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- PDB-8c13: Crystal structure of pVHL:ElonginC:ElonginB complex bound to PROT... -

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Basic information

Entry
Database: PDB / ID: 8c13
TitleCrystal structure of pVHL:ElonginC:ElonginB complex bound to PROTAC JW48
Components
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / E3 Ligase / PROTAC / VHL / Structural Genomics / Structural Genomics Consortium / SGC
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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / SKP1/BTB/POZ domain superfamily / Ubiquitin-like (UB roll) / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Roll / Alpha Beta
Similarity search - Domain/homology
Chem-SYF / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsKraemer, A. / Weckesser, J. / Knapp, S. / Structural Genomics Consortium (SGC)
Funding support Canada, 1items
OrganizationGrant numberCountry
The Structural Genomics Consortium (SGC) Canada
CitationJournal: Cell Chem Biol / Year: 2023
Title: Tracking the PROTAC degradation pathway in living cells highlights the importance of ternary complex measurement for PROTAC optimization.
Authors: Schwalm, M.P. / Kramer, A. / Dolle, A. / Weckesser, J. / Yu, X. / Jin, J. / Saxena, K. / Knapp, S.
History
DepositionDec 20, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 28, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
J: Elongin-B
K: Elongin-C
L: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,0354
Polymers44,1913
Non-polymers8441
Water36020
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4630 Å2
ΔGint-41 kcal/mol
Surface area17290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.797, 60.787, 97.228
Angle α, β, γ (deg.)90.000, 100.580, 90.000
Int Tables number5
Space group name H-MC121

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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: 13147.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
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: 12485.135 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
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: 18558.162 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli (E. coli) / References: UniProt: P40337
#4: Chemical ChemComp-SYF / (2~{S},4~{R})-1-[(2~{S})-2-[3-[2-[2-[2-(acetamidomethyl)-4-(6,7-dihydro-5~{H}-pyrrolo[1,2-a]imidazol-2-yl)phenoxy]ethoxy]ethoxy]propanoylamino]-3,3-dimethyl-butanoyl]-~{N}-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 844.030 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C44H57N7O8S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 2.43 Å3/Da / Density % sol: 49.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 18% PEG 3350, HEPES pH7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.999987 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: May 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999987 Å / Relative weight: 1
ReflectionResolution: 2.3→48.833 Å / Num. obs: 18781 / % possible obs: 99.1 % / Redundancy: 7 % / CC1/2: 0.997 / Rmerge(I) obs: 0.111 / Rpim(I) all: 0.046 / Rrim(I) all: 0.121 / Χ2: 1.02 / Net I/σ(I): 9.9
Reflection shellResolution: 2.3→2.38 Å / % possible obs: 99.8 % / Redundancy: 7.3 % / Rmerge(I) obs: 1.207 / Num. measured all: 13682 / Num. unique obs: 1874 / CC1/2: 0.752 / Rpim(I) all: 0.477 / Rrim(I) all: 1.299 / Χ2: 1.01 / Net I/σ(I) obs: 1.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
Aimlessdata scaling
MOLREPphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→47.833 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.93 / SU B: 19.417 / SU ML: 0.217 / Cross valid method: FREE R-VALUE / ESU R: 0.336 / ESU R Free: 0.242
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2612 921 4.905 %
Rwork0.2226 17854 -
all0.225 --
obs-18775 98.909 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 57.148 Å2
Baniso -1Baniso -2Baniso -3
1--2.992 Å2-0 Å2-0.233 Å2
2---0.663 Å2-0 Å2
3---3.498 Å2
Refinement stepCycle: LAST / Resolution: 2.3→47.833 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2704 0 60 20 2784
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0122831
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162576
X-RAY DIFFRACTIONr_angle_refined_deg0.7561.6523854
X-RAY DIFFRACTIONr_angle_other_deg0.2771.5846001
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1365340
X-RAY DIFFRACTIONr_dihedral_angle_2_deg2.95522
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.51110446
X-RAY DIFFRACTIONr_dihedral_angle_6_deg13.610123
X-RAY DIFFRACTIONr_chiral_restr0.0370.2435
X-RAY DIFFRACTIONr_chiral_restr_other0.0190.21
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.023312
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02544
X-RAY DIFFRACTIONr_nbd_refined0.1810.2488
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1720.22325
X-RAY DIFFRACTIONr_nbtor_refined0.1680.21378
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0750.21482
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1440.272
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.0690.28
X-RAY DIFFRACTIONr_nbd_other0.0990.252
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2040.23
X-RAY DIFFRACTIONr_mcbond_it1.0824.1381372
X-RAY DIFFRACTIONr_mcbond_other1.0814.1381372
X-RAY DIFFRACTIONr_mcangle_it1.8676.1981709
X-RAY DIFFRACTIONr_mcangle_other1.8676.21709
X-RAY DIFFRACTIONr_scbond_it1.0794.3091459
X-RAY DIFFRACTIONr_scbond_other1.0794.3091459
X-RAY DIFFRACTIONr_scangle_it1.8616.4122145
X-RAY DIFFRACTIONr_scangle_other1.866.4132146
X-RAY DIFFRACTIONr_lrange_it3.2151.0392933
X-RAY DIFFRACTIONr_lrange_other3.20951.0432933
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.3-2.360.295660.33213170.3313850.920.91699.85560.319
2.36-2.4240.276490.31413110.31213680.9450.92799.41520.303
2.424-2.4940.311630.28812660.28913320.9350.93999.77480.269
2.494-2.5710.366680.28211770.28612510.9430.94899.52040.266
2.571-2.6550.298610.27412070.27512730.940.95799.60720.254
2.655-2.7480.376610.24910980.25511680.9390.96399.22950.23
2.748-2.8510.317530.25711180.2611760.9520.96299.57480.237
2.851-2.9670.282540.2610640.26111220.9550.9699.64350.243
2.967-3.0990.364470.24910180.25410730.9220.96399.25440.237
3.099-3.2490.345480.2469270.25110190.9240.96395.6820.232
3.249-3.4240.283430.2339320.2359900.9430.9798.48480.225
3.424-3.630.233410.2248730.2249220.9610.97299.13230.22
3.63-3.880.219400.2018200.2028620.9710.97899.7680.202
3.88-4.1880.241490.197550.1938130.9620.97998.8930.191
4.188-4.5840.21540.1767070.1797680.9730.98399.08850.187
4.584-5.120.225440.186240.1846770.9730.9898.67060.193
5.12-5.90.246260.2165670.2176070.9570.97797.69360.227
5.9-7.1990.354280.2414430.2475180.9540.96790.92660.253
7.199-10.0680.193150.1643960.1654110.9770.9831000.181
10.068-47.8330.214110.2252350.2252470.9840.96299.59510.23
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)
10.80211.51291.09495.15062.20844.0119-0.06310.373-0.2688-0.53060.2064-0.41710.1427-0.0328-0.14330.1419-00.01410.391-0.16080.2772-11.6811-1.98074.0889
24.79410.30250.05413.21270.14673.29170.11040.0564-0.40050.11190.00190.10590.0474-0.2607-0.11230.03140.0098-0.04180.0271-0.01260.0931-11.5524.94520.3211
32.5796-2.47811.41454.1029-2.00611.6959-0.0707-0.2311-0.1160.34820.12540.1668-0.0621-0.0879-0.05460.0656-0.0015-0.01230.0333-0.01880.104310.7877-1.269136.3556
Refinement TLS groupSelection: ALL

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