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- PDB-7ni4: Human ATM kinase domain with bound M4076 inhibitor -

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Entry
Database: PDB / ID: 7ni4
TitleHuman ATM kinase domain with bound M4076 inhibitor
ComponentsSerine-protein kinase ATM
KeywordsSIGNALING PROTEIN / Kinase / inhibitor / DNA damage response / cancer research
Function / homology
Function and homology information


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 / 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 ...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 / 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 / positive regulation of telomere maintenance via telomere lengthening / regulation of microglial cell activation / meiotic telomere clustering / pre-B cell allelic exclusion / male meiotic nuclear division / histone mRNA catabolic process / female meiotic nuclear division / pexophagy / cellular response to X-ray / regulation of telomere maintenance via telomerase / peptidyl-serine autophosphorylation / DNA double-strand break processing / lipoprotein catabolic process / V(D)J recombination / regulation of autophagosome assembly / oocyte development / Impaired BRCA2 binding to PALB2 / reciprocal meiotic recombination / 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 / 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 / peroxisomal matrix / replicative senescence / Regulation of HSF1-mediated heat shock response / somitogenesis / signal transduction in response to DNA damage / regulation of cellular response to heat / cellular response to retinoic acid / ovarian follicle development / 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 / post-embryonic development / positive regulation of cell adhesion / Pexophagy / thymus development / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / determination of adult lifespan / regulation of autophagy / TP53 Regulates Transcription of DNA Repair Genes / Nonhomologous End-Joining (NHEJ) / Stabilization of p53 / Autodegradation of the E3 ubiquitin ligase COP1 / double-strand break repair via homologous recombination / brain development / G2/M DNA damage checkpoint / HDR through Homologous Recombination (HRR) / multicellular organism growth / DNA Damage/Telomere Stress Induced Senescence / Regulation of TP53 Activity through Methylation / cellular response to gamma radiation / Meiotic recombination / double-strand break repair via nonhomologous end joining / spindle / intrinsic apoptotic signaling pathway in response to DNA damage / cellular response to reactive oxygen species / positive regulation of neuron apoptotic process / cellular senescence / Regulation of TP53 Degradation / double-strand break repair / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / heart development / site of double-strand break / Processing of DNA double-strand break ends / peptidyl-serine phosphorylation / cytoplasmic vesicle / regulation of apoptotic process / neuron apoptotic process / Regulation of TP53 Activity through Phosphorylation / protein autophosphorylation / non-specific serine/threonine protein kinase / regulation of cell cycle / response to hypoxia / 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 / PIK-related kinase, FAT / FATC domain / FATC / FAT domain / FAT domain profile. ...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 / 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 / Armadillo-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-UGK / Serine-protein kinase ATM
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsStakyte, K. / Rotheneder, M.
Funding support Germany, 4items
OrganizationGrant numberCountry
German Research Foundation (DFG)CRC1054 Germany
German Research Foundation (DFG)CRC1064 Germany
German Research Foundation (DFG)CRC1361 Germany
Leibniz Association Germany
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: Molecular basis of human ATM kinase inhibition.
Authors: K Stakyte / M Rotheneder / K Lammens / J D Bartho / U Grädler / T Fuchß / U Pehl / A Alt / E van de Logt / K P Hopfner /
Abstract: Human checkpoint kinase ataxia telangiectasia-mutated (ATM) plays a key role in initiation of the DNA damage response following DNA double-strand breaks. ATM inhibition is a promising approach in ...Human checkpoint kinase ataxia telangiectasia-mutated (ATM) plays a key role in initiation of the DNA damage response following DNA double-strand breaks. ATM inhibition is a promising approach in cancer therapy, but, so far, detailed insights into the binding modes of known ATM inhibitors have been hampered due to the lack of high-resolution ATM structures. Using cryo-EM, we have determined the structure of human ATM to an overall resolution sufficient to build a near-complete atomic model and identify two hitherto unknown zinc-binding motifs. We determined the structure of the kinase domain bound to ATPγS and to the ATM inhibitors KU-55933 and M4076 at 2.8 Å, 2.8 Å and 3.0 Å resolution, respectively. The mode of action and selectivity of the ATM inhibitors can be explained by structural comparison and provide a framework for structure-based drug design.
History
DepositionFeb 11, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 1, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update
Revision 1.2Oct 20, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / em_admin / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 2.0Nov 3, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Other / Refinement description / Structure summary
Category: atom_site / em_admin ...atom_site / em_admin / em_entity_assembly / em_imaging / em_map / em_software / pdbx_chem_comp_depositor_info / pdbx_chem_comp_instance_depositor_info / pdbx_contact_author / pdbx_database_proc / pdbx_database_status / pdbx_depui_status_flags / pdbx_depui_upload / pdbx_nonpoly_scheme / pdbx_validate_close_contact / refine / refine_ls_restr
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.pdbx_auth_comp_id / _atom_site.pdbx_auth_seq_id / _em_admin.last_update / _em_entity_assembly.assembly_id / _em_imaging.detector_id / _em_imaging.sample_support_id / _em_imaging.scans_id / _em_map.file / _em_software.category / _pdbx_chem_comp_depositor_info.comp_id / _pdbx_chem_comp_depositor_info.formula / _pdbx_chem_comp_depositor_info.name / _pdbx_chem_comp_instance_depositor_info.auth_seq_id / _pdbx_chem_comp_instance_depositor_info.comp_id / _pdbx_chem_comp_instance_depositor_info.formula / _pdbx_database_status.date_accepted_terms_and_conditions / _pdbx_database_status.date_author_approval / _pdbx_depui_status_flags.is_grant_funded / _pdbx_depui_status_flags.post_rel_replacement_reason / _pdbx_depui_upload.file_name / _pdbx_depui_upload.file_size / _pdbx_depui_upload.file_type / _pdbx_nonpoly_scheme.auth_mon_id / _pdbx_nonpoly_scheme.auth_seq_num
Description: Ligand geometry / Provider: author / Type: Coordinate replacement
Revision 2.1Jul 10, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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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)703,2836
Polymers702,2552
Non-polymers1,0284
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area7150 Å2
ΔGint-45 kcal/mol
Surface area125130 Å2
MethodPISA

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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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-UGK / 8-(1,3-dimethylpyrazol-4-yl)-1-(3-fluoranyl-5-methoxy-pyridin-4-yl)-7-methoxy-3-methyl-imidazo[4,5-c]quinolin-2-one


Mass: 448.450 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H21FN6O3 / 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 dimer with bound KU-55933 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
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
Image recordingElectron dose: 42 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
EM softwareName: EPU / Category: image acquisition
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 455866 / Symmetry type: POINT

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