+Open data
-Basic information
Entry | Database: PDB / ID: 7z87 | ||||||
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Title | DNA-PK in the active state | ||||||
Components |
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Keywords | DNA BINDING PROTEIN / DNA-dependent protein kinase | ||||||
Function / homology | Function and homology information Ku70:Ku80 complex / negative regulation of t-circle formation / positive regulation of platelet formation / DNA end binding / T cell receptor V(D)J recombination / pro-B cell differentiation / small-subunit processome assembly / positive regulation of lymphocyte differentiation / DNA-dependent protein kinase activity / histone H2AXS139 kinase activity ...Ku70:Ku80 complex / negative regulation of t-circle formation / positive regulation of platelet formation / DNA end binding / T cell receptor V(D)J recombination / pro-B cell differentiation / small-subunit processome assembly / positive regulation of lymphocyte differentiation / DNA-dependent protein kinase activity / histone H2AXS139 kinase activity / DNA-dependent protein kinase complex / immature B cell differentiation / DNA-dependent protein kinase-DNA ligase 4 complex / cellular response to X-ray / immunoglobulin V(D)J recombination / nonhomologous end joining complex / nuclear telomere cap complex / DNA ligation / regulation of smooth muscle cell proliferation / Cytosolic sensors of pathogen-associated DNA / double-strand break repair via alternative nonhomologous end joining / double-strand break repair via classical nonhomologous end joining / regulation of epithelial cell proliferation / IRF3-mediated induction of type I IFN / telomere capping / recombinational repair / regulation of telomere maintenance / regulation of hematopoietic stem cell differentiation / U3 snoRNA binding / positive regulation of neurogenesis / protein localization to chromosome, telomeric region / cellular response to fatty acid / hematopoietic stem cell proliferation / cellular hyperosmotic salinity response / maturation of 5.8S rRNA / T cell lineage commitment / telomeric DNA binding / negative regulation of cGAS/STING signaling pathway / B cell lineage commitment / positive regulation of catalytic activity / 2-LTR circle formation / positive regulation of double-strand break repair via nonhomologous end joining / site of DNA damage / Lyases; Carbon-oxygen lyases; Other carbon-oxygen lyases / enzyme activator activity / 5'-deoxyribose-5-phosphate lyase activity / hematopoietic stem cell differentiation / positive regulation of protein kinase activity / ectopic germ cell programmed cell death / ATP-dependent activity, acting on DNA / somitogenesis / positive regulation of telomerase activity / mitotic G1 DNA damage checkpoint signaling / positive regulation of telomere maintenance via telomerase / DNA helicase activity / telomere maintenance / activation of innate immune response / neurogenesis / cellular response to leukemia inhibitory factor / cyclin binding / small-subunit processome / positive regulation of translation / positive regulation of erythrocyte differentiation / negative regulation of protein phosphorylation / protein-DNA complex / response to gamma radiation / Nonhomologous End-Joining (NHEJ) / peptidyl-threonine phosphorylation / brain development / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / protein destabilization / cellular response to gamma radiation / protein modification process / regulation of circadian rhythm / double-strand break repair via nonhomologous end joining / cellular response to insulin stimulus / rhythmic process / intrinsic apoptotic signaling pathway in response to DNA damage / double-strand break repair / E3 ubiquitin ligases ubiquitinate target proteins / T cell differentiation in thymus / heart development / double-stranded DNA binding / scaffold protein binding / peptidyl-serine phosphorylation / secretory granule lumen / DNA recombination / ficolin-1-rich granule lumen / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / chromosome, telomeric region / damaged DNA binding / transcription cis-regulatory region binding / non-specific serine/threonine protein kinase / protein kinase activity / response to xenobiotic stimulus / ribonucleoprotein complex / positive regulation of apoptotic process / protein domain specific binding / protein phosphorylation Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.91 Å | ||||||
Authors | Liang, S. / Blundell, T.L. | ||||||
Funding support | United Kingdom, 1items
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Citation | Journal: Nat Struct Mol Biol / Year: 2023 Title: Human DNA-dependent protein kinase activation mechanism. Authors: Shikang Liang / Tom L Blundell / Abstract: DNA-dependent protein kinase (DNA-PK), a multicomponent complex including the DNA-PK catalytic subunit and Ku70/80 heterodimer together with DNA, is central to human DNA damage response and repair. ...DNA-dependent protein kinase (DNA-PK), a multicomponent complex including the DNA-PK catalytic subunit and Ku70/80 heterodimer together with DNA, is central to human DNA damage response and repair. Using a DNA-PK-selective inhibitor (M3814), we identified from one dataset two cryo-EM structures of the human DNA-PK complex in different states, the intermediate state and the active state. Here we show that activation of the kinase is regulated through conformational changes caused by the binding ligand and the string region (residues 802-846) of the DNA-PK catalytic subunit, particularly the helix-hairpin-helix motif (residues 816-836) that interacts with DNA. These observations demonstrate the regulatory role of the ligand and explain why DNA-PK is DNA dependent. Cooperation and coordination among binding partners, disordered flexible regions and mechanically flexible HEAT repeats modulate the activation of the kinase. Together with previous findings, these results provide a better molecular understanding of DNA-PK catalysis. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7z87.cif.gz | 888.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7z87.ent.gz | 713.9 KB | Display | PDB format |
PDBx/mmJSON format | 7z87.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/z8/7z87 ftp://data.pdbj.org/pub/pdb/validation_reports/z8/7z87 | HTTPS FTP |
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-Related structure data
Related structure data | 14545MC 7z88C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 1 types, 1 molecules A
#1: Protein | Mass: 469673.219 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) References: UniProt: P78527, non-specific serine/threonine protein kinase |
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-X-ray repair cross-complementing protein ... , 2 types, 2 molecules BC
#2: Protein | Mass: 69945.039 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: XRCC6, G22P1 / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: P12956, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement, Lyases; Carbon-oxygen lyases; Other carbon-oxygen lyases |
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#3: Protein | Mass: 82812.438 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: XRCC5, G22P2 / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: P13010, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement |
-DNA chain , 2 types, 2 molecules DE
#4: DNA chain | Mass: 7900.079 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) |
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#5: DNA chain | Mass: 8078.203 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) |
-Non-polymers , 2 types, 195 molecules
#6: Chemical | ChemComp-1IX / (~{ |
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#7: Water | ChemComp-HOH / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Human DNA-dependent protein kinase / Type: COMPLEX / Entity ID: #1-#5 / Source: NATURAL |
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Source (natural) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.6 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2300 nm / Nominal defocus min: 1100 nm |
Image recording | Electron dose: 47.22 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 2.91 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 275300 / Symmetry type: POINT |