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- PDB-7sic: Human ATM Dimer -

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Basic information

Entry
Database: PDB / ID: 7sic
TitleHuman ATM Dimer
ComponentsSerine-protein kinase ATM
KeywordsSIGNALING PROTEIN / Kinase
Function / homology
Function and homology information


establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / cellular response to nitrosative stress / negative regulation of telomere capping / Sensing of DNA Double Strand Breaks / establishment of protein-containing complex localization to telomere / peptidyl-serine autophosphorylation / 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 / cellular response to nitrosative stress / negative regulation of telomere capping / Sensing of DNA Double Strand Breaks / establishment of protein-containing complex localization to telomere / peptidyl-serine autophosphorylation / meiotic telomere clustering / positive regulation of telomere maintenance via telomere lengthening / pre-B cell allelic exclusion / DNA-dependent protein kinase activity / male meiotic nuclear division / extrinsic component of synaptic vesicle membrane / histone H2AXS139 kinase activity / histone mRNA catabolic process / regulation of telomere maintenance via telomerase / female meiotic nuclear division / lipoprotein catabolic process / DNA double-strand break processing / 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) / 1-phosphatidylinositol-3-kinase activity / Resolution of D-loop Structures through Holliday Junction Intermediates / HDR through Single Strand Annealing (SSA) / response to ionizing radiation / negative regulation of B cell proliferation / TP53 Regulates Transcription of Caspase Activators and Caspases / mitotic spindle assembly checkpoint signaling / positive regulation of double-strand break repair / Impaired BRCA2 binding to RAD51 / 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 / ovarian follicle development / regulation of cellular response to heat / cellular response to retinoic acid / negative regulation of TORC1 signaling / positive regulation of telomere maintenance via telomerase / telomere maintenance / positive regulation of cell adhesion / Pexophagy / DNA damage checkpoint signaling / thymus development / regulation of signal transduction by p53 class mediator / post-embryonic development / determination of adult lifespan / cellular response to reactive oxygen species / DNA damage response, signal transduction by p53 class mediator / TP53 Regulates Transcription of DNA Repair Genes / Stabilization of p53 / Nonhomologous End-Joining (NHEJ) / Autodegradation of the E3 ubiquitin ligase COP1 / cellular response to gamma radiation / double-strand break repair via homologous recombination / brain development / G2/M DNA damage checkpoint / Regulation of TP53 Activity through Methylation / HDR through Homologous Recombination (HRR) / DNA Damage/Telomere Stress Induced Senescence / double-strand break repair via nonhomologous end joining / Meiotic recombination / spindle / multicellular organism growth / intrinsic apoptotic signaling pathway in response to DNA damage / cellular senescence / Regulation of TP53 Degradation / double-strand break repair / positive regulation of neuron apoptotic process / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / site of double-strand break / chromosome / heart development / protein autophosphorylation / Processing of DNA double-strand break ends / neuron apoptotic process / regulation of apoptotic process / Regulation of TP53 Activity through Phosphorylation / protein phosphorylation / non-specific serine/threonine protein kinase / regulation of cell cycle / regulation of autophagy / 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: 2.51 Å
AuthorsWarren, C. / Pavletich, N.P.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5F32CA247320 United States
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)CA008748 United States
CitationJournal: Elife / Year: 2022
Title: Structure of the human ATM kinase and mechanism of Nbs1 binding.
Authors: Christopher Warren / Nikola P Pavletich /
Abstract: DNA double-strand breaks (DSBs) can lead to mutations, chromosomal rearrangements, genome instability, and cancer. Central to the sensing of DSBs is the ATM (Ataxia-telangiectasia mutated) kinase, ...DNA double-strand breaks (DSBs) can lead to mutations, chromosomal rearrangements, genome instability, and cancer. Central to the sensing of DSBs is the ATM (Ataxia-telangiectasia mutated) kinase, which belongs to the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family. In response to DSBs, ATM is activated by the MRN (Mre11-Rad50-Nbs1) protein complex through a poorly understood process that also requires double-stranded DNA. Previous studies indicate that the FxF/Y motif of Nbs1 directly binds to ATM, and is required to retain active ATM at sites of DNA damage. Here, we report the 2.5 Å resolution cryo-EM structures of human ATM and its complex with the Nbs1 FxF/Y motif. In keeping with previous structures of ATM and its yeast homolog Tel1, the dimeric human ATM kinase adopts a symmetric, butterfly-shaped structure. The conformation of the ATM kinase domain is most similar to the inactive states of other PIKKs, suggesting that activation may involve an analogous realigning of the N and C lobes along with relieving the blockage of the substrate-binding site. We also show that the Nbs1 FxF/Y motif binds to a conserved hydrophobic cleft within the Spiral domain of ATM, suggesting an allosteric mechanism of activation. We evaluate the importance of these structural findings with mutagenesis and biochemical assays.
History
DepositionOct 13, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 2, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)703,3166
Polymers702,2552
Non-polymers1,0614
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Serine-protein kinase ATM / Ataxia telangiectasia mutated / A-T mutated


Mass: 351127.688 Da / Num. of mol.: 2
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
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: Human ATM Dimer / Type: COMPLEX / Entity ID: #1 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenConc.: 0.6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
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 defocus max: 1600 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 53.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameCategory
2SerialEMimage acquisition
7Cootmodel fitting
9PHENIXmodel refinement
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.51 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 303604 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00245314
ELECTRON MICROSCOPYf_angle_d0.52361234
ELECTRON MICROSCOPYf_dihedral_angle_d4.3325972
ELECTRON MICROSCOPYf_chiral_restr0.0367026
ELECTRON MICROSCOPYf_plane_restr0.0047708

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