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- EMDB-13490: ELONGIN-BC/LRR1/CUL2 multibody refinement -

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Basic information

Entry
Database: EMDB / ID: EMD-13490
TitleELONGIN-BC/LRR1/CUL2 multibody refinement
Map dataSharpened ELONGIN-BC/LRR1/CUL2 multibody refinement
Sample
  • Complex: CUL2-ELONGIN B/C-LRR1 bound to human replisome, multibody refinement
Function / homology
Function and homology information


cellular response to bleomycin / DNA secondary structure binding / Switching of origins to a post-replicative state / detection of abiotic stimulus / replication fork arrest / regulation of nuclear cell cycle DNA replication / Unwinding of DNA / epsilon DNA polymerase complex / DNA replication initiation / cell cycle phase transition ...cellular response to bleomycin / DNA secondary structure binding / Switching of origins to a post-replicative state / detection of abiotic stimulus / replication fork arrest / regulation of nuclear cell cycle DNA replication / Unwinding of DNA / epsilon DNA polymerase complex / DNA replication initiation / cell cycle phase transition / cellular response to cisplatin / DNA strand elongation involved in mitotic DNA replication / GINS complex / mitotic DNA replication preinitiation complex assembly / nuclear origin of replication recognition complex / nucleotide-excision repair, DNA gap filling / mitotic DNA replication / alpha DNA polymerase:primase complex / cellular response to hydroxyurea / DNA replication proofreading / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / anaphase-promoting complex binding / CMG complex / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / single-stranded DNA 3'-5' DNA exonuclease activity / DNA replication checkpoint signaling / Cul7-RING ubiquitin ligase complex / MCM complex / regulation of phosphorylation / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / DNA replication preinitiation complex / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / target-directed miRNA degradation / double-strand break repair via break-induced replication / elongin complex / mitotic DNA replication checkpoint signaling / replication fork protection complex / VCB complex / mitotic DNA replication initiation / positive regulation of protein autoubiquitination / protein neddylation / mitotic intra-S DNA damage checkpoint signaling / NEDD8 ligase activity / Cul5-RING ubiquitin ligase complex / positive regulation of double-strand break repair / Hydrolases; Acting on ester bonds; Exodeoxyribonucleases producing 5'-phosphomonoesters / regulation of DNA-templated DNA replication initiation / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / ubiquitin-ubiquitin ligase activity / Cul4A-RING E3 ubiquitin ligase complex / DNA strand elongation involved in DNA replication / Cul2-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / inner cell mass cell proliferation / negative regulation of type I interferon production / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / leading strand elongation / Cul3-RING ubiquitin ligase complex / DNA synthesis involved in DNA repair / branching morphogenesis of an epithelial tube / cochlea development / DNA unwinding involved in DNA replication / G1/S-Specific Transcription / positive regulation of double-strand break repair via homologous recombination / replication fork processing / DNA replication origin binding / Prolactin receptor signaling / nuclear replication fork / Apoptotic cleavage of cellular proteins / protein monoubiquitination / activation of protein kinase activity / mitotic G2 DNA damage checkpoint signaling / cullin family protein binding / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / DNA replication initiation / PCNA-Dependent Long Patch Base Excision Repair / Activation of the pre-replicative complex / protein K48-linked ubiquitination / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / embryonic organ development / error-prone translesion synthesis / Formation of HIV elongation complex in the absence of HIV Tat / Nuclear events stimulated by ALK signaling in cancer / Activation of ATR in response to replication stress / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / response to UV / base-excision repair, gap-filling / positive regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / cellular response to interleukin-4 / DNA helicase activity / Regulation of BACH1 activity
Similarity search - Function
DNA polymerase epsilon subunit B, N-terminal / DNA polymerases epsilon N terminal / Claspin / Timeless, C-terminal / Timeless PAB domain / Chromosome segregation in meiosis protein 3 / TIPIN/Csm3/Swi3 / Replication Fork Protection Component Swi3 / Timeless / DNA polymerase epsilon, subunit B ...DNA polymerase epsilon subunit B, N-terminal / DNA polymerases epsilon N terminal / Claspin / Timeless, C-terminal / Timeless PAB domain / Chromosome segregation in meiosis protein 3 / TIPIN/Csm3/Swi3 / Replication Fork Protection Component Swi3 / Timeless / DNA polymerase epsilon, subunit B / Timeless, N-terminal / Timeless protein / : / DNA polymerase alpha-binding protein Ctf4, C-terminal domain / Minichromosome loss protein Mcl1, middle region / Minichromosome loss protein, Mcl1, middle region / DNA polymerase epsilon, catalytic subunit A, C-terminal / DNA polymerase epsilon catalytic subunit / Domain of unknown function (DUF1744) / DUF1744 / CDC45 family / CDC45-like protein / DNA replication complex GINS protein Psf2 / GINS complex, subunit Psf1 / GINS complex, subunit Psf3 / GINS complex, subunit Psf3 superfamily / DNA replication complex GINS protein SLD5, C-terminal / GINS, helical bundle-like domain superfamily / GINS complex protein Sld5, alpha-helical domain / DNA replication complex GINS protein SLD5 C-terminus / GINS complex subunit Sld5 / GINS subunit, domain A / GINS complex protein / Leucine rich repeat 4 / MCM4, winged helix domain / Leucine Rich repeats (2 copies) / DNA polymerase alpha/delta/epsilon, subunit B / DNA replication licensing factor Mcm5 / DNA polymerase alpha/epsilon subunit B / DNA replication licensing factor Mcm3 / Mini-chromosome maintenance complex protein 4 / DNA replication licensing factor Mcm6 / DNA replication licensing factor Mcm7 / Mcm6, C-terminal winged-helix domain / MCM6 C-terminal winged-helix domain / DNA replication licensing factor Mcm2 / Mini-chromosome maintenance protein 2 / Mini-chromosome maintenance, conserved site / MCM family signature. / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / MCM N-terminal domain / MCM N-terminal domain / MCM OB domain / Cullin protein neddylation domain / MCM OB domain / Mini-chromosome maintenance protein / MCM, AAA-lid domain / MCM P-loop domain / MCM AAA-lid domain / MCM family domain profile. / minichromosome maintenance proteins / MCM domain / Cullin, conserved site / Cullin family signature. / Elongin B / Cullin / Elongin-C / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin protein neddylation domain / Anaphase-promoting complex subunit 4, WD40 domain / Anaphase-promoting complex subunit 4 WD40 domain / Cullin / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin family / Cullin family profile. / DNA polymerase family B, thumb domain / HMG boxes A and B DNA-binding domains profile. / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / high mobility group / High mobility group box domain / High mobility group box domain superfamily / DNA polymerase family B / DNA polymerase family B, exonuclease domain / DNA-directed DNA polymerase, family B, exonuclease domain / DNA-directed DNA polymerase, family B, multifunctional domain / DNA polymerase, palm domain superfamily / DNA polymerase type-B family / DNA-directed DNA polymerase, family B / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / SKP1/BTB/POZ domain superfamily / Leucine-rich repeat
Similarity search - Domain/homology
Cell division control protein 45 homolog / WD repeat and HMG-box DNA-binding protein 1 / DNA replication licensing factor MCM3 / DNA replication licensing factor MCM4 / DNA replication licensing factor MCM5 / DNA replication licensing factor MCM7 / DNA replication licensing factor MCM2 / DNA polymerase epsilon subunit 2 / E3 ubiquitin-protein ligase RBX1 / DNA polymerase epsilon catalytic subunit A ...Cell division control protein 45 homolog / WD repeat and HMG-box DNA-binding protein 1 / DNA replication licensing factor MCM3 / DNA replication licensing factor MCM4 / DNA replication licensing factor MCM5 / DNA replication licensing factor MCM7 / DNA replication licensing factor MCM2 / DNA polymerase epsilon subunit 2 / E3 ubiquitin-protein ligase RBX1 / DNA polymerase epsilon catalytic subunit A / Cullin-2 / DNA replication licensing factor MCM6 / DNA replication complex GINS protein PSF1 / Elongin-C / Elongin-B / Leucine-rich repeat protein 1 / DNA replication complex GINS protein SLD5 / DNA replication complex GINS protein PSF3 / TIMELESS-interacting protein / Claspin / Protein timeless homolog / DNA replication complex GINS protein PSF2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 8.0 Å
AuthorsJones MJ / Jenkyn-Bedford M / Yeeles JTP / Deegan TD
Funding support United Kingdom, 3 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_1201/12 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_UU_12016/13 United Kingdom
Wellcome Trust204678/Z/16/Z United Kingdom
CitationJournal: Nature / Year: 2021
Title: A conserved mechanism for regulating replisome disassembly in eukaryotes.
Authors: Michael Jenkyn-Bedford / Morgan L Jones / Yasemin Baris / Karim P M Labib / Giuseppe Cannone / Joseph T P Yeeles / Tom D Deegan /
Abstract: Replisome disassembly is the final step of eukaryotic DNA replication and is triggered by ubiquitylation of the CDC45-MCM-GINS (CMG) replicative helicase. Despite being driven by evolutionarily ...Replisome disassembly is the final step of eukaryotic DNA replication and is triggered by ubiquitylation of the CDC45-MCM-GINS (CMG) replicative helicase. Despite being driven by evolutionarily diverse E3 ubiquitin ligases in different eukaryotes (SCF in budding yeast, CUL2 in metazoa), replisome disassembly is governed by a common regulatory principle, in which ubiquitylation of CMG is suppressed before replication termination, to prevent replication fork collapse. Recent evidence suggests that this suppression is mediated by replication fork DNA. However, it is unknown how SCF and CUL2 discriminate terminated from elongating replisomes, to selectively ubiquitylate CMG only after termination. Here we used cryo-electron microscopy to solve high-resolution structures of budding yeast and human replisome-E3 ligase assemblies. Our structures show that the leucine-rich repeat domains of Dia2 and LRR1 are structurally distinct, but bind to a common site on CMG, including the MCM3 and MCM5 zinc-finger domains. The LRR-MCM interaction is essential for replisome disassembly and, crucially, is occluded by the excluded DNA strand at replication forks, establishing the structural basis for the suppression of CMG ubiquitylation before termination. Our results elucidate a conserved mechanism for the regulation of replisome disassembly in eukaryotes, and reveal a previously unanticipated role for DNA in preserving replisome integrity.
History
DepositionAug 31, 2021-
Header (metadata) releaseNov 10, 2021-
Map releaseNov 10, 2021-
UpdateJan 19, 2022-
Current statusJan 19, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.137
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.137
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_13490.png

Downloads & links

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Map

FileDownload / File: emd_13490.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened ELONGIN-BC/LRR1/CUL2 multibody refinement
Voxel sizeX=Y=Z: 2.0465 Å
Density
Contour LevelBy AUTHOR: 0.137 / Movie #1: 0.137
Minimum - Maximum-0.62754554 - 0.7915619
Average (Standard dev.)0.00011345202 (±0.008246743)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 450.22998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z2.04652.04652.0465
M x/y/z220220220
origin x/y/z0.0000.0000.000
length x/y/z450.230450.230450.230
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS220220220
D min/max/mean-0.6280.7920.000

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Supplemental data

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Mask #1

Fileemd_13490_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: ELONGIN-BC/LRR1/CUL2 multibody refinement

Fileemd_13490_additional_1.map
AnnotationELONGIN-BC/LRR1/CUL2 multibody refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: ELONGIN-BC/LRR1/CUL2 multibody refinement half 1

Fileemd_13490_half_map_1.map
AnnotationELONGIN-BC/LRR1/CUL2 multibody refinement half 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: ELONGIN-BC/LRR1/CUL2 multibody refinement half 2

Fileemd_13490_half_map_2.map
AnnotationELONGIN-BC/LRR1/CUL2 multibody refinement half 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : CUL2-ELONGIN B/C-LRR1 bound to human replisome, multibody refinement

EntireName: CUL2-ELONGIN B/C-LRR1 bound to human replisome, multibody refinement
Components
  • Complex: CUL2-ELONGIN B/C-LRR1 bound to human replisome, multibody refinement

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Supramolecule #1: CUL2-ELONGIN B/C-LRR1 bound to human replisome, multibody refinement

SupramoleculeName: CUL2-ELONGIN B/C-LRR1 bound to human replisome, multibody refinement
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#24
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)

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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: 7.6
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Pretreatment - Type: GLOW DISCHARGE
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 / Cs: 0.1 mm / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 0.8 µm
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 16721 / Average exposure time: 4.0 sec. / Average electron dose: 38.8 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2412000
CTF correctionSoftware - Name: RELION (ver. 3)
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 2)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 8.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2) / Number images used: 54000

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