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

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Basic information

Entry
Database: PDB / ID: 8cqk
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 30)
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 / 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-VYQ / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.62 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

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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)169,12816
Polymers166,94912
Non-polymers2,1794
Water1,72996
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area21550 Å2
ΔGint-160 kcal/mol
Surface area60900 Å2
Unit cell
Length a, b, c (Å)93.284, 93.284, 363.262
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-VYQ / (2~{S},4~{R})-1-[(2~{S})-2-[(1-fluoranylcyclopropyl)carbonylamino]-3,3-dimethyl-butanoyl]-~{N}-[(1~{S})-1-[2-methyl-4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 544.681 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H37FN4O4S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 96 / 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: 2.38 Å3/Da / Density % sol: 48.42 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M sodium cacodylate, 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: 0.99999 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: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.62→181.63 Å / Num. obs: 49883 / % possible obs: 100 % / Redundancy: 14.9 % / CC1/2: 0.995 / Rmerge(I) obs: 0.304 / Rpim(I) all: 0.082 / Rrim(I) all: 0.315 / Χ2: 1 / Net I/σ(I): 7 / Num. measured all: 742511
Reflection shellResolution: 2.62→2.76 Å / % possible obs: 100 % / Redundancy: 12.9 % / Rmerge(I) obs: 2.637 / Num. measured all: 91845 / Num. unique obs: 7147 / CC1/2: 0.428 / Rpim(I) all: 0.759 / Rrim(I) all: 2.746 / Χ2: 0.87 / Net I/σ(I) obs: 1.1

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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: 2.62→65.07 Å / SU ML: 0.41 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 31.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2897 2434 4.9 %Random selection
Rwork0.2461 ---
obs0.2482 49647 99.75 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.62→65.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10319 0 152 96 10567
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00610725
X-RAY DIFFRACTIONf_angle_d1.05914645
X-RAY DIFFRACTIONf_dihedral_angle_d13.4421484
X-RAY DIFFRACTIONf_chiral_restr0.0591696
X-RAY DIFFRACTIONf_plane_restr0.0081889
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.62-2.670.39241400.35852739X-RAY DIFFRACTION100
2.67-2.730.35451450.33752691X-RAY DIFFRACTION100
2.73-2.790.35391450.33232705X-RAY DIFFRACTION100
2.79-2.860.35451610.32272727X-RAY DIFFRACTION100
2.86-2.940.38811400.29892739X-RAY DIFFRACTION100
2.94-3.020.35951550.28842733X-RAY DIFFRACTION100
3.02-3.120.31831480.27852727X-RAY DIFFRACTION100
3.12-3.230.30921260.26782754X-RAY DIFFRACTION100
3.23-3.360.36991370.25332763X-RAY DIFFRACTION100
3.36-3.520.30621350.25542753X-RAY DIFFRACTION100
3.52-3.70.26451590.23942754X-RAY DIFFRACTION100
3.7-3.930.25711340.21832781X-RAY DIFFRACTION100
3.93-4.240.2451240.21482820X-RAY DIFFRACTION100
4.24-4.660.23751710.19592767X-RAY DIFFRACTION100
4.66-5.340.25721240.21632842X-RAY DIFFRACTION100
5.34-6.720.27551290.26392902X-RAY DIFFRACTION99
6.72-65.070.28511610.23393016X-RAY DIFFRACTION98

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