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