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- EMDB-12350: Human ATM kinase domain with bound M4076 inhibitor -

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Basic information

Entry
Database: EMDB / ID: EMD-12350
TitleHuman ATM kinase domain with bound M4076 inhibitor
Map dataHuman ATM kinase domain with bound inhibitor M4076, LAFTER filtered map
Sample
  • Complex: ATM dimer with bound KU-55933
    • Protein or peptide: Serine-protein kinase ATM
  • Ligand: ZINC ION
  • Ligand: 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
Function / homology
Function and homology information


positive regulation of DNA catabolic process / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / cellular response to nitrosative stress / positive regulation of DNA damage response, signal transduction by p53 class mediator / establishment of protein-containing complex localization to telomere / regulation of microglial cell activation / negative regulation of telomere capping / Sensing of DNA Double Strand Breaks / positive regulation of telomere maintenance via telomere lengthening ...positive regulation of DNA catabolic process / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / cellular response to nitrosative stress / positive regulation of DNA damage response, signal transduction by p53 class mediator / establishment of protein-containing complex localization to telomere / regulation of microglial cell activation / negative regulation of telomere capping / Sensing of DNA Double Strand Breaks / positive regulation of telomere maintenance via telomere lengthening / meiotic telomere clustering / pre-B cell allelic exclusion / DNA-dependent protein kinase activity / histone H2AXS139 kinase activity / male meiotic nuclear division / histone mRNA catabolic process / female meiotic nuclear division / regulation of telomere maintenance via telomerase / pexophagy / cellular response to X-ray / peptidyl-serine autophosphorylation / lipoprotein catabolic process / V(D)J recombination / oocyte development / Impaired BRCA2 binding to PALB2 / reciprocal meiotic recombination / DNA repair complex / 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 / Homologous DNA Pairing and Strand Exchange / 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 / mitotic spindle assembly checkpoint signaling / TP53 Regulates Transcription of Caspase Activators and Caspases / negative regulation of B cell proliferation / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / peroxisomal matrix / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / replicative senescence / positive regulation of cell adhesion / Regulation of HSF1-mediated heat shock response / somitogenesis / regulation of cellular response to heat / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / signal transduction in response to DNA damage / cellular response to retinoic acid / ovarian follicle development / negative regulation of TORC1 signaling / positive regulation of telomere maintenance via telomerase / Pexophagy / telomere maintenance / post-embryonic development / thymus development / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / regulation of autophagy / determination of adult lifespan / TP53 Regulates Transcription of DNA Repair Genes / Nonhomologous End-Joining (NHEJ) / Stabilization of p53 / double-strand break repair via homologous recombination / Autodegradation of the E3 ubiquitin ligase COP1 / brain development / multicellular organism growth / cellular response to gamma radiation / HDR through Homologous Recombination (HRR) / G2/M DNA damage checkpoint / Regulation of TP53 Activity through Methylation / DNA Damage/Telomere Stress Induced Senescence / spindle / Meiotic recombination / cellular response to reactive oxygen species / double-strand break repair via nonhomologous end joining / positive regulation of neuron apoptotic process / intrinsic apoptotic signaling pathway in response to DNA damage / double-strand break repair / cellular senescence / Regulation of TP53 Degradation / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / heart development / Processing of DNA double-strand break ends / cytoplasmic vesicle / peptidyl-serine phosphorylation / neuron apoptotic process / regulation of apoptotic process / Regulation of TP53 Activity through Phosphorylation / protein autophosphorylation / response to hypoxia / regulation of cell cycle / non-specific serine/threonine protein kinase / positive regulation of cell migration / positive regulation of apoptotic process / protein phosphorylation / protein serine kinase activity
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 / FAT domain / FATC 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 / PIK-related kinase, FAT / FAT domain / FATC 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
Serine-protein kinase ATM
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsStakyte K / Rotheneder M
Funding support Germany, 4 items
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, 2021-
Header (metadata) releaseSep 1, 2021-
Map releaseSep 1, 2021-
UpdateNov 3, 2021-
Current statusNov 3, 2021Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0213
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0213
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7ni4
  • Surface level: 0.0213
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_12350.png

Downloads & links

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Map

FileDownload / File: emd_12350.map.gz / Format: CCP4 / Size: 1.4 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman ATM kinase domain with bound inhibitor M4076, LAFTER filtered map
Voxel sizeX=Y=Z: 0.5295 Å
Density
Contour LevelBy AUTHOR: 0.0213 / Movie #1: 0.0213
Minimum - Maximum-0.09557491 - 0.14437355
Average (Standard dev.)8.4902036e-05 (±0.002505585)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions720720720
Spacing720720720
CellA=B=C: 381.24 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.52950.52950.5295
M x/y/z720720720
origin x/y/z0.0000.0000.000
length x/y/z381.240381.240381.240
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS720720720
D min/max/mean-0.0960.1440.000

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Supplemental data

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Additional map: Human ATM kinase domain with bound inhibitor M4076, unfiltered map

Fileemd_12350_additional_1.map
AnnotationHuman ATM kinase domain with bound inhibitor M4076, unfiltered map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Human ATM kinase domain with bound inhibitor M4076, half map 2

Fileemd_12350_half_map_1.map
AnnotationHuman ATM kinase domain with bound inhibitor M4076, half map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Human ATM kinase domain with bound inhibitor M4076, half map 1

Fileemd_12350_half_map_2.map
AnnotationHuman ATM kinase domain with bound inhibitor M4076, half map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : ATM dimer with bound KU-55933

EntireName: ATM dimer with bound KU-55933
Components
  • Complex: ATM dimer with bound KU-55933
    • Protein or peptide: Serine-protein kinase ATM
  • Ligand: ZINC ION
  • Ligand: 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

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Supramolecule #1: ATM dimer with bound KU-55933

SupramoleculeName: ATM dimer with bound KU-55933 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: Serine-protein kinase ATM

MacromoleculeName: Serine-protein kinase ATM / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 351.127688 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSLVLNDLLI CCRQLEHDRA TERKKEVEKF KRLIRDPETI KHLDRHSDSK QGKYLNWDAV FRFLQKYIQK ETECLRIAKP NVSASTQAS RQKKMQEISS LVKYFIKCAN RRAPRLKCQE LLNYIMDTVK DSSNGAIYGA DCSNILLKDI LSVRKYWCEI S QQQWLELF ...String:
MSLVLNDLLI CCRQLEHDRA TERKKEVEKF KRLIRDPETI KHLDRHSDSK QGKYLNWDAV FRFLQKYIQK ETECLRIAKP NVSASTQAS RQKKMQEISS LVKYFIKCAN RRAPRLKCQE LLNYIMDTVK DSSNGAIYGA DCSNILLKDI LSVRKYWCEI S QQQWLELF SVYFRLYLKP SQDVHRVLVA RIIHAVTKGC CSQTDGLNSK FLDFFSKAIQ CARQEKSSSG LNHILAALTI FL KTLAVNF RIRVCELGDE ILPTLLYIWT QHRLNDSLKE VIIELFQLQI YIHHPKGAKT QEKGAYESTK WRSILYNLYD LLV NEISHI GSRGKYSSGF RNIAVKENLI ELMADICHQV FNEDTRSLEI SQSYTTTQRE SSDYSVPCKR KKIELGWEVI KDHL QKSQN DFDLVPWLQI ATQLISKYPA SLPNCELSPL LMILSQLLPQ QRHGERTPYV LRCLTEVALC QDKRSNLESS QKSDL LKLW NKIWCITFRG ISSEQIQAEN FGLLGAIIQG SLVEVDREFW KLFTGSACRP SCPAVCCLTL ALTTSIVPGT VKMGIE QNM CEVNRSFSLK ESIMKWLLFY QLEGDLENST EVPPILHSNF PHLVLEKILV SLTMKNCKAA MNFFQSVPEC EHHQKDK EE LSFSEVEELF LQTTFDKMDF LTIVRECGIE KHQSSIGFSV HQNLKESLDR CLLGLSEQLL NNYSSEITNS ETLVRCSR L LVGVLGCYCY MGVIAEEEAY KSELFQKAKS LMQCAGESIT LFKNKTNEEF RIGSLRNMMQ LCTRCLSNCT KKSPNKIAS GFFLRLLTSK LMNDIADICK SLASFIKKPF DRGEVESMED DTNGNLMEVE DQSSMNLFND YPDSSVSDAN EPGESQSTIG AINPLAEEY LSKQDLLFLD MLKFLCLCVT TAQTNTVSFR AADIRRKLLM LIDSSTLEPT KSLHLHMYLM LLKELPGEEY P LPMEDVLE LLKPLSNVCS LYRRDQDVCK TILNHVLHVV KNLGQSNMDS ENTRDAQGQF LTVIGAFWHL TKERKYIFSV RM ALVNCLK TLLEADPYSK WAILNVMGKD FPVNEVFTQF LADNHHQVRM LAAESINRLF QDTKGDSSRL LKALPLKLQQ TAF ENAYLK AQEGMREMSH SAENPETLDE IYNRKSVLLT LIAVVLSCSP ICEKQALFAL CKSVKENGLE PHLVKKVLEK VSET FGYRR LEDFMASHLD YLVLEWLNLQ DTEYNLSSFP FILLNYTNIE DFYRSCYKVL IPHLVIRSHF DEVKSIANQI QEDWK SLLT DCFPKILVNI LPYFAYEGTR DSGMAQQRET ATKVYDMLKS ENLLGKQIDH LFISNLPEIV VELLMTLHEP ANSSAS QST DLCDFSGDLD PAPNPPHFPS HVIKATFAYI SNCHKTKLKS ILEILSKSPD SYQKILLAIC EQAAETNNVY KKHRILK IY HLFVSLLLKD IKSGLGGAWA FVLRDVIYTL IHYINQRPSC IMDVSLRSFS LCCDLLSQVC QTAVTYCKDA LENHLHVI V GTLIPLVYEQ VEVQKQVLDL LKYLVIDNKD NENLYITIKL LDPFPDHVVF KDLRITQQKI KYSRGPFSLL EEINHFLSV SVYDALPLTR LEGLKDLRRQ LELHKDQMVD IMRASQDNPQ DGIMVKLVVN LLQLSKMAIN HTGEKEVLEA VGSCLGEVGP IDFSTIAIQ HSKDASYTKA LKLFEDKELQ WTFIMLTYLN NTLVEDCVKV RSAAVTCLKN ILATKTGHSF WEIYKMTTDP M LAYLQPFR TSRKKFLEVP RFDKENPFEG LDDINLWIPL SENHDIWIKT LTCAFLDSGG TKCEILQLLK PMCEVKTDFC QT VLPYLIH DILLQDTNES WRNLLSTHVQ GFFTSCLRHF SQTSRSTTPA NLDSESEHFF RCCLDKKSQR TMLAVVDYMR RQK RPSSGT IFNDAFWLDL NYLEVAKVAQ SCAAHFTALL YAEIYADKKS MDDQEKRSLA FEEGSQSTTI SSLSEKSKEE TGIS LQDLL LEIYRSIGEP DSLYGCGGGK MLQPITRLRT YEHEAMWGKA LVTYDLETAI PSSTRQAGII QALQNLGLCH ILSVY LKGL DYENKDWCPE LEELHYQAAW RNMQWDHCTS VSKEVEGTSY HESLYNALQS LRDREFSTFY ESLKYARVKE VEEMCK RSL ESVYSLYPTL SRLQAIGELE SIGELFSRSV THRQLSEVYI KWQKHSQLLK DSDFSFQEPI MALRTVILEI LMEKEMD NS QRECIKDILT KHLVELSILA RTFKNTQLPE RAIFQIKQYN SVSCGVSEWQ LEEAQVFWAK KEQSLALSIL KQMIKKLD A SCAANNPSLK LTYTECLRVC GNWLAETCLE NPAVIMQTYL EKAVEVAGNY DGESSDELRN GKMKAFLSLA RFSDTQYQR IENYMKSSEF ENKQALLKRA KEEVGLLREH KIQTNRYTVK VQRELELDEL ALRALKEDRK RFLCKAVENY INCLLSGEEH DMWVFRLCS LWLENSGVSE VNGMMKRDGM KIPTYKFLPL MYQLAARMGT KMMGGLGFHE VLNNLISRIS MDHPHHTLFI I LALANANR DEFLTKPEVA RRSRITKNVP KQSSQLDEDR TEAANRIICT IRSRRPQMVR SVEALCDAYI ILANLDATQW KT QRKGINI PADQPITKLK NLEDVVVPTM EIKVDHTGEY GNLVTIQSFK AEFRLAGGVN LPKIIDCVGS DGKERRQLVK GRD DLRQDA VMQQVFQMCN TLLQRNTETR KRKLTICTYK VVPLSQRSGV LEWCTGTVPI GEFLVNNEDG AHKRYRPNDF SAFQ CQKKM MEVQKKSFEE KYEVFMDVCQ NFQPVFRYFC MEKFLDPAIW FEKRLAYTRS VATSSIVGYI LGLGDRHVQN ILINE QSAE LVHIDLGVAF EQGKILPTPE TVPFRLTRDI VDGMGITGVE GVFRRCCEKT MEVMRNSQET LLTIVEVLLY DPLFDW TMN PLKALYLQQR PEDETELHPT LNADDQECKR NLSDIDQSFN KVAERVLMRL QEKLKGVEEG TVLSVGGQVN LLIQQAI DP KNLSRLFPGW KAWV

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #3: 8-(1,3-dimethylpyrazol-4-yl)-1-(3-fluoranyl-5-methoxy-pyridin-4-y...

MacromoleculeName: 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
type: ligand / ID: 3 / Number of copies: 2 / Formula: UGK
Molecular weightTheoretical: 448.45 Da
Chemical component information

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

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 42.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 455866
FSC plot (resolution estimation)

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