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- PDB-8cqe: pVHL:EloB:EloC in complex with (2S,4R)-1-((S)-2-(1-Fluorocyclopro... -

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Basic information

Entry
Database: PDB / ID: 8cqe
TitlepVHL:EloB:EloC in complex with (2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(2-methyl-4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 37)
Components
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / Inhibitor / E3 ligase complex
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 / Replication of the SARS-CoV-1 genome / VCB complex / 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 / Replication of the SARS-CoV-1 genome / VCB complex / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / intracellular membraneless organelle / SUMOylation of ubiquitinylation proteins / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / negative regulation of transcription elongation by RNA polymerase II / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / negative regulation of signal transduction / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / ubiquitin-like ligase-substrate adaptor activity / Formation of HIV elongation complex in the absence of HIV Tat / 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 / protein serine/threonine kinase binding / transcription corepressor binding / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / Vif-mediated degradation of APOBEC3G / Inactivation of CSF3 (G-CSF) signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Evasion by RSV of host interferon responses / Regulation of expression of SLITs and ROBOs / cell morphogenesis / ubiquitin-protein transferase activity / transcription corepressor activity / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / microtubule cytoskeleton / regulation of gene expression / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / Replication of the SARS-CoV-2 genome / protein-macromolecule adaptor activity / molecular adaptor activity / cellular response to hypoxia / DNA-binding transcription factor binding / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / protein stabilization / protein ubiquitination / cilium / 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 / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / 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-C / Elongin B ...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-C / Elongin B / 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-VFO / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsCasement, R. / Phuong Vu, L. / Ciulli, A. / Gutschow, M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)BB/M010996/1 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2023
Title: Expanding the Structural Diversity at the Phenylene Core of Ligands for the von Hippel-Lindau E3 Ubiquitin Ligase: Development of Highly Potent Hypoxia-Inducible Factor-1 alpha Stabilizers.
Authors: Vu, L.P. / Diehl, C.J. / Casement, R. / Bond, A.G. / Steinebach, C. / Strasek, N. / Bricelj, A. / Perdih, A. / Schnakenburg, G. / Sosic, I. / Ciulli, A. / Gutschow, M.
History
DepositionMar 6, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
G: Elongin-B
H: Elongin-C
I: von Hippel-Lindau disease tumor suppressor
J: Elongin-B
K: Elongin-C
L: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)169,24816
Polymers166,94912
Non-polymers2,2994
Water905
1
A: Elongin-B
B: Elongin-C
C: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,3124
Polymers41,7373
Non-polymers5751
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4630 Å2
ΔGint-41 kcal/mol
Surface area16010 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)42,3124
Polymers41,7373
Non-polymers5751
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4670 Å2
ΔGint-38 kcal/mol
Surface area16240 Å2
MethodPISA
3
G: Elongin-B
H: Elongin-C
I: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,3124
Polymers41,7373
Non-polymers5751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4630 Å2
ΔGint-39 kcal/mol
Surface area16040 Å2
MethodPISA
4
J: Elongin-B
K: Elongin-C
L: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,3124
Polymers41,7373
Non-polymers5751
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4630 Å2
ΔGint-39 kcal/mol
Surface area15580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.971, 92.971, 362.047
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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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: 11956.372 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli BL21(DE3) (bacteria) / 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.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15369
#3: Protein
von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18806.273 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P40337
#4: Chemical
ChemComp-VFO / (2~{S},4~{R})-1-[(2~{S})-2-[(1-fluoranylcyclopropyl)carbonylamino]-3,3-dimethyl-butanoyl]-~{N}-[(1~{S})-7-fluoranyl-6-(4-methyl-1,3-thiazol-5-yl)-1,2,3,4-tetrahydronaphthalen-1-yl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 574.682 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C29H36F2N4O4S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.36 Å3/Da / Density % sol: 47.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M sodium cacodylate, pH 6.0-6.3, 15-20% polyethylene glycol 3350, 0.2 M magnesium acetate, 10 mM DTT
PH range: 6.0-6.3

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.99 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 9, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99 Å / Relative weight: 1
ReflectionResolution: 2.85→181.02 Å / Num. obs: 38541 / % possible obs: 100 % / Redundancy: 25.5 % / CC1/2: 0.987 / Rmerge(I) obs: 0.897 / Rpim(I) all: 0.18 / Rrim(I) all: 0.915 / Χ2: 1.03 / Net I/σ(I): 5.1 / Num. measured all: 984482
Reflection shellResolution: 2.85→3 Å / % possible obs: 100 % / Redundancy: 25.8 % / Rmerge(I) obs: 4.704 / Num. measured all: 142660 / Num. unique obs: 5521 / CC1/2: 0.465 / Rpim(I) all: 0.938 / Rrim(I) all: 4.798 / Χ2: 0.89 / Net I/σ(I) obs: 1.3

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Processing

Software
NameVersionClassification
PHENIX1.18.2refinement
Aimlessversion 0.7.8data scaling
XDS1.0.5data reduction
PHASER1.20.1-4487phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.85→90.05 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 32.12 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2968 1923 5.02 %Random
Rwork0.2426 ---
obs0.2454 38308 99.66 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.85→90.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10330 0 160 5 10495
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00510756
X-RAY DIFFRACTIONf_angle_d0.94914688
X-RAY DIFFRACTIONf_dihedral_angle_d15.21576
X-RAY DIFFRACTIONf_chiral_restr0.0541698
X-RAY DIFFRACTIONf_plane_restr0.0071896
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.85-2.920.37911460.33292556X-RAY DIFFRACTION100
2.92-30.37851200.30752551X-RAY DIFFRACTION100
3-3.090.30171260.2932533X-RAY DIFFRACTION100
3.09-3.190.36771170.28712578X-RAY DIFFRACTION100
3.19-3.30.33151210.2852579X-RAY DIFFRACTION100
3.3-3.430.30611290.26542565X-RAY DIFFRACTION100
3.43-3.590.33211570.24922558X-RAY DIFFRACTION100
3.59-3.780.27411430.23592572X-RAY DIFFRACTION100
3.78-4.010.25931470.21832568X-RAY DIFFRACTION100
4.01-4.320.26011360.20212589X-RAY DIFFRACTION100
4.32-4.760.23731430.18482612X-RAY DIFFRACTION100
4.76-5.450.25521400.21372637X-RAY DIFFRACTION99
5.45-6.860.32691340.2682669X-RAY DIFFRACTION99
6.86-90.050.31731640.23792818X-RAY DIFFRACTION98

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