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- PDB-8bah: Human Mre11-Nbs1 complex -

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Basic information

Entry
Database: PDB / ID: 8bah
TitleHuman Mre11-Nbs1 complex
Components
  • Double-strand break repair protein MRE11
  • Nibrin
KeywordsHYDROLASE / DNA repair / complex
Function / homology
Function and homology information


telomere maintenance via telomere trimming / chromosomal region / telomeric 3' overhang formation / mitochondrial double-strand break repair via homologous recombination / Mre11 complex / negative regulation of double-strand break repair via nonhomologous end joining / blastocyst growth / negative regulation of telomere capping / meiotic DNA double-strand break formation / BRCA1-C complex ...telomere maintenance via telomere trimming / chromosomal region / telomeric 3' overhang formation / mitochondrial double-strand break repair via homologous recombination / Mre11 complex / negative regulation of double-strand break repair via nonhomologous end joining / blastocyst growth / negative regulation of telomere capping / meiotic DNA double-strand break formation / BRCA1-C complex / Sensing of DNA Double Strand Breaks / protection from non-homologous end joining at telomere / regulation of mitotic recombination / R-loop processing / t-circle formation / single-stranded DNA endodeoxyribonuclease activity / phosphorylation-dependent protein binding / homologous chromosome pairing at meiosis / DNA strand resection involved in replication fork processing / nuclease activity / homologous recombination / nuclear inclusion body / 3'-5'-DNA exonuclease activity / DNA double-strand break processing / chromatin-protein adaptor activity / Impaired BRCA2 binding to PALB2 / double-strand break repair via alternative nonhomologous end joining / protein localization to site of double-strand break / Cytosolic sensors of pathogen-associated DNA / isotype switching / HDR through MMEJ (alt-NHEJ) / mitotic G2/M transition checkpoint / IRF3-mediated induction of type I IFN / reciprocal meiotic recombination / mitotic intra-S DNA damage checkpoint signaling / regulation of DNA-templated DNA replication initiation / sister chromatid cohesion / 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) / positive regulation of double-strand break repair / Impaired BRCA2 binding to RAD51 / mitotic G2 DNA damage checkpoint signaling / positive regulation of telomere maintenance / telomere maintenance in response to DNA damage / neuromuscular process controlling balance / Presynaptic phase of homologous DNA pairing and strand exchange / protein K63-linked ubiquitination / neuroblast proliferation / telomere maintenance via telomerase / positive regulation of double-strand break repair via homologous recombination / 3'-5' exonuclease activity / telomere maintenance / intrinsic apoptotic signaling pathway / DNA damage response, signal transduction by p53 class mediator / protein serine/threonine kinase activator activity / DNA damage checkpoint signaling / replication fork / DNA endonuclease activity / meiotic cell cycle / Nonhomologous End-Joining (NHEJ) / double-strand break repair via homologous recombination / G2/M DNA damage checkpoint / PML body / DNA Damage/Telomere Stress Induced Senescence / Meiotic recombination / HDR through Homologous Recombination (HRR) / double-strand break repair via nonhomologous end joining / double-strand break repair / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / manganese ion binding / site of double-strand break / Processing of DNA double-strand break ends / double-stranded DNA binding / DNA-binding transcription factor binding / DNA recombination / Regulation of TP53 Activity through Phosphorylation / histone binding / damaged DNA binding / Hydrolases; Acting on ester bonds / chromosome, telomeric region / cell population proliferation / regulation of cell cycle / cadherin binding / DNA repair / DNA damage response / negative regulation of apoptotic process / nucleolus / Golgi apparatus / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
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 / DNA double-strand break repair protein Mre11 / Mre11, DNA-binding ...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 / DNA double-strand break repair protein Mre11 / Mre11, DNA-binding / Mre11, capping domain / Mre11 DNA-binding presumed domain / Mre11 DNA-binding presumed domain / Mre11 nuclease, N-terminal metallophosphatase domain / Forkhead associated domain / Forkhead-associated (FHA) domain profile. / FHA domain / Forkhead-associated (FHA) domain / SMAD/FHA domain superfamily / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / BRCA1 C Terminus (BRCT) domain / Metallo-dependent phosphatase-like / BRCT domain / BRCT domain superfamily
Similarity search - Domain/homology
: / Nibrin / Double-strand break repair protein MRE11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.13 Å
AuthorsBartho, J.D. / Rotheneder, M. / Stakyte, K. / Lammens, K. / Hopfner, K.P.
Funding support Germany, 4items
OrganizationGrant numberCountry
German Research Foundation (DFG)CRC1361 Germany
German Research Foundation (DFG)SFB1361 Germany
German Research Foundation (DFG)GRK1721 Germany
German Research Foundation (DFG)CRC1054 Germany
CitationJournal: Mol Cell / Year: 2023
Title: Cryo-EM structure of the Mre11-Rad50-Nbs1 complex reveals the molecular mechanism of scaffolding functions.
Authors: Matthias Rotheneder / Kristina Stakyte / Erik van de Logt / Joseph D Bartho / Katja Lammens / Yilan Fan / Aaron Alt / Brigitte Kessler / Christophe Jung / Wynand P Roos / Barbara ...Authors: Matthias Rotheneder / Kristina Stakyte / Erik van de Logt / Joseph D Bartho / Katja Lammens / Yilan Fan / Aaron Alt / Brigitte Kessler / Christophe Jung / Wynand P Roos / Barbara Steigenberger / Karl-Peter Hopfner /
Abstract: The DNA double-strand break repair complex Mre11-Rad50-Nbs1 (MRN) detects and nucleolytically processes DNA ends, activates the ATM kinase, and tethers DNA at break sites. How MRN can act both as ...The DNA double-strand break repair complex Mre11-Rad50-Nbs1 (MRN) detects and nucleolytically processes DNA ends, activates the ATM kinase, and tethers DNA at break sites. How MRN can act both as nuclease and scaffold protein is not well understood. The cryo-EM structure of MRN from Chaetomium thermophilum reveals a 2:2:1 complex with a single Nbs1 wrapping around the autoinhibited Mre11 nuclease dimer. MRN has two DNA-binding modes, one ATP-dependent mode for loading onto DNA ends and one ATP-independent mode through Mre11's C terminus, suggesting how it may interact with DSBs and intact DNA. MRNs two 60-nm-long coiled-coil domains form a linear rod structure, the apex of which is assembled by the two joined zinc-hook motifs. Apices from two MRN complexes can further dimerize, forming 120-nm spanning MRN-MRN structures. Our results illustrate the architecture of MRN and suggest how it mechanistically integrates catalytic and tethering functions.
History
DepositionOct 11, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 11, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 1, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.2Dec 13, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Double-strand break repair protein MRE11
B: Double-strand break repair protein MRE11
C: Nibrin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)253,3107
Polymers253,0903
Non-polymers2204
Water00
1


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

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Components

#1: Protein Double-strand break repair protein MRE11 / Double-strand break repair protein MRE11A / Meiotic recombination 11 homolog 1 / MRE11 homolog 1 / ...Double-strand break repair protein MRE11A / Meiotic recombination 11 homolog 1 / MRE11 homolog 1 / Meiotic recombination 11 homolog A / MRE11 homolog A


Mass: 84008.633 Da / Num. of mol.: 2 / Mutation: H129N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MRE11, HNGS1, MRE11A / Plasmid: pACEMam1_pMDC / Cell line (production host): HEK293T / Production host: Homo sapiens (human)
References: UniProt: P49959, Hydrolases; Acting on ester bonds
#2: Protein Nibrin / Cell cycle regulatory protein p95 / Nijmegen breakage syndrome protein 1


Mass: 85073.023 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NBN, NBS, NBS1, P95 / Plasmid: pACEMam1_pMDC / Cell line (production host): HEK293T / Production host: Homo sapiens (human) / References: UniProt: O60934
#3: Chemical
ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mn / 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 Mre11-Nbs1 complex / Type: COMPLEX
Details: Human Mre11-dimer with Nbs1 C-terminal chain bound.
Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293T / Plasmid: pACEMam1_pMDC
Buffer solutionpH: 7
Details: 20 mM HEPES (pH 7.0), 140 mM NaCl, 5 mM MgCl2, 1 mM MnCl2, 0.020 mM ZnCl2, 0.2 mM TCEP, 2 mM ATPgS, plus 0.05 percent beta-OG
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2140 mMSodium chlorideNaCl1
35 mMMagnesium chlorideMgCl21
41 mMManganese chlorideMnCl21
50.02 mMZinc chlorideZnCl21
60.2 mMTCEPC9H15O6P1
72 mMATPgSC10H16N5O12P3S1
80.05 percentOctyl beta-D-glucopyranosideC14H28O61
SpecimenConc.: 0.29 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 288 K

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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 magnification: 13000 X / Nominal defocus max: 2800 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 10 sec. / Electron dose: 43 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 3 / Num. of real images: 11325
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV
Image scansMovie frames/image: 40

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameCategory
1Topazparticle selection
2cryoSPARCparticle selection
3EPUimage acquisition
5cryoSPARCCTF correction
6CTFFINDCTF correction
9Cootmodel fitting
11Cootmodel refinement
12PHENIXmodel refinement
13cryoSPARCinitial Euler assignment
14cryoSPARCfinal Euler assignment
16cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.13 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 282838 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037052
ELECTRON MICROSCOPYf_angle_d0.4419526
ELECTRON MICROSCOPYf_dihedral_angle_d10.2732639
ELECTRON MICROSCOPYf_chiral_restr0.0411037
ELECTRON MICROSCOPYf_plane_restr0.0041249

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