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- EMDB-19569: Open non-crosslinked structure Brd4BD2-MZ1-(NEDD8)-CRL2VHL -

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Basic information

Entry
Database: EMDB / ID: EMD-19569
TitleOpen non-crosslinked structure Brd4BD2-MZ1-(NEDD8)-CRL2VHL
Map data
Sample
  • Complex: Open non-crosslinked structure of Brd4BD2-MZ1-(NEDD8)-CRL2VHL
KeywordsE3 ligase / cullin / BET bromodomain / PROTAC / LIGASE
Function / homology
Function and homology information


negative regulation of DNA-templated DNA replication / regulation of cellular response to hypoxia / negative regulation of receptor signaling pathway via JAK-STAT / negative regulation of beige fat cell differentiation / RHOBTB3 ATPase cycle / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / Cul7-RING ubiquitin ligase complex / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling ...negative regulation of DNA-templated DNA replication / regulation of cellular response to hypoxia / negative regulation of receptor signaling pathway via JAK-STAT / negative regulation of beige fat cell differentiation / RHOBTB3 ATPase cycle / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / Cul7-RING ubiquitin ligase complex / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / target-directed miRNA degradation / cellular response to chemical stress / elongin complex / positive regulation of protein autoubiquitination / RNA polymerase II transcription initiation surveillance / Replication of the SARS-CoV-1 genome / protein neddylation / transcription elongation factor activity / NEDD8 ligase activity / negative regulation of response to oxidative stress / protein K27-linked ubiquitination / VCB complex / Cul5-RING ubiquitin ligase complex / ribosome-associated ubiquitin-dependent protein catabolic process / ubiquitin-ubiquitin ligase activity / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / SUMOylation of ubiquitinylation proteins / Cul3-RING ubiquitin ligase complex / negative regulation of type I interferon production / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / negative regulation of mitophagy / Prolactin receptor signaling / histone H4K8ac reader activity / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / negative regulation of transcription elongation by RNA polymerase II / Cul4B-RING E3 ubiquitin ligase complex / RNA polymerase II C-terminal domain binding / histone H3K27ac reader activity / negative regulation of DNA damage checkpoint / ubiquitin ligase complex scaffold activity / P-TEFb complex binding / histone H3K9ac reader activity / histone H4 reader activity / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / histone H4K5ac reader activity / histone H4K12ac reader activity / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / host-mediated suppression of viral transcription / histone H4K16ac reader activity / positive regulation of G2/M transition of mitotic cell cycle / protein monoubiquitination / cullin family protein binding / negative regulation of signal transduction / positive regulation of T-helper 17 cell lineage commitment / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / ubiquitin-like ligase-substrate adaptor activity / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / signal transduction in response to DNA damage / negative regulation of TORC1 signaling / Nuclear events stimulated by ALK signaling in cancer / protein K48-linked ubiquitination / negative regulation of insulin receptor signaling pathway / Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide / RNA polymerase II CTD heptapeptide repeat kinase activity / RNA Polymerase II Pre-transcription Events / regulation of cellular response to insulin stimulus / positive regulation of TORC1 signaling / rescue of stalled cytosolic ribosome / intrinsic apoptotic signaling pathway / transcription-coupled nucleotide-excision repair / post-translational protein modification / negative regulation of autophagy / transcription corepressor binding / negative regulation of canonical NF-kappaB signal transduction / cellular response to amino acid stimulus / site of DNA damage / condensed nuclear chromosome / Regulation of BACH1 activity / protein serine/threonine kinase binding / T cell activation / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / transcription coregulator activity / G1/S transition of mitotic cell cycle / positive regulation of transcription elongation by RNA polymerase II / negative regulation of canonical Wnt signaling pathway / cell morphogenesis / transcription initiation at RNA polymerase II promoter / Degradation of DVL / Degradation of CRY and PER proteins / transcription elongation by RNA polymerase II / Degradation of GLI1 by the proteasome
Similarity search - Function
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 / Zinc finger, RING-H2-type / RING-H2 zinc finger domain ...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 / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / : / Cullin protein neddylation domain / Elongin-C / Elongin B / Cullin, conserved site / Cullin family signature. / Cullin, N-terminal / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin alpha solenoid domain / Cullin / : / Cullin alpha+beta domain / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / SKP1/BTB/POZ domain superfamily / Zinc finger RING-type profile. / Zinc finger, RING-type / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Zinc finger, RING/FYVE/PHD-type / 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 / von Hippel-Lindau disease tumor suppressor / E3 ubiquitin-protein ligase RBX1 / Cullin-2 / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsCiulli A / Crowe C / Nakasone MA
Funding supportEuropean Union, United Kingdom, Switzerland, 4 items
OrganizationGrant numberCountry
European Research Council (ERC)European Union
Wellcome Trust United Kingdom
Medical Research Council (MRC, United Kingdom) United Kingdom
Innovative Medicines Initiative Switzerland
Citation
Journal: Sci Adv / Year: 2024
Title: Mechanism of degrader-targeted protein ubiquitinability.
Authors: Charlotte Crowe / Mark A Nakasone / Sarah Chandler / Conner Craigon / Gajanan Sathe / Michael H Tatham / Nikolai Makukhin / Ronald T Hay / Alessio Ciulli /
Abstract: Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived ...Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable and long-lived degrader-mediated ternary complexes drive fast and profound target degradation; however, the mechanisms by which they affect target ubiquitination remain elusive. Here, we show cryo-EM structures of the VHL Cullin 2 RING E3 ligase with the degrader MZ1 directing target protein Brd4 toward UBE2R1-ubiquitin, and Lys at optimal positioning for nucleophilic attack. In vitro ubiquitination and mass spectrometry illuminate a patch of favorably ubiquitinable lysines on one face of Brd4, with cellular degradation and ubiquitinomics confirming the importance of Lys and nearby Lys/Lys, identifying the "ubiquitination zone." Our results demonstrate the proficiency of MZ1 in positioning the substrate for catalysis, the favorability of Brd4 for ubiquitination by UBE2R1, and the flexibility of CRL2 for capturing suboptimal lysines. We propose a model for ubiquitinability of degrader-recruited targets, providing a mechanistic blueprint for further rational drug design.
#1: Journal: 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 21, 2024-
Map releaseFeb 21, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19569.png

Downloads & links

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Map

FileDownload / File: emd_19569.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 512 pix.
= 378.88 Å		0.74 Å/pix.
x 512 pix.
= 378.88 Å		0.74 Å/pix.
x 512 pix.
= 378.88 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.74 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.5669689 - 0.7885539
Average (Standard dev.)0.00050089794 (±0.007897719)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 378.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_19569_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_19569_half_map_2.map
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Sample components

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Entire : Open non-crosslinked structure of Brd4BD2-MZ1-(NEDD8)-CRL2VHL

EntireName: Open non-crosslinked structure of Brd4BD2-MZ1-(NEDD8)-CRL2VHL
Components
  • Complex: Open non-crosslinked structure of Brd4BD2-MZ1-(NEDD8)-CRL2VHL

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Supramolecule #1: Open non-crosslinked structure of Brd4BD2-MZ1-(NEDD8)-CRL2VHL

SupramoleculeName: Open non-crosslinked structure of Brd4BD2-MZ1-(NEDD8)-CRL2VHL
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 GLACIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 26.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.2 µm / Nominal defocus min: 1.7 µm

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 132697
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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