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- PDB-13de: Cryo-EM structure of ATR-ATRIP-ETAA1 AAD (S95D/S111D) -

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Basic information

Entry
Database: PDB / ID: 13de
TitleCryo-EM structure of ATR-ATRIP-ETAA1 AAD (S95D/S111D)
Components
  • ATR-interacting protein
  • Ewing's tumor-associated antigen 1
  • Serine/threonine-protein kinase ATR
KeywordsNUCLEAR PROTEIN / kinase / PI3K-related kinase / complex / activator / replication stress response / replication checkpoint
Function / homology
Function and homology information


ATR-ATRIP complex / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / nuclear membrane disassembly / establishment of protein-containing complex localization to telomere / MutSalpha complex binding / histone H2AXS139 kinase activity / MutLalpha complex binding / response to arsenic-containing substance / mitotic G2/M transition checkpoint ...ATR-ATRIP complex / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / nuclear membrane disassembly / establishment of protein-containing complex localization to telomere / MutSalpha complex binding / histone H2AXS139 kinase activity / MutLalpha complex binding / response to arsenic-containing substance / mitotic G2/M transition checkpoint / regulation of double-strand break repair / nucleobase-containing compound metabolic process / regulation of DNA damage checkpoint / positive regulation of DNA damage response, signal transduction by p53 class mediator / protein localization to chromosome, telomeric region / K63-linked polyubiquitin modification-dependent protein binding / HDR through Single Strand Annealing (SSA) / negative regulation of DNA replication / positive regulation of protein serine/threonine kinase activity / replicative senescence / Impaired BRCA2 binding to RAD51 / nuclear replication fork / replication fork processing / Regulation of HSF1-mediated heat shock response / response to mechanical stimulus / Presynaptic phase of homologous DNA pairing and strand exchange / Activation of ATR in response to replication stress / interstrand cross-link repair / regulation of cellular response to heat / positive regulation of telomere maintenance via telomerase / DNA damage checkpoint signaling / telomere maintenance / Meiotic synapsis / protein serine/threonine kinase activator activity / site of DNA damage / TP53 Regulates Transcription of DNA Repair Genes / Fanconi Anemia Pathway / cellular response to gamma radiation / PML body / G2/M DNA damage checkpoint / cellular response to UV / nuclear envelope / double-strand break repair / chromosome / Processing of DNA double-strand break ends / Regulation of TP53 Activity through Phosphorylation / protein kinase activity / non-specific serine/threonine protein kinase / DNA replication / nuclear speck / response to xenobiotic stimulus / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / DNA damage response / DNA binding / nucleoplasm / ATP binding / nucleus
Similarity search - Function
Ewing's tumour-associated antigen 1 / Ewing's tumour-associated antigen 1 homologue / ATR-interacting protein / : / : / ATR-interacting protein N-terminal domain / ATRIP C-terminal domain / : / Serine/threonine-protein kinase ATR, N-HEAT region / : ...Ewing's tumour-associated antigen 1 / Ewing's tumour-associated antigen 1 homologue / ATR-interacting protein / : / : / ATR-interacting protein N-terminal domain / ATRIP C-terminal domain / : / Serine/threonine-protein kinase ATR, N-HEAT region / : / Serine/threonine-protein kinase ATR, M-HEAT region / UME domain / UME (NUC010) domain / Domain in UVSB PI-3 kinase, MEI-41 and ESR-1 / : / Serine/threonine-protein kinase ATR-like, HEAT repeats / HEAT, type 2 / HEAT repeat profile. / : / FATC domain / PIK-related kinase, FAT / FAT domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / Armadillo-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Serine/threonine-protein kinase ATR / ATR-interacting protein / Ewing's tumor-associated antigen 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsLi, B. / Pavletich, N.P.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5R01GM149915 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA008748 United States
CitationJournal: Nat Struct Mol Biol / Year: 2026
Title: Structural mechanism of TOPBP1 activating the ATR-ATRIP replication checkpoint kinase.
Authors: Buren Li / Ayat Yaseen / Nikola P Pavletich /
Abstract: The ATR protein kinase preserves genomic integrity during DNA replication by controlling checkpoints needed for the orderly progression of S phase and for the responses to replication stress. ATR, ...The ATR protein kinase preserves genomic integrity during DNA replication by controlling checkpoints needed for the orderly progression of S phase and for the responses to replication stress. ATR, with its obligate partner ATRIP, is activated by the TOPBP1 and ETAA1 proteins, which control different branches of ATR signaling. TOPBP1 is essential for induction of the S phase checkpoint in response to stalled replication forks, while ETAA1 is required for timely progression to mitosis from an unperturbed S phase. TOPBP1 and ETAA1 contain ATR-activating domains (AADs) of limited homology, but how they activate ATR has not yet been fully elucidated. Here we present the 3.0-Å cryo-EM structure of the human ATR-ATRIP complex bound to the TOPBP1 AAD, showing that TOPBP1 activates ATR by inducing a global conformational change that allosterically realigns active site residues in the kinase domain ~70 Å away. We also present the 3.3-Å structure of the ATR-ATRIP-ETAA1 AAD complex, which reveals a binding mode distinct from TOPBP1. Our data suggest that the distinct binding modes of TOPBP1 and ETAA1 contribute to the different cellular contexts and outcomes of ATR-ATRIP activation.
History
DepositionApr 30, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 5, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 5, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Aug 5, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Aug 5, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine/threonine-protein kinase ATR
C: ATR-interacting protein
B: Serine/threonine-protein kinase ATR
D: ATR-interacting protein
F: Ewing's tumor-associated antigen 1
E: Ewing's tumor-associated antigen 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)832,38216
Polymers831,0116
Non-polymers1,37110
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 3 types, 6 molecules ABCDFE

#1: Protein Serine/threonine-protein kinase ATR / Ataxia telangiectasia and Rad3-related protein / FRAP-related protein 1


Mass: 304008.312 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ATR, FRP1 / Production host: Homo sapiens (human)
References: UniProt: Q13535, non-specific serine/threonine protein kinase
#2: Protein ATR-interacting protein / ATM and Rad3-related-interacting protein


Mass: 88192.039 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ATRIP, AGS1 / Production host: Homo sapiens (human) / References: UniProt: Q8WXE1
#3: Protein Ewing's tumor-associated antigen 1 / Ewing's tumor-associated antigen 16


Mass: 23305.000 Da / Num. of mol.: 2 / Mutation: S95D, S111D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ETAA1, ETAA16 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9NY74

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Non-polymers , 3 types, 10 molecules

#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM

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Details

Has ligand of interestN
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: ATR-ATRIP-ETAA1 AAD (S95D/S111D) / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
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: 1700 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 53 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.1_5286model refinement
13RELION5.0beta3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1340199 / Symmetry type: POINT

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