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- EMDB-72976: Human EEPD1 EEP domain dimer -

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Basic information

Entry
Database: EMDB / ID: EMD-72976
TitleHuman EEPD1 EEP domain dimer
Map data
Sample
  • Complex: Human endonuclease/exonuclease/phosphatase family domain-containing protein 1
    • Protein or peptide: Endonuclease/exonuclease/phosphatase family domain-containing protein 1
KeywordsEndonuclease/Exonuclease/Phosphatase Fold / dimerization / helix-hairpin-helix domains / replication stress response / DNA BINDING PROTEIN
Function / homology
Function and homology information


catalytic activity / positive regulation of cholesterol efflux / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / DNA repair / DNA binding / plasma membrane
Similarity search - Function
Competence protein ComEA, helix-hairpin-helix domain / : / Helix-hairpin-helix motif / Endonuclease/exonuclease/phosphatase / Endonuclease/Exonuclease/phosphatase family / RuvA domain 2-like / Endonuclease/exonuclease/phosphatase superfamily / Helix-hairpin-helix DNA-binding motif, class 1 / Helix-hairpin-helix DNA-binding motif class 1
Similarity search - Domain/homology
Endonuclease/exonuclease/phosphatase family domain-containing protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsLiu M / Shen R / Tainer J
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)P01 CA092584 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 CA220430 United States
CitationJournal: Nucleic Acids Res / Year: 2026
Title: EEPD1 evolved a unique DNA clamping dimer protecting reversed replication forks.
Authors: Runze Shen / Altaf H Sarker / Yue Chen / Min Liu / Sunetra Roy / Andrew S Arvai / Albino Bacolla / Zamal Ahmed / Panagiotis Katsonis / Michal Hammel / Isao Kuraoka / Miaw-Sheue Tsai / ...Authors: Runze Shen / Altaf H Sarker / Yue Chen / Min Liu / Sunetra Roy / Andrew S Arvai / Albino Bacolla / Zamal Ahmed / Panagiotis Katsonis / Michal Hammel / Isao Kuraoka / Miaw-Sheue Tsai / Corydon Irie / Lukas Webb / Olivier Lichtarge / Chi-Lin Tsai / Susan E Tsutakawa / Katharina Schlacher / John A Tainer /
Abstract: Exonuclease/endonuclease/phosphatase (EEP)-fold hydrolases are canonically monomeric phosphodiesterases exemplified by APE1, DNase I, and TDP2 nucleases. While EEP family domain containing protein 1 ...Exonuclease/endonuclease/phosphatase (EEP)-fold hydrolases are canonically monomeric phosphodiesterases exemplified by APE1, DNase I, and TDP2 nucleases. While EEP family domain containing protein 1 (EEPD1) acts in DNA stress responses, its proposed nuclease activities are enigmatic. Here, we integrate hybrid structural methods, evolution, biochemistry, cancer genomics, plus molecular and cell biology to define EEPD1 structure, assembly, and function at stalled DNA replication forks. Results imply EEPD1 surprisingly requires both unique EEP domain dimer and distinctive tandem Helix-hairpin-Helix [(HhH)2] domains to clamp double-stranded (ds) DNA at reversed DNA replication forks for fork protection. Small-angle X-ray Scattering (SAXS), crystal, and cryo-EM structures unveil an unprecedented tryptophan handshake dimer, conserved interface di-Trp-Pro pocket, and adjustable "wrist" enabling an open-closed conformational switch. EEPD1 dimer cooperatively binds complex dsDNA replication fork intermediates but alone lacks nuclease activity due to loss of key EEP catalytic residues during Metazoan evolution and atmospheric oxygen buildup. Instead, EEPD1 prevents nucleolytic degradation of reversed replication forks by MRE11. Furthermore, cancer bioinformatics support oxidative damage-dependent EEPD1 association as a significant modulator of overall patient survival. Collective findings uncover unexpected EEP dimer and fork protection function in clamping, not cleaving, reversed replication forks for metazoan oxidative stress responses controlling genome stability and cancer outcomes.
History
DepositionOct 1, 2025-
Header (metadata) releaseApr 15, 2026-
Map releaseApr 15, 2026-
UpdateApr 15, 2026-
Current statusApr 15, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72976.png

Downloads & links

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Map

FileDownload / File: emd_72976.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.79 Å/pix.
x 300 pix.
= 236.4 Å		0.79 Å/pix.
x 300 pix.
= 236.4 Å		0.79 Å/pix.
x 300 pix.
= 236.4 Å

Surface

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Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.788 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.6255512 - 0.9489201
Average (Standard dev.)-0.00020017337 (±0.016012516)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 236.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_72976_msk_1.map
Projections & Slices
AxesZYX

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Half map: #2

Fileemd_72976_half_map_1.map
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Half map: #1

Fileemd_72976_half_map_2.map
Projections & Slices
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Sample components

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Entire : Human endonuclease/exonuclease/phosphatase family domain-containi...

EntireName: Human endonuclease/exonuclease/phosphatase family domain-containing protein 1
Components
  • Complex: Human endonuclease/exonuclease/phosphatase family domain-containing protein 1
    • Protein or peptide: Endonuclease/exonuclease/phosphatase family domain-containing protein 1

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Supramolecule #1: Human endonuclease/exonuclease/phosphatase family domain-containi...

SupramoleculeName: Human endonuclease/exonuclease/phosphatase family domain-containing protein 1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 65 KDa

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Macromolecule #1: Endonuclease/exonuclease/phosphatase family domain-containing pro...

MacromoleculeName: Endonuclease/exonuclease/phosphatase family domain-containing protein 1
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 64.912172 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MASWSHPQFE KGAENLYFQS NAGSTLGCHR SIPRDPSDLS HSRKFSAACN FSNILVNQER LNINTATEEE LMTLPGVTRA VARSIVEYR EYIGGFKKVE DLALVSGVGA TKLEQVKFEI CVSSKGSSAQ HSPSSLRRDL LAEQQPHHLA TAVPLTPRVN I NTATPAQL ...String:
MASWSHPQFE KGAENLYFQS NAGSTLGCHR SIPRDPSDLS HSRKFSAACN FSNILVNQER LNINTATEEE LMTLPGVTRA VARSIVEYR EYIGGFKKVE DLALVSGVGA TKLEQVKFEI CVSSKGSSAQ HSPSSLRRDL LAEQQPHHLA TAVPLTPRVN I NTATPAQL MSVRGLSEKM ALSIVDFRRE HGPFRSVEDL VRMDGINAAF LDRIRHQVFA ERSRPPSTHT NGGLTFTAKP HP SPTSLSL QSEDLDLPPG GPTQIISTRP SVEAFGGTRD GRPVLRLATW NLQGCSVEKA NNPGVREVVC MTLLENSIKL LAV QELLDR EALEKFCTEL NQPTLPNIRK WKGPRGCWKA VVAEKPSNQL QKGAGYAGFL WDAAAGMELR DAGSQESSPS NGHG KLAGP SPYLGRFKVG SHDLTLVNLH LAALTLLGSE NPSKNHSDGH RLASFAQTLQ ETLKGEKDVI ILGDFGQGPD SNDYD ILRK EKFHHLIPAH TFTNISTKNP QGSKSLDNIW ISKSLKKVFT GHWAVVREGL TNPWIPDNWS WGGVASEHCP VLAEFY TEK DWSKKDAPRN GSGVALERSE ANIKHER

UniProtKB: Endonuclease/exonuclease/phosphatase family domain-containing protein 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: 9
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 2745 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 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: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 46575
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9yi2:
Human EEPD1 EEP domain dimer

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