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- PDB-9l4f: ATR-ATRIP bound with ATPgammaS -

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Basic information

Entry
Database: PDB / ID: 9l4f
TitleATR-ATRIP bound with ATPgammaS
Components
  • ATR-interacting protein
  • Serine/threonine-protein kinase ATR
KeywordsCELL CYCLE / ATR-ATRIP ATPgammaS
Function / homology
Function and homology information


ATR-ATRIP complex / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / MutSalpha complex binding / establishment of protein-containing complex localization to telomere / nuclear membrane disassembly / MutLalpha complex binding / response to arsenic-containing substance / regulation of double-strand break repair / mitotic G2/M transition checkpoint ...ATR-ATRIP complex / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / MutSalpha complex binding / establishment of protein-containing complex localization to telomere / nuclear membrane disassembly / MutLalpha complex binding / response to arsenic-containing substance / regulation of double-strand break repair / mitotic G2/M transition checkpoint / positive regulation of DNA damage response, signal transduction by p53 class mediator / nucleobase-containing compound metabolic process / protein localization to chromosome, telomeric region / HDR through Single Strand Annealing (SSA) / K63-linked polyubiquitin modification-dependent protein binding / Impaired BRCA2 binding to RAD51 / negative regulation of DNA replication / replication fork processing / site of DNA damage / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / Regulation of HSF1-mediated heat shock response / interstrand cross-link repair / Activation of ATR in response to replication stress / response to mechanical stimulus / regulation of cellular response to heat / positive regulation of telomere maintenance via telomerase / Meiotic synapsis / telomere maintenance / DNA damage checkpoint signaling / TP53 Regulates Transcription of DNA Repair Genes / Fanconi Anemia Pathway / G2/M DNA damage checkpoint / cellular response to gamma radiation / PML body / cellular response to UV / nuclear envelope / double-strand break repair / peptidyl-serine phosphorylation / chromosome / Processing of DNA double-strand break ends / protein autophosphorylation / Regulation of TP53 Activity through Phosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / DNA replication / non-specific serine/threonine protein kinase / protein kinase activity / response to xenobiotic stimulus / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / DNA damage response / Golgi apparatus / DNA binding / nucleoplasm / ATP binding / nucleus
Similarity search - Function
ATR-interacting protein / 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 repeat profile. / HEAT, type 2 / : / FATC domain / PIK-related kinase, FAT ...ATR-interacting protein / 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 repeat profile. / HEAT, type 2 / : / 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
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / Serine/threonine-protein kinase ATR / ATR-interacting protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.22 Å
AuthorsWang, G.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Sci Bull (Beijing) / Year: 2025
Title: Molecular architecture and inhibition mechanism of human ATR-ATRIP.
Authors: Guangxian Wang / Po Wang / Zexuan Zheng / Qingjun Zhang / Chenchen Xu / Xinyi Xu / Lingfei Jian / Zhanpeng Zhao / Gang Cai / Xuejuan Wang /
Abstract: The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master regulator of DNA damage response and replication stress in humans. Targeting ATR is the focus of oncology drug pipelines ...The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master regulator of DNA damage response and replication stress in humans. Targeting ATR is the focus of oncology drug pipelines with a number of potent, selective ATR inhibitors currently in clinical development. Here, we determined the cryo-EM structures of the human ATR-ATRIP complex in the presence of VE-822 and RP-3500, two ATR inhibitors currently in Phase II clinical trials, achieving an overall resolution of approximately 3 Å. These structures yield a near-complete atomic model of the ATR-ATRIP complex, revealing subunit stoichiometry, intramolecular and intermolecular interactions, and critical regulatory sites including an insertion in the PIKK regulatory domain (PRD). Structural comparison provides insights into the modes of action and selectivity of ATR inhibitors. The divergent binding modes near the solvent side and in the rear pocket area of VE-822 and RP-3500, particularly their disparate binding orientations, lead to varying conformational changes in the active site. Surprisingly, one ATR-ATRIP complex binds four VE-822 molecules, with two in the ATR active site and two at the ATR-ATR dimer interface. The binding and selectivity of RP-3500 depend on two bound water molecules, which may be further enhanced by the substitution of these bound waters. Our study provides a structural framework for understanding ATR regulation and holds promise for assisting future efforts in rational drug design targeting ATR.
History
DepositionDec 20, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0May 21, 2025Provider: repository / Type: Initial release
Revision 1.1Jun 4, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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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
D: ATR-interacting protein
C: ATR-interacting protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)776,4416
Polymers775,3954
Non-polymers1,0462
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

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


Mass: 301756.781 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: 85940.664 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: Chemical ChemComp-AGS / PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-GAMMA-S / ADENOSINE 5'-(3-THIOTRIPHOSPHATE) / ADENOSINE 5'-(GAMMA-THIOTRIPHOSPHATE) / ADENOSINE-5'-DIPHOSPHATE MONOTHIOPHOSPHATE


Mass: 523.247 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O12P3S / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP-gamma-S, energy-carrying molecule analogue*YM
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: ATR-ATRIP / Type: CELL / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 6.22 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 40429 / Symmetry type: POINT

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