination / STRUCTURAL PROTEIN
Function / homology
Function and homology information


histone H3K23ub reader activity / histone H3K18ub reader activity / histone H3K14ub reader activity / : / epigenetic programming of gene expression / regulation of telomere capping / regulation of establishment of protein localization to telomere / chromosomal DNA methylation maintenance following DNA replication / negative regulation of vascular associated smooth muscle cell apoptotic process / monoubiquitinated protein deubiquitination ...histone H3K23ub reader activity / histone H3K18ub reader activity / histone H3K14ub reader activity / : / epigenetic programming of gene expression / regulation of telomere capping / regulation of establishment of protein localization to telomere / chromosomal DNA methylation maintenance following DNA replication / negative regulation of vascular associated smooth muscle cell apoptotic process / monoubiquitinated protein deubiquitination / DNA-methyltransferase activity / regulation of retrograde transport, endosome to Golgi / cellular response to bisphenol A / deubiquitinase activity / DNA (cytosine-5-)-methyltransferase / : / DNA (cytosine-5-)-methyltransferase activity / female germ cell nucleus / DNA alkylation repair / SUMOylation of DNA methylation proteins / STAT3 nuclear events downstream of ALK signaling / methyl-CpG binding / K48-linked deubiquitinase activity / symbiont-mediated disruption of host cell PML body / DNA methylation-dependent constitutive heterochromatin formation / negative regulation of gene expression via chromosomal CpG island methylation / lncRNA binding / protein deubiquitination / negative regulation of gluconeogenesis / pericentric heterochromatin / positive regulation of vascular associated smooth muscle cell proliferation / heterochromatin / Nuclear events stimulated by ALK signaling in cancer / negative regulation of TORC1 signaling / transcription-coupled nucleotide-excision repair / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / Regulation of PTEN localization / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / regulation of signal transduction by p53 class mediator / replication fork / DNA methylation / PRC2 methylates histones and DNA / Defective pyroptosis / cellular response to amino acid stimulus / promoter-specific chromatin binding / regulation of protein stability / regulation of circadian rhythm / PML body / NoRC negatively regulates rRNA expression / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / p53 binding / Regulation of TP53 Degradation / rhythmic process / chromosome / methylation / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / Ub-specific processing proteases / protein stabilization / nuclear body / protein ubiquitination / negative regulation of gene expression / cysteine-type endopeptidase activity / positive regulation of gene expression / DNA-templated transcription / negative regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / proteolysis / DNA binding / zinc ion binding / nucleoplasm / nucleus / cytosol
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 / Ubiquitin carboxyl-terminal hydrolase 7, ICP0-binding domain / ICP0-binding domain of Ubiquitin-specific protease 7 / DNA methylase, C-5 cytosine-specific, conserved site / C-5 cytosine-specific DNA methylases C-terminal signature. ...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 / Ubiquitin carboxyl-terminal hydrolase 7, ICP0-binding domain / ICP0-binding domain of Ubiquitin-specific protease 7 / DNA methylase, C-5 cytosine-specific, conserved site / C-5 cytosine-specific DNA methylases C-terminal signature. / Ubiquitin carboxyl-terminal hydrolase, C-terminal / Ubiquitin-specific protease C-terminal / MATH domain / CXXC zinc finger domain / Zinc finger, CXXC-type / Zinc finger CXXC-type profile. / : / : / MATH/TRAF domain / MATH/TRAF domain profile. / meprin and TRAF homology / TRAF-like / 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. / Ubiquitin specific protease (USP) domain signature 2. / Ubiquitin specific protease (USP) domain signature 1. / Ubiquitin specific protease, conserved site / Peptidase C19, ubiquitin carboxyl-terminal hydrolase / Ubiquitin carboxyl-terminal hydrolase / Ubiquitin specific protease domain / Ubiquitin specific protease (USP) domain profile. / Papain-like cysteine peptidase superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
DNA (cytosine-5)-methyltransferase 1 / Ubiquitin carboxyl-terminal hydrolase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.75 Å
AuthorsNakamura N / Arita K
Funding support Japan, 6 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)JP18H02392 Japan
Japan Society for the Promotion of Science (JSPS)JP19H05294 Japan
Japan Society for the Promotion of Science (JSPS)JP19H05741 Japan
Japan Society for the Promotion of Science (JSPS)19H05285 Japan
Japan Society for the Promotion of Science (JSPS)21H00272 Japan
Japan Society for the Promotion of Science (JSPS)24K02001 Japan
CitationJournal: Structure / Year: 2025
Title: Structures of USP7 in active and inactive states bound to DNMT1 revealed by cryo-EM.
Authors: Nao Nakamura / Sae Yoshimi / Amika Kikuchi / Hiroki Onoda / Satomi Kori / Makoto Nakanishi / Atsuya Nishiyama / Kyohei Arita /
Abstract: The ubiquitin signal generated by UHRF1 is essential for DNA methylation maintenance by recruiting DNA methyltransferase 1 (DNMT1) to hemimethylated DNA through strong binding of its replication foci ...The ubiquitin signal generated by UHRF1 is essential for DNA methylation maintenance by recruiting DNA methyltransferase 1 (DNMT1) to hemimethylated DNA through strong binding of its replication foci targeting sequence (RFTS) domain to ubiquitinated histone H3. The ubiquitin-specific protease 7 (USP7) forms a complex with DNMT1 and removes ubiquitin from H3. However, it remains unknown how USP7 deubiquitinates ubiquitinated H3 upon strong binding of the DNMT1 RFTS domain. Here, we show the activation mechanism of USP7 by combining biochemical and structural studies. USP7 is inactive toward ubiquitinated H3 in complex with the RFTS domain. However, when complexed with DNMT1, USP7 efficiently deubiquitinates ubiquitinated H3. Cryogenic electron microscopy (cryo-EM) single particle analysis revealed that USP7 bound to DNMT1 undergoes an open (inactive) and closed (active) conformational transition. Our findings provide mechanistic insights into the activation of USP7 upon binding to DNMT1 and contribute to a better understanding of the deubiquitination process in DNA methylation maintenance.
History
DepositionOct 18, 2024-
Header (metadata) releaseJun 25, 2025-
Map releaseJun 25, 2025-
UpdateJan 14, 2026-
Current statusJan 14, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_62000.png

Downloads & links

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Map

FileDownload / File: emd_62000.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1.38 Å/pix.
x 180 pix.
= 248.55 Å		1.38 Å/pix.
x 180 pix.
= 248.55 Å		1.38 Å/pix.
x 180 pix.
= 248.55 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.38083 Å
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Contour LevelBy AUTHOR: 0.0565
Minimum - Maximum-0.61594594 - 1.0313601
Average (Standard dev.)0.00079884223 (±0.024366844)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 248.54999 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_62000_msk_1.map
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Half map: #2

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Half map: #1

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Sample components

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Entire : DNMT1:USP7

EntireName: DNMT1:USP7
Components
  • Complex: DNMT1:USP7
    • Protein or peptide: Ubiquitin carboxyl-terminal hydrolase 7
    • Protein or peptide: DNA (cytosine-5)-methyltransferase 1

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Supramolecule #1: DNMT1:USP7

SupramoleculeName: DNMT1:USP7 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Ubiquitin carboxyl-terminal hydrolase 7

MacromoleculeName: Ubiquitin carboxyl-terminal hydrolase 7 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: ubiquitinyl hydrolase 1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 128.884203 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: GPLGSMNHQQ QQQQQKAGEQ QLSEPEDMEM EAGDTDDPPR ITQNPVINGN VALSDGHNTA EEDMEDDTSW RSEATFQFTV ERFSRLSES VLSPPCFVRN LPWKIMVMPR FYPDRPHQKS VGFFLQCNAE SDSTSWSCHA QAVLKIINYR DDEKSFSRRI S HLFFHKEN ...String:
GPLGSMNHQQ QQQQQKAGEQ QLSEPEDMEM EAGDTDDPPR ITQNPVINGN VALSDGHNTA EEDMEDDTSW RSEATFQFTV ERFSRLSES VLSPPCFVRN LPWKIMVMPR FYPDRPHQKS VGFFLQCNAE SDSTSWSCHA QAVLKIINYR DDEKSFSRRI S HLFFHKEN DWGFSNFMAW SEVTDPEKGF IDDDKVTFEV FVQADAPHGV AWDSKKHTGY VGLKNQGATC YMNSLLQTLF FT NQLRKAV YMMPTEGDDS SKSVPLALQR VFYELQHSDK PVGTKKLTKS FGWETLDSFM QHDVQELCRV LLDNVENKMK GTC VEGTIP KLFRGKMVSY IQCKEVDYRS DRREDYYDIQ LSIKGKKNIF ESFVDYVAVE QLDGDNKYDA GEHGLQEAEK GVKF LTLPP VLHLQLMRFM YDPQTDQNIK INDRFEFPEQ LPLDEFLQKT DPKDPANYIL HAVLVHSGDN HGGHYVVYLN PKGDG KWCK FDDDVVSRCT KEEAIEHNYG GHDDDLSVRH CTNAYMLVYI RESKLSEVLQ AVTDHDIPQQ LVERLQEEKR IEAQKR KER QEAHLYMQVQ IVAEDQFCGH QGNDMYDEEK VKYTVFKVLK NSSLAEFVQS LSQTMGFPQD QIRLWPMQAR SNGTKRP AM LDNEADGNKT MIELSDNENP WTIFLETVDP ELAASGATLP KFDKDHDVML FLKMYDPKTR SLNYCGHIYT PISCKIRD L LPVMCDRAGF IQDTSLILYE EVKPNLTERI QDYDVSLDKA LDELMDGDII VFQKDDPEND NSELPTAKEY FRDLYHRVD VIFCDKTIPN DPGFVVTLSN RMNYFQVAKT VAQRLNTDPM LLQFFKSQGY RDGPGNPLRH NYEGTLRDLL QFFKPRQPKK LYYQQLKMK ITDFENRRSF KCIWLNSQFR EEEITLYPDK HGCVRDLLEE CKKAVELGEK ASGKLRLLEI VSYKIIGVHQ E DELLECLS PATSRTFRIE EIPLDQVDID KENEMLVTVA HFHKEVFGTF GIPFLLRIHQ GEHFREVMKR IQSLLDIQEK EF EKFKFAI VMMGRHQYIN EDEYEVNLKD FEPQPGNMSH PRPWLGLDHF NKAPKRSRYT YLEKAIKIHN

UniProtKB: Ubiquitin carboxyl-terminal hydrolase 7

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Macromolecule #2: DNA (cytosine-5)-methyltransferase 1

MacromoleculeName: DNA (cytosine-5)-methyltransferase 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: DNA (cytosine-5-)-methyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 143.559531 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GPPTTPKCIQ CGQYLDDPDL KYGQHPPDAV DEPQMLTNEK LSIFDANESG FESYEALPQH KLTCFSVYCK HGHLCPIDTG LIEKNIELF FSGSAKPIYD DDPSLEGGVN GKNLGPINEW WITGFDGGEK ALIGFSTSFA EYILMDPSPE YAPIFGLMQE K IYISKIVV ...String:
GPPTTPKCIQ CGQYLDDPDL KYGQHPPDAV DEPQMLTNEK LSIFDANESG FESYEALPQH KLTCFSVYCK HGHLCPIDTG LIEKNIELF FSGSAKPIYD DDPSLEGGVN GKNLGPINEW WITGFDGGEK ALIGFSTSFA EYILMDPSPE YAPIFGLMQE K IYISKIVV EFLQSNSDST YEDLINKIET TVPPSGLNLN RFTEDSLLRH AQFVVEQVES YDEAGDSDEQ PIFLTPCMRD LI KLAGVTL GQRRAQARRQ TIRHSTREKD RGPTKATTTK LVYQIFDTFF AEQIEKDDRE DKENAFKRRR CGVCEVCQQP ECG KCKACK DMVKFGGSGR SKQACQERRC PNMAMKEADD DEEVDDNIPE MPSPKKMHQG KKKKQNKNRI SWVGEAVKTD GKKS YYKKV CIDAETLEVG DCVSVIPDDS SKPLYLARVT ALWEDSSNGQ MFHAHWFCAG TDTVLGATSD PLELFLVDEC EDMQL SYIH SKVKVIYKAP SENWAMEGGM DPESLLEGDD GKTYFYQLWY DQDYARFESP PKTQPTEDNK FKFCVSCARL AEMRQK EIP RVLEQLEDLD SRVLYYSATK NGILYRVGDG VYLPPEAFTF NIKLSSPVKR PRKEPVDEDL YPEHYRKYSD YIKGSNL DA PEPYRIGRIK EIFCPKKSNG RPNETDIKIR VNKFYRPENT HKSTPASYHA DINLLYWSDE EAVVDFKAVQ GRCTVEYG E DLPECVQVYS MGGPNRFYFL EAYNAKSKSF EDPPNHARSP GNKGKGKGKG KGKPKSQACE PSEPEIEIKL PKLRTLDVF SGCGGLSEGF HQAGISDTLW AIEMWDPAAQ AFRLNNPGST VFTEDCNILL KLVMAGETTN SRGQRLPQKG DVEMLCGGPP CQGFSGMNR FNSRTYSKFK NSLVVSFLSY CDYYRPRFFL LENVRNFVSF KRSMVLKLTL RCLVRMGYQC TFGVLQAGQY G VAQTRRRA IILAAAPGEK LPLFPEPLHV FAPRACQLSV VVDDKKFVSN ITRLSSGPFR TITVRDTMSD LPEVRNGASA LE ISYNGEP QSWFQRQLRG AQYQPILRDH ICKDMSALVA ARMRHIPLAP GSDWRDLPNI EVRLSDGTMA RKLRYTHHDR KNG RSSSGA LRGVCSCVEA GKACDPAARQ FNTLIPWCLP HTGNRHNHWA GLYGRLEWDG FFSTTVTNPE PMGKQGRVLH PEQH RVVSV RECARSQGFP DTYRLFGNIL DKHRQVGNAV PPPLAKAIGL EIKLCMLAKA RESASAKIKE EEAAKD

UniProtKB: DNA (cytosine-5)-methyltransferase 1

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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: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 62.918 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 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: PDB ENTRY
PDB model - PDB ID:

4wxx

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.75 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 73679
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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