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- PDB-8cql: pVHL:EloB:EloC in complex with (2S,4R)-N-((S)-1-(5-Fluoro-2-metho... -

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Basic information

Entry
Database: PDB / ID: 8cql
TitlepVHL:EloB:EloC in complex with (2S,4R)-N-((S)-1-(5-Fluoro-2-methoxy-4-(4-methylthiazol-5-yl)phenyl)ethyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 33)
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 / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / positive regulation of cell differentiation / 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 / Replication of the SARS-CoV-2 genome / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / cellular response to hypoxia / molecular adaptor activity / 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-VH3 / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 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)169,26416
Polymers166,94912
Non-polymers2,3154
Water4,179232
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area21810 Å2
ΔGint-159 kcal/mol
Surface area60730 Å2
Unit cell
Length a, b, c (Å)92.688, 92.688, 359.622
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-VH3 / (2~{S},4~{R})-1-[(2~{S})-2-[(1-fluoranylcyclopropyl)carbonylamino]-3,3-dimethyl-butanoyl]-~{N}-[(1~{S})-1-[5-fluoranyl-2-methoxy-4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 578.671 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C28H36F2N4O5S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 232 / 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: 2.33 Å3/Da / Density % sol: 47.23 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 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: 0.9999 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: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.38→359.62 Å / Num. obs: 64412 / % possible obs: 100 % / Redundancy: 6.4 % / CC1/2: 0.997 / Rmerge(I) obs: 0.257 / Rpim(I) all: 0.109 / Rrim(I) all: 0.28 / Χ2: 0.99 / Net I/σ(I): 6.1 / Num. measured all: 414491
Reflection shellResolution: 2.38→2.51 Å / % possible obs: 100 % / Redundancy: 6.6 % / Rmerge(I) obs: 2.324 / Num. measured all: 60409 / Num. unique obs: 9218 / CC1/2: 0.36 / Rpim(I) all: 0.976 / Rrim(I) all: 2.524 / Χ2: 0.92 / Net I/σ(I) obs: 1

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Processing

Software
NameVersionClassification
PHENIX1.18.2refinement
Aimless0.7.8data scaling
XDS1.0.5data reduction
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.38→64.53 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.97 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.275 3235 5.06 %Random selection
Rwork0.2258 ---
obs0.2283 63971 99.46 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.38→64.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10345 0 160 232 10737
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00710768
X-RAY DIFFRACTIONf_angle_d1.15414698
X-RAY DIFFRACTIONf_dihedral_angle_d16.031499
X-RAY DIFFRACTIONf_chiral_restr0.0551696
X-RAY DIFFRACTIONf_plane_restr0.0081891
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.38-2.410.33291320.30062512X-RAY DIFFRACTION98
2.41-2.450.3891170.30552580X-RAY DIFFRACTION98
2.45-2.490.34771400.30662557X-RAY DIFFRACTION99
2.49-2.530.37341500.30472580X-RAY DIFFRACTION99
2.53-2.580.33231210.29872623X-RAY DIFFRACTION100
2.58-2.630.36951350.2942607X-RAY DIFFRACTION100
2.63-2.680.33511430.29392587X-RAY DIFFRACTION100
2.68-2.740.36171510.29172623X-RAY DIFFRACTION100
2.74-2.810.36221140.28322642X-RAY DIFFRACTION100
2.81-2.880.31581390.26252608X-RAY DIFFRACTION100
2.88-2.950.30481330.24062628X-RAY DIFFRACTION100
2.95-3.040.27531340.2422625X-RAY DIFFRACTION100
3.04-3.140.26391610.24092621X-RAY DIFFRACTION100
3.14-3.250.29241530.24132609X-RAY DIFFRACTION100
3.25-3.380.29481580.22172634X-RAY DIFFRACTION100
3.38-3.530.23081410.20632658X-RAY DIFFRACTION100
3.54-3.720.24921450.20192655X-RAY DIFFRACTION100
3.72-3.950.26721480.19022637X-RAY DIFFRACTION100
3.95-4.260.22691650.18952663X-RAY DIFFRACTION100
4.26-4.690.25241360.17162709X-RAY DIFFRACTION100
4.69-5.370.23721430.19872689X-RAY DIFFRACTION99
5.37-6.760.27151290.2452786X-RAY DIFFRACTION100
6.76-64.530.23931470.21042903X-RAY DIFFRACTION98

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