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- EMDB-19567: Closed crosslinked structure of (NEDD8)-CRL2VHL-MZ1-Brd4BD2-Ub(G7... -

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Basic information

Entry
Database: EMDB / ID: EMD-19567
TitleClosed crosslinked structure of (NEDD8)-CRL2VHL-MZ1-Brd4BD2-Ub(G76S, K48C)-UBE2R1(C93K, S138C, C191S, C223S)-Ub
Map dataCryo-EM structure of the (NEDD8)-CRL2VHL-MZ1-Brd4BD2 ternary complex primed for catalysis with UBE2R1-Ub.
Sample
  • Complex: Closed crosslinked structure of (NEDD8)-CRL2VHL-MZ1-Brd4BD2-Ub(G76S, K48C)-UBE2R1(C93K, S138C, C191S, C223S)-Ub
KeywordsE3 ligase / Cullin / PROTAC / BET bromodomain / LIGASE
Function / homology
Function and homology information


positive regulation of inclusion body assembly / regulation of cellular response to hypoxia / (E3-independent) E2 ubiquitin-conjugating enzyme / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / regulation of proteolysis / target-directed miRNA degradation / response to growth factor ...positive regulation of inclusion body assembly / regulation of cellular response to hypoxia / (E3-independent) E2 ubiquitin-conjugating enzyme / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / regulation of proteolysis / target-directed miRNA degradation / response to growth factor / elongin complex / VCB complex / protein neddylation / negative regulation of cAMP-mediated signaling / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / E2 ubiquitin-conjugating enzyme / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / intracellular non-membrane-bounded organelle / SUMOylation of ubiquitinylation proteins / negative regulation of transcription elongation by RNA polymerase II / TGF-beta receptor signaling activates SMADs / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / ubiquitin conjugating enzyme activity / RNA polymerase II C-terminal domain binding / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / negative regulation of DNA damage checkpoint / P-TEFb complex binding / ubiquitin-like ligase-substrate adaptor activity / DNA replication initiation / negative regulation by host of viral transcription / anatomical structure morphogenesis / Tat-mediated elongation of the HIV-1 transcript / cellular response to interferon-beta / Formation of HIV-1 elongation complex containing HIV-1 Tat / protein K48-linked ubiquitination / Formation of HIV elongation complex in the absence of HIV Tat / negative regulation of signal transduction / positive regulation of T-helper 17 cell lineage commitment / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / negative regulation of TORC1 signaling / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Endosomal Sorting Complex Required For Transport (ESCRT) / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Regulation of FZD by ubiquitination / TICAM1,TRAF6-dependent induction of TAK1 complex / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1-dependent activation of IRF3/IRF7 / RNA Polymerase II Pre-transcription Events / APC/C:Cdc20 mediated degradation of Cyclin B / positive regulation of G2/M transition of mitotic cell cycle / p75NTR recruits signalling complexes / Downregulation of ERBB4 signaling / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / APC-Cdc20 mediated degradation of Nek2A / PINK1-PRKN Mediated Mitophagy / histone reader activity / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Pexophagy / Regulation of innate immune responses to cytosolic DNA / VLDLR internalisation and degradation / InlA-mediated entry of Listeria monocytogenes into host cells / Downregulation of ERBB2:ERBB3 signaling / NF-kB is activated and signals survival / NRIF signals cell death from the nucleus / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Regulation of BACH1 activity / Translesion synthesis by REV1 / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Translesion synthesis by POLK / MAP3K8 (TPL2)-dependent MAPK1/3 activation / TICAM1, RIP1-mediated IKK complex recruitment / RNA polymerase II CTD heptapeptide repeat kinase activity / intrinsic apoptotic signaling pathway / Downregulation of TGF-beta receptor signaling / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / negative regulation of autophagy / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER
Similarity search - Function
Nedd8-like ubiquitin / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Cullin protein neddylation domain ...Nedd8-like ubiquitin / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Cullin protein neddylation 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 / Cullin / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin family / Cullin family profile. / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / Ubiquitin-conjugating enzyme, active site / Ubiquitin-conjugating (UBC) active site signature. / Ubiquitin-conjugating enzyme E2, catalytic domain homologues / Ubiquitin-conjugating enzyme E2 / Ubiquitin-conjugating enzyme / Ubiquitin-conjugating (UBC) core domain profile. / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Ubiquitin-conjugating enzyme/RWD-like / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / SKP1/BTB/POZ domain superfamily / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Bromodomain, conserved site / Bromodomain signature. / Ubiquitin family / Bromodomain / Ubiquitin homologues / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Elongin-C / Bromodomain-containing protein 4 / Polyubiquitin-C / von Hippel-Lindau disease tumor suppressor / Ubiquitin-conjugating enzyme E2 R1 / Cullin-2 / Elongin-B / NEDD8
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsCiulli A / Crowe C / Nakasone MA
Funding supportEuropean Union, United Kingdom, Switzerland, 5 items
OrganizationGrant numberCountry
European Research Council (ERC)European Union
Medical Research Council (MRC, United Kingdom) United Kingdom
Innovative Medicines Initiative Switzerland
Wellcome Trust United Kingdom
Cancer Research UK United Kingdom
CitationJournal: Biorxiv / Year: 2024
Title: Mechanism of degrader-targeted protein ubiquitinability
Authors: Crowe C / Nakasone MA / Chandler S / Tatham MH / Makukhin N / Hay RT / Ciulli A
History
DepositionFeb 5, 2024-
Header (metadata) releaseFeb 28, 2024-
Map releaseFeb 28, 2024-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19567.png

Downloads & links

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Map

FileDownload / File: emd_19567.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of the (NEDD8)-CRL2VHL-MZ1-Brd4BD2 ternary complex primed for catalysis with UBE2R1-Ub.
Voxel sizeX=Y=Z: 0.825 Å
Density
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.8583815 - 1.2370622
Average (Standard dev.)-0.00006806529 (±0.011533733)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 396.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_19567_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_19567_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Closed crosslinked structure of (NEDD8)-CRL2VHL-MZ1-Brd4BD2-Ub(G7...

EntireName: Closed crosslinked structure of (NEDD8)-CRL2VHL-MZ1-Brd4BD2-Ub(G76S, K48C)-UBE2R1(C93K, S138C, C191S, C223S)-Ub
Components
  • Complex: Closed crosslinked structure of (NEDD8)-CRL2VHL-MZ1-Brd4BD2-Ub(G76S, K48C)-UBE2R1(C93K, S138C, C191S, C223S)-Ub

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Supramolecule #1: Closed crosslinked structure of (NEDD8)-CRL2VHL-MZ1-Brd4BD2-Ub(G7...

SupramoleculeName: Closed crosslinked structure of (NEDD8)-CRL2VHL-MZ1-Brd4BD2-Ub(G76S, K48C)-UBE2R1(C93K, S138C, C191S, C223S)-Ub
type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 190 kDa/nm

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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: 7.8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.7 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 38.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 149823
FSC plot (resolution estimation)

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