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Yorodumi- PDB-8oxm: ATM(Q2971A) activated by oxidative stress in complex with Mg AMP-... -
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-Basic information
Entry | Database: PDB / ID: 8oxm | ||||||||||||
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Title | ATM(Q2971A) activated by oxidative stress in complex with Mg AMP-PNP and p53 peptide | ||||||||||||
Components |
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Keywords | SIGNALING PROTEIN / Ataxia-Telangiectasia Mutated / ATM / kinase / oxidative stress | ||||||||||||
Function / homology | Function and homology information positive regulation of DNA catabolic process / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / positive regulation of DNA damage response, signal transduction by p53 class mediator / cellular response to nitrosative stress / establishment of protein-containing complex localization to telomere / regulation of microglial cell activation / negative regulation of telomere capping / Sensing of DNA Double Strand Breaks / positive regulation of telomere maintenance via telomere lengthening ...positive regulation of DNA catabolic process / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / positive regulation of DNA damage response, signal transduction by p53 class mediator / cellular response to nitrosative stress / establishment of protein-containing complex localization to telomere / regulation of microglial cell activation / negative regulation of telomere capping / Sensing of DNA Double Strand Breaks / positive regulation of telomere maintenance via telomere lengthening / meiotic telomere clustering / DNA-dependent protein kinase activity / histone H2AXS139 kinase activity / male meiotic nuclear division / histone mRNA catabolic process / pre-B cell allelic exclusion / female meiotic nuclear division / pexophagy / cellular response to X-ray / regulation of telomere maintenance via telomerase / peptidyl-serine autophosphorylation / lipoprotein catabolic process / V(D)J recombination / oocyte development / Impaired BRCA2 binding to PALB2 / reciprocal meiotic recombination / 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 / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / negative regulation of helicase activity / regulation of cell cycle G2/M phase transition / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / oxidative stress-induced premature senescence / oligodendrocyte apoptotic process / DNA repair complex / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / 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 / Homologous DNA Pairing and Strand Exchange / mRNA transcription / bone marrow development / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / circadian behavior / histone deacetylase regulator activity / germ cell nucleus / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / regulation of DNA damage response, signal transduction by p53 class mediator / Resolution of D-loop Structures through Holliday Junction Intermediates / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / HDR through Single Strand Annealing (SSA) / negative regulation of glial cell proliferation / negative regulation of neuroblast proliferation / Impaired BRCA2 binding to RAD51 / Regulation of TP53 Activity through Association with Co-factors / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / 1-phosphatidylinositol-3-kinase activity / mitochondrial DNA repair / T cell lineage commitment / response to ionizing radiation / negative regulation of DNA replication / ER overload response / mitotic spindle assembly checkpoint signaling / B cell lineage commitment / positive regulation of cardiac muscle cell apoptotic process / thymocyte apoptotic process / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / TP53 Regulates Transcription of Caspase Activators and Caspases / cardiac septum morphogenesis / negative regulation of B cell proliferation / positive regulation of execution phase of apoptosis / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / mitotic G2 DNA damage checkpoint signaling / Zygotic genome activation (ZGA) / necroptotic process / positive regulation of release of cytochrome c from mitochondria / Presynaptic phase of homologous DNA pairing and strand exchange / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / peroxisomal matrix Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||||||||
Authors | Howes, A.C. / Perisic, O. / Williams, R.L. | ||||||||||||
Funding support | United Kingdom, 3items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8oxm.cif.gz | 1.3 MB | Display | PDBx/mmCIF format |
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PDB format | pdb8oxm.ent.gz | 883.5 KB | Display | PDB format |
PDBx/mmJSON format | 8oxm.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8oxm_validation.pdf.gz | 1.8 MB | Display | wwPDB validaton report |
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Full document | 8oxm_full_validation.pdf.gz | 1.9 MB | Display | |
Data in XML | 8oxm_validation.xml.gz | 149.2 KB | Display | |
Data in CIF | 8oxm_validation.cif.gz | 222.9 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ox/8oxm ftp://data.pdbj.org/pub/pdb/validation_reports/ox/8oxm | HTTPS FTP |
-Related structure data
Related structure data | 17265MC 8oxoC 8oxpC 8oxqC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein/peptide | 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 | 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 / Production host: Homo sapiens (human) References: UniProt: Q13315, non-specific serine/threonine protein kinase #3: Chemical | #4: Chemical | #5: Chemical | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: ATM(Q2971A) dimer activated by H2O2 and bound to Mg AMP-PNP and p53 substrate peptide Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) / Cell: Kidney (Embryonic) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm |
Specimen holder | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 39.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software |
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 30707 / Symmetry type: POINT | ||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 7SIC Accession code: 7SIC / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 244.25 Å2 | ||||||||||||||||||||||||||||
Refine LS restraints |
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