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- PDB-8p0f: Crystal structure of the VCB complex with compound 1. -

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Basic information

Entry
Database: PDB / ID: 8p0f
TitleCrystal structure of the VCB complex with compound 1.
Components
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / Inhibitor / Ligand / PROTAC
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-WBN / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.98 Å
AuthorsBader, G. / Boettcher, J. / Wolkerstorfer, B.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Chemrxiv / Year: 2023
Title: Drugit: Crowd-sourcing molecular design of non-peptidic VHL binders
Authors: Scott, T. / Smethurst, C. / Westermaier, Y. / Mayer, M. / Greb, P. / Kousek, R. / Biberger, T. / Bader, G. / Jandova, Z. / Schmalhorst, P. / Fuchs, J. / Magarkar, A. / Hoenke, C. / ...Authors: Scott, T. / Smethurst, C. / Westermaier, Y. / Mayer, M. / Greb, P. / Kousek, R. / Biberger, T. / Bader, G. / Jandova, Z. / Schmalhorst, P. / Fuchs, J. / Magarkar, A. / Hoenke, C. / Gerstberger, T. / Combs, S. / Pape, R. / Phul, S. / Kothiwale, S. / Bergner, A. / Moretti, R.
History
DepositionMay 10, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 31, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 20, 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.pdbx_database_id_DOI / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: von Hippel-Lindau disease tumor suppressor
B: Elongin-C
C: Elongin-B
D: von Hippel-Lindau disease tumor suppressor
E: Elongin-C
F: Elongin-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,7319
Polymers82,8516
Non-polymers8803
Water5,927329
1
A: von Hippel-Lindau disease tumor suppressor
B: Elongin-C
C: Elongin-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,8835
Polymers41,4253
Non-polymers4582
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4810 Å2
ΔGint-42 kcal/mol
Surface area17140 Å2
2
D: von Hippel-Lindau disease tumor suppressor
E: Elongin-C
F: Elongin-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,8484
Polymers41,4253
Non-polymers4231
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4620 Å2
ΔGint-37 kcal/mol
Surface area16920 Å2
Unit cell
Length a, b, c (Å)47.387, 47.720, 98.756
Angle α, β, γ (deg.)81.70, 76.66, 82.80
Int Tables number1
Space group name H-MP1

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Components

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Protein , 3 types, 6 molecules ADBECF

#1: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18702.291 Da / Num. of mol.: 2
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
#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.: 2
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 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: 11748.406 Da / Num. of mol.: 2
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

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Non-polymers , 3 types, 332 molecules

#4: Chemical ChemComp-WBN / (3~{R},5~{R})-~{N}-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-5-oxidanyl-2-oxidanylidene-1-pyridin-2-yl-piperidine-3-carboxamide


Mass: 422.500 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H22N4O3S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 329 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.58 Å3/Da / Density % sol: 52.39 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 30 % PEG

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 17, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.98→95.4 Å / Num. obs: 33557 / % possible obs: 87.3 % / Redundancy: 3.4 % / CC1/2: 1 / Net I/σ(I): 8.9
Reflection shellResolution: 1.98→2.25 Å / Num. unique obs: 1679 / CC1/2: 0.7

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
XDSdata reduction
Aimlessdata scaling
STARANISOdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.98→35.68 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.909 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.401 / SU Rfree Blow DPI: 0.248
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.2565 1680 5.01 %RANDOM
Rwork0.2288 ---
obs0.2302 33550 58.1 %-
Displacement parametersBiso mean: 58.92 Å2
Baniso -1Baniso -2Baniso -3
1-8.3305 Å22.1832 Å22.108 Å2
2---2.9881 Å20.9599 Å2
3----5.3424 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: LAST / Resolution: 1.98→35.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5438 0 61 329 5828
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00811112HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9520135HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3283SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1717HARMONIC5
X-RAY DIFFRACTIONt_it5625HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.99
X-RAY DIFFRACTIONt_other_torsion15.8
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion730SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact9089SEMIHARMONIC4
LS refinement shellResolution: 1.98→2.16 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.335 -4.92 %
Rwork0.2886 638 -
all0.2908 671 -
obs--5.07 %
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)
16.4362-0.9186-1.47940.38690.39420.8477-0.5446-0.4399-0.02690.04730.2723-0.0696-0.00610.02110.27220.15130.16010.0905-0.07240.0097-0.153512.5931-23.779637.9772
25.01720.70930.35431.74450.07312.6055-0.69350.40350.344-0.08780.37290.0818-0.20480.19370.32060.1758-0.0694-0.014-0.12230.0371-0.162432.8596-14.076422.1464
33.5432-1.05850.14842.7087-2.20093.0402-0.56561.18350.4744-0.25660.29240.2584-0.0235-0.0660.27310.112-0.3018-0.18010.07550.212-0.225928.0519-8.45935.861
41.07480.45960.57317.2715-1.8651.7910.08660.09110.0241-0.39640.01690.1237-0.06520.1186-0.10340.04590.07430.0341-0.1083-0.0233-0.109920.6317-9.2606-33.4831
52.68631.2994-0.07334.65151.48513.86010.3244-0.0514-0.08120.3265-0.28910.08180.3164-0.3253-0.03530.0837-0.0026-0.0753-0.12650.0274-0.124512.3566-29.2205-15.8644
62.3071-1.3354-2.251.95622.26865.03710.365-0.1750.01120.7694-0.3949-0.14180.4425-0.14230.02990.2072-0.231-0.0706-0.06450.0494-0.25511.4507-24.72511.4573
70.35010.0973-0.52120.7990.36030.1274-0.1053-0.03470.0165-0.00610.10240.0477-0.0358-0.0220.0029-0.19980.04320.0205-0.11510.1079-0.125610.8964-10.37042.0558
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|62 - A|207 }A62 - 207
2X-RAY DIFFRACTION2{ B|16 - B|111 }B16 - 111
3X-RAY DIFFRACTION3{ C|1 - C|104 }C1 - 104
4X-RAY DIFFRACTION4{ D|62 - D|207 }D62 - 207
5X-RAY DIFFRACTION5{ E|16 - E|111 }E16 - 111
6X-RAY DIFFRACTION6{ F|1 - F|104 }F1 - 104
7X-RAY DIFFRACTION7{ A|301 - A|301 D|301 - D|301 }A301
8X-RAY DIFFRACTION7{ A|301 - A|301 D|301 - D|301 }D301

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