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- PDB-8oxo: ATM(Q2971A) dimeric C-terminal region activated by oxidative stre... -

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Basic information

Entry
Database: PDB / ID: 8oxo
TitleATM(Q2971A) dimeric C-terminal region activated by oxidative stress in complex with Mg AMP-PNP and p53 peptide
Components
  • Cellular tumor antigen p53
  • Serine-protein kinase ATM
KeywordsSIGNALING PROTEIN / Kinase / Ataxia-Telangiectasia Mutated / ATM / p53
Function / homology
Function and homology information


cellular response to nitrosative stress / negative regulation of telomere capping / peptidyl-serine autophosphorylation / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / Sensing of DNA Double Strand Breaks / establishment of protein-containing complex localization to telomere / positive regulation of telomere maintenance via telomere lengthening / negative regulation of B cell proliferation / regulation of telomere maintenance via telomerase ...cellular response to nitrosative stress / negative regulation of telomere capping / peptidyl-serine autophosphorylation / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / Sensing of DNA Double Strand Breaks / establishment of protein-containing complex localization to telomere / positive regulation of telomere maintenance via telomere lengthening / negative regulation of B cell proliferation / regulation of telomere maintenance via telomerase / extrinsic component of synaptic vesicle membrane / DNA-dependent protein kinase activity / histone mRNA catabolic process / pre-B cell allelic exclusion / histone H2AXS139 kinase activity / DNA double-strand break processing / cellular response to X-ray / regulation of autophagosome assembly / pexophagy / positive regulation of autophagosome assembly / negative regulation of helicase activity / Impaired BRCA2 binding to PALB2 / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / Transcriptional activation of cell cycle inhibitor p21 / negative regulation of pentose-phosphate shunt / DNA repair complex / Activation of NOXA and translocation to mitochondria / ATP-dependent DNA/DNA annealing activity / regulation of cell cycle G2/M phase transition / oligodendrocyte apoptotic process / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / bone marrow development / circadian behavior / cellular response to actinomycin D / positive regulation of programmed necrotic cell death / RUNX3 regulates CDKN1A transcription / reciprocal meiotic recombination / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / mRNA transcription / Urea cycle / Regulation of TP53 Activity through Association with Co-factors / ER overload response / hematopoietic stem cell differentiation / cellular response to stress / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / 1-phosphatidylinositol-3-kinase activity / mitotic spindle assembly checkpoint signaling / TP53 Regulates Transcription of Caspase Activators and Caspases / response to ionizing radiation / intrinsic apoptotic signaling pathway by p53 class mediator / entrainment of circadian clock by photoperiod / response to starvation / Homologous DNA Pairing and Strand Exchange / Defective homologous recombination repair (HRR) due to BRCA1 loss of function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / HDR through Single Strand Annealing (SSA) / Zygotic genome activation (ZGA) / mitotic G2 DNA damage checkpoint signaling / Resolution of D-loop Structures through Holliday Junction Intermediates / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / PI5P Regulates TP53 Acetylation / positive regulation of release of cytochrome c from mitochondria / hematopoietic progenitor cell differentiation / Association of TriC/CCT with target proteins during biosynthesis / negative regulation of telomere maintenance via telomerase / SUMOylation of transcription factors / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / peroxisomal matrix / positive regulation of double-strand break repair / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / Transcriptional Regulation by VENTX / Impaired BRCA2 binding to RAD51 / replicative senescence / TFIID-class transcription factor complex binding / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / positive regulation of DNA damage response, signal transduction by p53 class mediator / viral process / positive regulation of intrinsic apoptotic signaling pathway / Pyroptosis / determination of adult lifespan / positive regulation of RNA polymerase II transcription preinitiation complex assembly / Regulation of HSF1-mediated heat shock response / negative regulation of fibroblast proliferation / general transcription initiation factor binding / positive regulation of execution phase of apoptosis / type II interferon-mediated signaling pathway / Presynaptic phase of homologous DNA pairing and strand exchange / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / cellular response to glucose starvation / core promoter sequence-specific DNA binding / cellular response to retinoic acid / cis-regulatory region sequence-specific DNA binding
Similarity search - Function
Telomere-length maintenance and DNA damage repair / Serine/threonine-protein kinase ATM, plant / ATM, catalytic domain / Telomere-length maintenance and DNA damage repair / Telomere-length maintenance and DNA damage repair / Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / : ...Telomere-length maintenance and DNA damage repair / Serine/threonine-protein kinase ATM, plant / ATM, catalytic domain / Telomere-length maintenance and DNA damage repair / Telomere-length maintenance and DNA damage repair / Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / : / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family / FATC domain / PIK-related kinase, FAT / FAT domain / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / p53-like transcription factor, DNA-binding / Phosphatidylinositol 3- and 4-kinases signature 1. / 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-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Cellular tumor antigen p53 / Serine-protein kinase ATM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsHowes, A.C. / Perisic, O. / Williams, R.L.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Cancer Research UKC14801/A21211 United Kingdom
Cancer Research UKDRCPGM/100014 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184308 United Kingdom
CitationJournal: Sci Adv / Year: 2023
Title: Structural insights into the activation of ataxia-telangiectasia mutated by oxidative stress.
Authors: Anna C Howes / Olga Perisic / Roger L Williams /
Abstract: Ataxia-telangiectasia mutated (ATM) is a master kinase regulating DNA damage response that is activated by DNA double-strand breaks. However, ATM is also directly activated by reactive oxygen ...Ataxia-telangiectasia mutated (ATM) is a master kinase regulating DNA damage response that is activated by DNA double-strand breaks. However, ATM is also directly activated by reactive oxygen species, but how oxidative activation is achieved remains unknown. We determined the cryo-EM structure of an HO-activated ATM and showed that under oxidizing conditions, ATM formed an intramolecular disulfide bridge between two protomers that are rotated relative to each other when compared to the basal state. This rotation is accompanied by release of the substrate-blocking PRD region and twisting of the N-lobe relative to the C-lobe, which greatly optimizes catalysis. This active site remodeling enabled us to capture a substrate (p53) bound to the enzyme. This provides the first structural insights into how ATM is activated during oxidative stress.
History
DepositionMay 2, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
E: Cellular tumor antigen p53
A: Serine-protein kinase ATM
F: Cellular tumor antigen p53
B: Serine-protein kinase ATM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)733,92810
Polymers732,7364
Non-polymers1,1926
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, Only the C-terminal region of the ATM(Q2971A) dimer from local refinement is shown. The whole molecule is present in the sample.
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area12550 Å2
ΔGint-149 kcal/mol
Surface area128630 Å2

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Components

#1: Protein/peptide Cellular tumor antigen p53 / Antigen NY-CO-13 / Phosphoprotein p53 / Tumor suppressor p53


Mass: 1362.438 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: Custom synthesized peptide / Source: (synth.) Homo sapiens (human) / References: UniProt: P04637
#2: Protein Serine-protein kinase ATM / Ataxia telangiectasia mutated / A-T mutated


Mass: 365005.562 Da / Num. of mol.: 2 / Mutation: Q2971A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ATM / Cell (production host): Kidney (Embryonic) / Cell line (production host): Expi293F / Production host: Homo sapiens (human)
References: UniProt: Q13315, non-specific serine/threonine protein kinase
#3: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: ATM(Q2971A) dimeric C-terminal region activated by H2O2 and bound to Mg AMP-PNP and p53 substrate peptide
Type: COMPLEX
Details: Only the C-terminal region of the ATM (Q2971A) dimer from local refinement is shown, with AMP-PNP and p53 substrate peptide bound in the structure. Please note, the whole dimer molecule is present in the sample.
Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: Kidney (Embryonic)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 39.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
EM software
IDNameVersionCategory
7UCSF Chimeramodel fitting
8Cootmodel fitting
10PHENIXmodel refinement
14RELION3.13D reconstruction
15RELION43D reconstruction
16cryoSPARC43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 30707 / Symmetry type: POINT
Atomic model buildingPDB-ID: 7SIC

7sic


Accession code: 7SIC / Source name: PDB / Type: experimental model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 152.88 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.001724420
ELECTRON MICROSCOPYf_angle_d0.492532982
ELECTRON MICROSCOPYf_chiral_restr0.03563736
ELECTRON MICROSCOPYf_plane_restr0.00434186
ELECTRON MICROSCOPYf_dihedral_angle_d2.80963252

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