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- PDB-8oxp: ATM(Q2971A) in complex with Mg AMP-PNP -

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Basic information

Entry
Database: PDB / ID: 8oxp
TitleATM(Q2971A) in complex with Mg AMP-PNP
ComponentsSerine-protein kinase ATM
KeywordsSIGNALING PROTEIN / Ataxia-Telangiectasia Mutated / ATM / kinase
Function / homology
Function and homology information


establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / peptidyl-serine autophosphorylation / meiotic telomere clustering / cellular response to nitrosative stress / negative regulation of telomere capping / establishment of protein-containing complex localization to telomere / Sensing of DNA Double Strand Breaks / lipoprotein catabolic process / positive regulation of telomere maintenance via telomere lengthening ...establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / peptidyl-serine autophosphorylation / meiotic telomere clustering / cellular response to nitrosative stress / negative regulation of telomere capping / establishment of protein-containing complex localization to telomere / Sensing of DNA Double Strand Breaks / lipoprotein catabolic process / positive regulation of telomere maintenance via telomere lengthening / oocyte development / DNA-dependent protein kinase activity / extrinsic component of synaptic vesicle membrane / histone mRNA catabolic process / pre-B cell allelic exclusion / female meiotic nuclear division / regulation of telomere maintenance via telomerase / histone H2AXS139 kinase activity / male meiotic nuclear division / cellular response to X-ray / DNA double-strand break processing / V(D)J recombination / DNA repair complex / regulation of autophagosome assembly / pexophagy / Impaired BRCA2 binding to PALB2 / reciprocal meiotic recombination / negative regulation of B cell proliferation / positive regulation of DNA damage response, signal transduction by p53 class mediator / 1-phosphatidylinositol-3-kinase activity / cellular response to stress / mitotic spindle assembly checkpoint signaling / TP53 Regulates Transcription of Caspase Activators and Caspases / HDR through Single Strand Annealing (SSA) / response to ionizing radiation / 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) / 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 / positive regulation of double-strand break repair / peroxisomal matrix / Impaired BRCA2 binding to RAD51 / replicative senescence / somitogenesis / Regulation of HSF1-mediated heat shock response / post-embryonic development / Presynaptic phase of homologous DNA pairing and strand exchange / ovarian follicle development / cellular response to retinoic acid / thymus development / regulation of cellular response to heat / determination of adult lifespan / signal transduction in response to DNA damage / positive regulation of telomere maintenance via telomerase / multicellular organism growth / negative regulation of TORC1 signaling / DNA damage checkpoint signaling / positive regulation of cell adhesion / telomere maintenance / regulation of signal transduction by p53 class mediator / Pexophagy / DNA damage response, signal transduction by p53 class mediator / regulation of autophagy / TP53 Regulates Transcription of DNA Repair Genes / cellular response to reactive oxygen species / brain development / Nonhomologous End-Joining (NHEJ) / Stabilization of p53 / cellular response to gamma radiation / Autodegradation of the E3 ubiquitin ligase COP1 / double-strand break repair via homologous recombination / intrinsic apoptotic signaling pathway in response to DNA damage / G2/M DNA damage checkpoint / Regulation of TP53 Activity through Methylation / DNA Damage/Telomere Stress Induced Senescence / double-strand break repair via nonhomologous end joining / Meiotic recombination / cellular senescence / HDR through Homologous Recombination (HRR) / spindle / heart development / neuron apoptotic process / Regulation of TP53 Degradation / positive regulation of neuron apoptotic process / double-strand break repair / protein autophosphorylation / chromosome / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / site of double-strand break / Processing of DNA double-strand break ends / regulation of apoptotic process / Regulation of TP53 Activity through Phosphorylation / protein phosphorylation / non-specific serine/threonine protein kinase / regulation of cell cycle / protein stabilization
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 / FATC domain / PIK-related kinase, FAT / FAT domain / FATC / FATC domain ...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 / FATC domain / PIK-related kinase, FAT / FAT domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / 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 / Serine-protein kinase ATM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 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
A: Serine-protein kinase ATM
B: Serine-protein kinase ATM
hetero molecules


Theoretical massNumber of molelcules
Total (without water)731,2038
Polymers730,0112
Non-polymers1,1926
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area9870 Å2
ΔGint-74 kcal/mol
Surface area236060 Å2

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Components

#1: 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
#2: 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
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#4: 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 bound to Mg AMP-PNP / Type: COMPLEX / Entity ID: #1 / 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: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1207435 / 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: 316.9 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.001745288
ELECTRON MICROSCOPYf_angle_d0.44561200
ELECTRON MICROSCOPYf_chiral_restr0.03477024
ELECTRON MICROSCOPYf_plane_restr0.00327702
ELECTRON MICROSCOPYf_dihedral_angle_d3.67615970

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