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- PDB-7sid: Human ATM Dimer Bound to Nbs1 -

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Basic information

Entry
Database: PDB / ID: 7sid
TitleHuman ATM Dimer Bound to Nbs1
Components
  • Nibrin
  • Serine-protein kinase ATM
KeywordsSIGNALING PROTEIN / Kinase
Function / homology
Function and homology information


telomere maintenance via telomere trimming / chromosomal region / telomeric 3' overhang formation / Mre11 complex / DNA-dependent protein kinase activity / positive regulation of DNA catabolic process / histone H2AXS139 kinase activity / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / blastocyst growth ...telomere maintenance via telomere trimming / chromosomal region / telomeric 3' overhang formation / Mre11 complex / DNA-dependent protein kinase activity / positive regulation of DNA catabolic process / histone H2AXS139 kinase activity / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / blastocyst growth / positive regulation of DNA damage response, signal transduction by p53 class mediator / establishment of protein-containing complex localization to telomere / cellular response to nitrosative stress / negative regulation of telomere capping / Sensing of DNA Double Strand Breaks / BRCA1-C complex / protection from non-homologous end joining at telomere / positive regulation of telomere maintenance via telomere lengthening / R-loop processing / regulation of microglial cell activation / meiotic telomere clustering / t-circle formation / pre-B cell allelic exclusion / phosphorylation-dependent protein binding / male meiotic nuclear division / histone mRNA catabolic process / female meiotic nuclear division / double-strand break repair via alternative nonhomologous end joining / pexophagy / cellular response to X-ray / regulation of telomere maintenance via telomerase / DNA strand resection involved in replication fork processing / chromatin-protein adaptor activity / peptidyl-serine autophosphorylation / homologous recombination / nuclear inclusion body / DNA double-strand break processing / lipoprotein catabolic process / V(D)J recombination / positive regulation of telomere maintenance / regulation of autophagosome assembly / oocyte development / Impaired BRCA2 binding to PALB2 / isotype switching / HDR through MMEJ (alt-NHEJ) / protein localization to site of double-strand break / positive regulation of kinase activity / mitotic G2/M transition checkpoint / reciprocal meiotic recombination / regulation of DNA-templated DNA replication initiation / DNA repair complex / 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 / DNA duplex unwinding / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / 1-phosphatidylinositol-3-kinase activity / response to ionizing radiation / TP53 Regulates Transcription of Caspase Activators and Caspases / mitotic spindle assembly checkpoint signaling / negative regulation of B cell proliferation / mitotic G2 DNA damage checkpoint signaling / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / Presynaptic phase of homologous DNA pairing and strand exchange / telomere maintenance in response to DNA damage / protein K63-linked ubiquitination / peroxisomal matrix / neuromuscular process controlling balance / DNA damage response, signal transduction by p53 class mediator / replicative senescence / neuroblast proliferation / Regulation of HSF1-mediated heat shock response / somitogenesis / signal transduction in response to DNA damage / positive regulation of double-strand break repair via homologous recombination / regulation of cellular response to heat / cellular response to retinoic acid / ovarian follicle development / positive regulation of protein autophosphorylation / negative regulation of TORC1 signaling / positive regulation of telomere maintenance via telomerase / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / telomere maintenance / intrinsic apoptotic signaling pathway / post-embryonic development / positive regulation of cell adhesion / Pexophagy / protein serine/threonine kinase activator activity / thymus development / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / determination of adult lifespan / replication fork / regulation of autophagy / meiotic cell cycle / TP53 Regulates Transcription of DNA Repair Genes
Similarity search - Function
Nibrin, C-terminal / Nibrin / DNA damage repair protein Nbs1 / DNA damage repair protein Nbs1 / Nibrin, second BRCT domain / Nibrin, second BRCT domain superfamily / Second BRCT domain on Nijmegen syndrome breakage protein / Nibrin-related / Telomere-length maintenance and DNA damage repair / Serine/threonine-protein kinase ATM, plant ...Nibrin, C-terminal / Nibrin / DNA damage repair protein Nbs1 / DNA damage repair protein Nbs1 / Nibrin, second BRCT domain / Nibrin, second BRCT domain superfamily / Second BRCT domain on Nijmegen syndrome breakage protein / Nibrin-related / 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 / PIK-related kinase, FAT / FATC domain / FATC / FAT domain / FAT domain profile. / FATC domain profile. / FATC domain / PIK-related kinase / Forkhead associated domain / Forkhead-associated (FHA) domain profile. / FHA domain / Forkhead-associated (FHA) domain / BRCA1 C Terminus (BRCT) domain / SMAD/FHA domain superfamily / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / BRCT domain / BRCT domain superfamily / Armadillo-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Nibrin / Serine-protein kinase ATM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.53 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: Nibrin
C: Serine-protein kinase ATM
D: Nibrin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)710,3468
Polymers709,2854
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: Protein/peptide Nibrin / Cell cycle regulatory protein p95 / Nijmegen breakage syndrome protein 1


Mass: 3514.947 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: C-terminal 28aa of Human Nbs1 / Source: (synth.) Homo sapiens (human) / References: UniProt: O60934
#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
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 Bound to Nbs1 / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenConc.: 0.42 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: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 51.6 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
3D reconstructionResolution: 2.53 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 224367 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00245484
ELECTRON MICROSCOPYf_angle_d0.48361464
ELECTRON MICROSCOPYf_dihedral_angle_d6.3365994
ELECTRON MICROSCOPYf_chiral_restr0.0367048
ELECTRON MICROSCOPYf_plane_restr0.0087740

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