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- PDB-9zd1: Cryo-EM structure of ATR-ATRIP-TOPBP1 AAD -

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Basic information

Entry
Database: PDB / ID: 9zd1
TitleCryo-EM structure of ATR-ATRIP-TOPBP1 AAD
Components
  • ATR-interacting protein
  • DNA topoisomerase 2-binding protein 1
  • Serine/threonine-protein kinase ATR
KeywordsNUCLEAR PROTEIN / kinase / PI3K-related kinase / complex / replication stress response / replication checkpoint
Function / homology
Function and homology information


broken chromosome clustering / ATR-ATRIP complex / BRCA1-B 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 / phosphorylation-dependent protein binding / histone H2AXS139 kinase activity ...broken chromosome clustering / ATR-ATRIP complex / BRCA1-B 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 / phosphorylation-dependent protein binding / histone H2AXS139 kinase activity / homologous recombination / DNA replication checkpoint signaling / MutLalpha complex binding / response to arsenic-containing substance / double-strand break repair via classical nonhomologous end joining / double-strand break repair via alternative nonhomologous end joining / mitotic DNA replication checkpoint signaling / protein localization to site of double-strand break / mitotic G2/M transition checkpoint / regulation of double-strand break repair / nucleobase-containing compound metabolic process / chromatin-protein adaptor activity / 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 / DNA metabolic process / response to ionizing radiation / HDR through Single Strand Annealing (SSA) / negative regulation of DNA replication / mitotic G2 DNA damage checkpoint signaling / replicative senescence / Impaired BRCA2 binding to RAD51 / male germ cell nucleus / replication fork processing / chromosome organization / Regulation of HSF1-mediated heat shock response / DNA replication initiation / 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 / condensed nuclear chromosome / TP53 Regulates Transcription of DNA Repair Genes / Fanconi Anemia Pathway / cellular response to gamma radiation / PML body / double-strand break repair via homologous recombination / G2/M DNA damage checkpoint / spindle pole / cellular response to UV / nuclear envelope / double-strand break repair / chromosome / site of double-strand break / Processing of DNA double-strand break ends / Regulation of TP53 Activity through Phosphorylation / nuclear body / protein kinase activity / non-specific serine/threonine protein kinase / DNA replication / response to xenobiotic stimulus / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / centrosome / DNA damage response / DNA binding / nucleoplasm / ATP binding / identical protein binding / nucleus
Similarity search - Function
: / : / TopBP1, BRCT0 domain / TopBP1, first BRCT domain / : / : / TopBP1/SLF1, BRCT domain / ATR-interacting protein / : / : ...: / : / TopBP1, BRCT0 domain / TopBP1, first BRCT domain / : / : / TopBP1/SLF1, BRCT domain / ATR-interacting protein / : / : / ATR-interacting protein N-terminal domain / ATRIP C-terminal domain / : / Serine/threonine-protein kinase ATR, N-HEAT region / Secretoglobin superfamily / : / 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. / BRCA1 C Terminus (BRCT) domain / breast cancer carboxy-terminal domain / 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 / BRCT domain profile. / BRCT domain / BRCT domain superfamily / 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 / DNA topoisomerase 2-binding protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 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
DepositionNov 24, 2025Deposition 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
B: Serine/threonine-protein kinase ATR
C: ATR-interacting protein
D: ATR-interacting protein
I: DNA topoisomerase 2-binding protein 1
J: DNA topoisomerase 2-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)834,34316
Polymers832,9726
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 ABCDIJ

#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 DNA topoisomerase 2-binding protein 1 / DNA topoisomerase II-beta-binding protein 1 / TopBP1 / DNA topoisomerase II-binding protein 1


Mass: 24285.584 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TOPBP1, KIAA0259 / Production host: Escherichia coli (E. coli) / References: UniProt: Q92547

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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-TOPBP1 AAD / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.83 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTris-HClTris-HCl1
280 mMsodium chlorideNaCl1
30.5 mMtris-(2-carboxyethyl) phosphineTCEP1
SpecimenConc.: 0.7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K

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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: 1800 nm / Nominal defocus min: 300 nm
Image recordingElectron dose: 53 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION3particle selection
2PHENIX1.20.1_4487model refinement
3SerialEMimage acquisition
11RELION3final Euler assignment
13RELION33D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 479450 / Symmetry type: POINT

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