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- PDB-8bdo: VCB in complex with compound 21 -

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Basic information

Entry
Database: PDB / ID: 8bdo
TitleVCB in complex with compound 21
Components
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / PROTAC / degrader / complex / E3 ligase / VHL / VCB / VH032
Function / homology
Function and homology information


regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / VCB complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex ...regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / VCB complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / intracellular non-membrane-bounded organelle / SUMOylation of ubiquitinylation proteins / negative regulation of transcription elongation by RNA polymerase II / 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 / ubiquitin-like ligase-substrate adaptor activity / 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 / negative regulation of signal transduction / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / negative regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / negative regulation of autophagy / transcription corepressor binding / Evasion by RSV of host interferon responses / transcription elongation by RNA polymerase II / transcription initiation at RNA polymerase II promoter / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / Vif-mediated degradation of APOBEC3G / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / cell morphogenesis / Inactivation of CSF3 (G-CSF) signaling / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / transcription corepressor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Antigen processing: Ubiquitination & Proteasome degradation / protein-macromolecule adaptor activity / Neddylation / Replication of the SARS-CoV-2 genome / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / proteasome-mediated ubiquitin-dependent protein catabolic process / protein-containing complex assembly / DNA-binding transcription factor binding / amyloid fibril formation / molecular adaptor activity / protein stabilization / protein ubiquitination / negative regulation of cell population proliferation / negative regulation of gene expression / ubiquitin protein ligase binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / mitochondrion / proteolysis / nucleoplasm / nucleus / plasma membrane / cytosol
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 / Elongin B / Elongin-C ...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 / Elongin B / Elongin-C / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SKP1/BTB/POZ domain superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Chem-QFF / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.8 Å
AuthorsSorrell, F.J. / Mueller, J.E. / Lehmann, M. / Wegener, A.
Funding support Germany, 1items
OrganizationGrant numberCountry
Not funded Germany
CitationJournal: Chemmedchem / Year: 2023
Title: Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design.
Authors: Krieger, J. / Sorrell, F.J. / Wegener, A.A. / Leuthner, B. / Machrouhi-Porcher, F. / Hecht, M. / Leibrock, E.M. / Muller, J.E. / Eisert, J. / Hartung, I.V. / Schlesiger, S.
History
DepositionOct 19, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Apr 26, 2023Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Elongin-B
B: Elongin-C
C: von Hippel-Lindau disease tumor suppressor
D: Elongin-B
E: Elongin-C
F: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,2368
Polymers83,2676
Non-polymers9692
Water3,405189
1
A: Elongin-B
B: Elongin-C
C: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1184
Polymers41,6333
Non-polymers4851
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4700 Å2
ΔGint-40 kcal/mol
Surface area16550 Å2
MethodPISA
2
D: Elongin-B
E: Elongin-C
F: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1184
Polymers41,6333
Non-polymers4851
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4690 Å2
ΔGint-40 kcal/mol
Surface area16610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.306, 67.256, 349.704
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21D
12B
22E
13C
23F

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11METMETLYSLYSAA1 - 1041 - 104
21METMETLYSLYSDD1 - 1041 - 104
12METMETCYSCYSBB16 - 1121 - 97
22METMETCYSCYSEE16 - 1121 - 97
13VALVALGLUGLUCC62 - 20411 - 153
23VALVALGLUGLUFF62 - 20411 - 153

NCS ensembles :
ID
1
2
3

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Components

#1: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 11852.389 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370
#2: Protein Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 10974.616 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369
#3: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18806.273 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli (E. coli) / References: UniProt: P40337
#4: Chemical ChemComp-QFF / (2~{S},4~{R})-1-[(2~{R})-3-methyl-2-(3-methyl-1,2-oxazol-5-yl)butanoyl]-~{N}-[4-(4-methyl-1,3-thiazol-5-yl)phenoxy]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 484.568 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H28N4O5S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 189 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.21 Å3/Da / Density % sol: 44.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 10-20% PEG 8000, 0.2 M magnesium acetate and 0.1 M sodium cacodylate pH 6.5, 1mM Compound soak

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 19, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→174.85 Å / Num. obs: 18741 / % possible obs: 99.9 % / Redundancy: 6 % / CC1/2: 0.994 / Rmerge(I) obs: 0.325 / Rpim(I) all: 0.145 / Rrim(I) all: 0.357 / Net I/σ(I): 4.6 / Num. measured all: 111796 / Scaling rejects: 1
Reflection shellResolution: 2.8→2.95 Å / Redundancy: 6.4 % / Rmerge(I) obs: 2.63 / Num. unique obs: 2668 / CC1/2: 0.527 / Rpim(I) all: 1.128 / Rrim(I) all: 2.866 / % possible all: 99.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.7.4data scaling
PHASERphasing
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5nw1

5nw1


Resolution: 2.8→174.85 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.872 / SU B: 35.292 / SU ML: 0.611 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.512 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3209 890 4.8 %RANDOM
Rwork0.2392 ---
obs0.2433 17781 99.86 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 150.97 Å2 / Biso mean: 67.35 Å2 / Biso min: 24.3 Å2
Baniso -1Baniso -2Baniso -3
1-4.25 Å20 Å20 Å2
2--2.96 Å2-0 Å2
3----7.21 Å2
Refinement stepCycle: final / Resolution: 2.8→174.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5312 0 68 189 5569
Biso mean--79.46 56.01 -
Num. residues----667
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0135516
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175233
X-RAY DIFFRACTIONr_angle_refined_deg1.4031.6657497
X-RAY DIFFRACTIONr_angle_other_deg1.0821.58612044
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1865659
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.1421.01297
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.08815913
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6361546
X-RAY DIFFRACTIONr_chiral_restr0.0470.2727
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.026139
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021249
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A28800.09
12D28800.09
21B25610.08
22E25610.08
31C44750.08
32F44750.08
LS refinement shellResolution: 2.8→2.873 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.38 70 -
Rwork0.416 1309 -
all-1379 -
obs--100 %

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