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- PDB-6gmx: pVHL:EloB:EloC in complex with 6-chlorothiochroman-4-one -

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Basic information

Entry
Database: PDB / ID: 6gmx
TitlepVHL:EloB:EloC in complex with 6-chlorothiochroman-4-one
Components
  • (Elongin-B) x 2
  • (Elongin-C) x 2
  • von Hippel-Lindau disease tumor suppressor
KeywordsONCOPROTEIN / E3 ubiquitin ligase / tumor supressor / PROTAC / fragment-based drug discovery
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, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / Elongin C; Chain C, domain 1 / 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 ...von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / Elongin C; Chain C, domain 1 / 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 / Potassium Channel Kv1.1; Chain A / Potassium Channel Kv1.1; Chain A / 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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / Ubiquitin-like (UB roll) / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Roll / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
ACETATE ION / 6-chloranyl-2,3-dihydrothiochromen-4-one / ISOPROPYL ALCOHOL / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.533 Å
AuthorsVan Molle, I. / Lucas, X. / Ciulli, A.
Funding support United Kingdom, 5items
OrganizationGrant numberCountry
European Research CouncilERC-2012-StG-311460
European CommissionH2020-MSCA-IF-2015-806323
European CommissionEC PIEF-GA-2010-275683
Welcome Trust 100476/Z/12/Z United Kingdom
Welcome Trust 094090/Z/10/Z United Kingdom
CitationJournal: J. Med. Chem. / Year: 2018
Title: Surface Probing by Fragment-Based Screening and Computational Methods Identifies Ligandable Pockets on the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase.
Authors: Lucas, X. / Van Molle, I. / Ciulli, A.
History
DepositionMay 28, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 8, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 5, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _citation_author.name

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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)167,70520
Polymers166,94912
Non-polymers7568
Water6,395355
1
A: Elongin-B
B: Elongin-C
C: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9965
Polymers41,7373
Non-polymers2592
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4850 Å2
ΔGint-32 kcal/mol
Surface area15680 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)41,8565
Polymers41,7373
Non-polymers1192
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4840 Å2
ΔGint-25 kcal/mol
Surface area15740 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)41,7974
Polymers41,7373
Non-polymers601
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4840 Å2
ΔGint-35 kcal/mol
Surface area16020 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)42,0556
Polymers41,7373
Non-polymers3183
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5090 Å2
ΔGint-32 kcal/mol
Surface area16100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.000, 94.000, 365.490
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number91
Space group name H-MP4122
Space group name HallP4w2c

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Components

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Protein , 5 types, 12 molecules AGJBHKCFILDE

#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.: 3
Source method: isolated from a genetically manipulated source
Details: S-(DIMETHYLARSENIC)CYSTEINE modification / 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.: 3
Source method: isolated from a genetically manipulated source
Details: 2nd N at N-treminus resulting from cloning / 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.: 4
Source method: isolated from a genetically manipulated source
Details: residues 54-213 GS at N-terminus from cloning S-(DIMETHYLARSENIC)CYSTEINE modification
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli (E. coli) / References: UniProt: P40337
#4: 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: 11852.390 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: S-(DIMETHYLARSENIC)CYSTEINE modification / Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370
#5: 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: 11078.599 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: 2nd N at N-treminus resulting from cloning / Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369

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Non-polymers , 4 types, 363 molecules

#6: Chemical ChemComp-F7B / 6-chloranyl-2,3-dihydrothiochromen-4-one


Mass: 198.669 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H7ClOS
#7: Chemical
ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL / Isopropyl alcohol


Mass: 60.095 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#8: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 355 / Source method: isolated from a natural source / Formula: H2O

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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: 2.59 Å3/Da / Density % sol: 52.43 %
Crystal growTemperature: 285 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Na cacodylate pH 6.0, 0.2 M Mg acetate, 15% PEG3350, 5mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 2, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.37→94 Å / Num. obs: 67228 / % possible obs: 99.5 % / Redundancy: 12.7 % / Biso Wilson estimate: 48.55 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.24 / Net I/σ(I): 14.7
Reflection shellResolution: 2.37→2.52 Å / Mean I/σ(I) obs: 2.2 / CC1/2: 0.828

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
XDSdata reduction
XDSdata scaling
BUSTER-TNTphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.533→94 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.3609 --
Rwork0.1883 --
obs-55720 99.85 %
Refinement stepCycle: LAST / Resolution: 2.533→94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10416 0 48 355 10819

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