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- PDB-8oxm: ATM(Q2971A) activated by oxidative stress in complex with Mg AMP-... -

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Basic information

Entry
Database: PDB / ID: 8oxm
TitleATM(Q2971A) activated by oxidative stress in complex with Mg AMP-PNP and p53 peptide
Components
  • Cellular tumor antigen p53
  • Serine-protein kinase ATM
KeywordsSIGNALING 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 / negative regulation of telomere capping / Sensing of DNA Double Strand Breaks / cellular response to nitrosative stress / establishment of protein-containing complex localization to telomere / regulation of microglial cell activation / meiotic telomere clustering / 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 / negative regulation of telomere capping / Sensing of DNA Double Strand Breaks / cellular response to nitrosative stress / establishment of protein-containing complex localization to telomere / regulation of microglial cell activation / meiotic telomere clustering / positive regulation of telomere maintenance via telomere lengthening / pre-B cell allelic exclusion / male meiotic nuclear division / histone mRNA catabolic process / extrinsic component of synaptic vesicle membrane / female meiotic nuclear division / regulation of telomere maintenance via telomerase / cellular response to X-ray / peptidyl-serine autophosphorylation / DNA double-strand break processing / lipoprotein catabolic process / regulation of autophagosome assembly / V(D)J recombination / pexophagy / Impaired BRCA2 binding to PALB2 / oocyte development / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / negative regulation of helicase activity / 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 / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / Activation of NOXA and translocation to mitochondria / regulation of cell cycle G2/M phase transition / regulation of fibroblast apoptotic process / reciprocal meiotic recombination / intrinsic apoptotic signaling pathway in response to hypoxia / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / glucose catabolic process to lactate via pyruvate / positive regulation of mitochondrial membrane permeability / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / DNA repair complex / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / positive regulation of DNA damage response, signal transduction by p53 class mediator / RUNX3 regulates CDKN1A transcription / 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 / regulation of DNA damage response, signal transduction by p53 class mediator / 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) / histone deacetylase regulator activity / negative regulation of glial cell proliferation / Resolution of D-loop Structures through Holliday Junction Intermediates / 1-phosphatidylinositol-3-kinase activity / Regulation of TP53 Activity through Association with Co-factors / negative regulation of neuroblast proliferation / HDR through Single Strand Annealing (SSA) / T cell lineage commitment / mitochondrial DNA repair / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / positive regulation of double-strand break repair / response to ionizing radiation / ER overload response / B cell lineage commitment / Impaired BRCA2 binding to RAD51 / thymocyte apoptotic process / mitotic spindle assembly checkpoint signaling / negative regulation of B cell proliferation / cellular response to stress / TP53 Regulates Transcription of Caspase Activators and Caspases / negative regulation of mitophagy / cardiac septum morphogenesis / negative regulation of DNA replication / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / negative regulation of telomere maintenance via telomerase / mitotic G2 DNA damage checkpoint signaling / Zygotic genome activation (ZGA) / positive regulation of release of cytochrome c from mitochondria / Association of TriC/CCT with target proteins during biosynthesis / necroptotic process / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / peroxisomal matrix / rRNA transcription / TFIID-class transcription factor complex 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 / FATC domain / 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 / FATC domain / p53 transactivation domain / P53 transactivation motif / PIK-related kinase, FAT / FAT domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / Phosphatidylinositol 3- and 4-kinases signature 1. / p53-like transcription factor, DNA-binding / 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: 3.3 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
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area13380 Å2
ΔGint-150 kcal/mol
Surface area242320 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 / 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) dimer activated by H2O2 and bound to Mg AMP-PNP and p53 substrate peptide
Type: COMPLEX / 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
VitrificationCryogen 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
13RELION3.13D reconstruction
14RELION43D reconstruction
15cryoSPARC43D reconstruction
16PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.3 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: 244.25 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.001744992
ELECTRON MICROSCOPYf_angle_d0.467860798
ELECTRON MICROSCOPYf_chiral_restr0.03546984
ELECTRON MICROSCOPYf_plane_restr0.00347648
ELECTRON MICROSCOPYf_dihedral_angle_d3.42215924

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