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- PDB-5nvy: pVHL:EloB:EloC in complex with (2S,4R)-1-((S)-2-acetamidopropanoy... -

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Basic information

Entry
Database: PDB / ID: 5nvy
TitlepVHL:EloB:EloC in complex with (2S,4R)-1-((S)-2-acetamidopropanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl) pyrrolidine-2-carboxamide (ligand 11)
Components
  • Elongin-B
  • Elongin-C
  • Von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / protein complex / ubiquitin ligase / hypoxia inducible factor
Function / homology
Function and homology information


regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / target-directed miRNA degradation / transcription elongation factor activity / 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 / target-directed miRNA degradation / transcription elongation factor activity / elongin complex / VCB complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / intracellular membraneless 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 / 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 / cell morphogenesis / 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 / ubiquitin-protein transferase activity / transcription corepressor activity / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / Replication of the SARS-CoV-2 genome / protein-macromolecule adaptor activity / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / DNA-binding transcription factor binding / proteasome-mediated ubiquitin-dependent protein catabolic process / 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 / negative regulation of apoptotic process / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / enzyme binding / 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
Chem-9B5 / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
Model detailspVHL:EloB:EloC in complex with (2S,4R)-1-((S)-2-acetamidopropanoyl)-4-hydroxy-N-(4-(4-methylthiazol- ...pVHL:EloB:EloC in complex with (2S,4R)-1-((S)-2-acetamidopropanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl) pyrrolidine-2-carboxamide (ligand 11)
AuthorsSoares, P. / Gadd, M.S. / Ciulli, A.
Funding support1items
OrganizationGrant numberCountry
European Research CouncilERC-2012-StG-311460 DrugE3CRLs
CitationJournal: J. Med. Chem. / Year: 2018
Title: Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)- ...Title: Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298).
Authors: Soares, P. / Gadd, M.S. / Frost, J. / Galdeano, C. / Ellis, L. / Epemolu, O. / Rocha, S. / Read, K.D. / Ciulli, A.
History
DepositionMay 4, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 20, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2018Group: 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.year / _citation_author.name
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)168,67116
Polymers166,94912
Non-polymers1,7224
Water6,593366
1
A: Elongin-B
B: Elongin-C
C: Von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1684
Polymers41,7373
Non-polymers4311
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4660 Å2
ΔGint-38 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)42,1684
Polymers41,7373
Non-polymers4311
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4770 Å2
ΔGint-39 kcal/mol
Surface area16920 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)42,1684
Polymers41,7373
Non-polymers4311
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4710 Å2
ΔGint-37 kcal/mol
Surface area16720 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)42,1684
Polymers41,7373
Non-polymers4311
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4670 Å2
ΔGint-38 kcal/mol
Surface area16770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.085, 93.085, 362.983
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number91
Space group name H-MP4122
Components on special symmetry positions
IDModelComponents
11A-214-

HOH

21I-433-

HOH

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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 / Plasmid: pCDFDuet-1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / 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 / Plasmid: pCDFDuet-1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / 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 / Plasmid: pHAT4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P40337
#4: Chemical
ChemComp-9B5 / (2~{S},4~{R})-1-[(2~{S})-2-acetamidopropanoyl]-~{N}-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 430.521 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H26N4O4S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 366 / Source method: isolated from a natural source / Formula: H2O
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: 2.35 Å3/Da / Density % sol: 47.77 % / Mosaicity: 0.26 °
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.4 / Details: PEG 3350, MgOAc, Sodium cacodylate, DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 1, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.9→48.76 Å / Num. obs: 36661 / % possible obs: 100 % / Redundancy: 8.5 % / CC1/2: 0.99 / Rmerge(I) obs: 0.225 / Rpim(I) all: 0.082 / Rrim(I) all: 0.24 / Net I/σ(I): 7.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) all% possible all
2.9-3.038.91.1010.8520.3861.168100
10.05-48.767.40.1240.990.050.13499.1

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Processing

Software
NameVersionClassification
Aimless0.5.9data scaling
REFMAC5.8.0123refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1VCB

1vcb


Resolution: 2.9→48.76 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.914 / SU B: 39.697 / SU ML: 0.387 / SU R Cruickshank DPI: 0.3536 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.452
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2686 1893 5.2 %RANDOM
Rwork0.2025 ---
obs0.206 34701 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 167 Å2 / Biso mean: 61.108 Å2 / Biso min: 17.62 Å2
Baniso -1Baniso -2Baniso -3
1--0.5 Å2-0 Å2-0 Å2
2---0.5 Å20 Å2
3---1 Å2
Refinement stepCycle: final / Resolution: 2.9→48.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10788 0 120 366 11274
Biso mean--41.18 40.54 -
Num. residues----1338
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01911156
X-RAY DIFFRACTIONr_bond_other_d0.0020.0210739
X-RAY DIFFRACTIONr_angle_refined_deg1.251.99815146
X-RAY DIFFRACTIONr_angle_other_deg0.883.00324721
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.22151322
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.62823.411516
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.846151892
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.4851596
X-RAY DIFFRACTIONr_chiral_restr0.0650.21711
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02112320
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022496
LS refinement shellResolution: 2.9→2.975 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 137 -
Rwork0.285 2505 -
all-2642 -
obs--99.7 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.8322-1.74580.82213.5953-1.60154.94470.03930.31780.0388-0.5147-0.2433-0.1120.06990.34310.2040.50540.00010.00840.52950.03430.0144.71464.80647.6
26.50420.79-0.12122.6493-0.51343.84670.0448-0.47350.06010.0313-0.1106-0.2688-0.0590.03560.06580.32450.0244-0.01370.60160.05310.035848.32561.13165.186
36.7213-0.2172-2.28921.81840.0962.6546-0.1421-0.30940.05340.03610.0635-0.00020.0544-0.03010.07850.3731-0.0518-0.03650.70430.09840.024427.31654.33182.344
45.0346-1.36072.69543.6736-1.82866.049-0.18550.71860.2987-0.41-0.05960.0239-0.64771.35710.24510.6258-0.1976-0.01660.90730.02490.031248.2718.07447.317
57.54580.92981.47691.8926-0.76825.5591-0.05350.66940.23750.0932-0.0019-0.2068-0.28990.48090.05540.4678-0.05840.00390.75940.02910.042152.814.08865.121
66.4546-0.7578-1.19681.92150.38392.8918-0.1959-0.3977-0.11350.13040.1048-0.0948-0.0902-0.29150.09110.4241-0.0356-0.04210.72530.0650.021231.7917.7582.037
74.8983-1.22830.79411.5273-1.49344.42580.12020.20580.3677-0.316-0.15570.0004-0.25110.26070.03550.6074-0.08930.01950.73660.04460.04463.13412.98347.459
87.40131.16570.42.6629-1.13662.7379-0.0958-0.99990.36260.0928-0.0342-0.0995-0.19560.44740.130.4974-0.00620.00381.0685-0.06160.02916.76910.83565.243
95.1164-1.083-1.57871.95370.72854.9319-0.2846-0.4696-0.13490.13580.02780.00620.13390.82160.25680.4582-0.0270.00520.84320.07460.016-14.4736.78982.326
104.9947-1.5453-0.16551.5911-0.67755.45610.0080.14580.0199-0.2633-0.11250.105-0.13450.34840.10460.4751-0.05560.00020.5360.01310.0214-0.88760.62347.726
115.99431.17280.36181.7625-0.67842.85060.0042-0.64760.0490.0044-0.1653-0.1278-0.19810.4280.16110.3739-0.01570.01020.81030.02910.01722.12658.50665.494
124.5628-0.3185-2.41961.5630.14495.9028-0.2612-0.5317-0.140.03520.02040.08690.13180.65530.24080.347-0.0254-0.00640.65540.0860.0203-19.06653.9682.603
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 104
2X-RAY DIFFRACTION2B16 - 112
3X-RAY DIFFRACTION3C62 - 202
4X-RAY DIFFRACTION4D1 - 103
5X-RAY DIFFRACTION5E16 - 112
6X-RAY DIFFRACTION6F62 - 204
7X-RAY DIFFRACTION7G1 - 103
8X-RAY DIFFRACTION8H16 - 112
9X-RAY DIFFRACTION9I62 - 204
10X-RAY DIFFRACTION10J1 - 103
11X-RAY DIFFRACTION11K16 - 112
12X-RAY DIFFRACTION12L62 - 204

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