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- PDB-9eqj: Crystal structure of pVHL:EloB:EloC in complex with MP-1-39 -

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Basic information

Entry
Database: PDB / ID: 9eqj
TitleCrystal structure of pVHL:EloB:EloC in complex with MP-1-39
Components
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / E3 ligase / von Hippel-Lindau tumor-suppressor protein
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 / VCB complex / elongin complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / intracellular membraneless organelle ...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 / VCB complex / elongin complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / intracellular membraneless organelle / Cul2-RING ubiquitin ligase complex / 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 / Tat-mediated elongation of the HIV-1 transcript / ubiquitin-like ligase-substrate adaptor activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / negative regulation of signal transduction / 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 / protein serine/threonine kinase binding / RNA Polymerase II Pre-transcription Events / negative regulation of autophagy / transcription corepressor binding / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / Vif-mediated degradation of APOBEC3G / Inactivation of CSF3 (G-CSF) signaling / cell morphogenesis / Evasion by RSV of host interferon responses / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / 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 / microtubule cytoskeleton / regulation of gene expression / Replication of the SARS-CoV-2 genome / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / DNA-binding transcription factor binding / molecular adaptor activity / cellular response to hypoxia / 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 / 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-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 / SKP1/BTB/POZ domain superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
: / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsKroupova, A. / Pierri, M. / Liu, X. / Ciulli, A.
Funding support Switzerland, United Kingdom, 2items
OrganizationGrant numberCountry
Innovative Medicines Initiative875510 Switzerland
UK Research and Innovation (UKRI)EP/X025225/1 United Kingdom
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2024
Title: Stereochemical inversion at a 1,4-cyclohexyl PROTAC linker fine-tunes conformation and binding affinity.
Authors: Pierri, M. / Liu, X. / Kroupova, A. / Rutter, Z. / Hallatt, A.J. / Ciulli, A.
History
DepositionMar 21, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 28, 2024Provider: repository / Type: Initial release

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,3118
Polymers82,8516
Non-polymers1,4602
Water5,098283
1
A: Elongin-B
B: Elongin-C
C: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1554
Polymers41,4253
Non-polymers7301
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Elongin-B
E: Elongin-C
F: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1554
Polymers41,4253
Non-polymers7301
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)47.237, 47.345, 99.746
Angle α, β, γ (deg.)81.410, 76.780, 80.490
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 1 through 64 or (resid 65...
d_2ens_1(chain "D" and ((resid 1 and (name N or name...
d_1ens_2(chain "B" and ((resid 16 through 17 and (name N...
d_2ens_2(chain "E" and ((resid 16 through 17 and (name N...
d_1ens_3(chain "C" and ((resid 62 and (name N or name...
d_2ens_3(chain "F" and (resid 62 through 195 or (resid 196...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1METMETMETMETAA1 - 1031 - 103
d_21ens_1METMETARGARGDD1 - 801 - 80
d_22ens_1ASPASPMETMETDD83 - 10383 - 103
d_11ens_2METMETSERSERBB16 - 471 - 32
d_12ens_2ASNASNCYSCYSBB58 - 11243 - 97
d_21ens_2METMETCYSCYSEE16 - 1121 - 97
d_11ens_3VALVALGLUGLUCC62 - 20411 - 153
d_12ens_3A1H6OA1H6OA1H6OA1H6OCG301
d_21ens_3VALVALGLUGLUFF62 - 20411 - 153
d_22ens_3A1H6OA1H6OA1H6OA1H6OFH301

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(-0.07147759024, -0.953570860894, -0.292563783384), (-0.99741065314, 0.0706645928431, 0.0133605509501), (0.00793366856193, 0.292761214256, -0.956152669991)-15.0488173074, -4.30653143325, -78.1230938317
2given(-0.130030070634, -0.955469652005, -0.264896064198), (-0.991261466346, 0.119290080441, 0.0563079216916), (-0.0222010375372, 0.269902984061, -0.962631545882)-13.3749640293, -2.42410235419, -78.1315181871
3given(-0.162796594203, -0.963972001322, -0.210369317114), (-0.986621365949, 0.157168722285, 0.0433159669091), (-0.00869190253179, 0.214606554892, -0.976661905384)-12.3135367513, -2.009442052, -79.6458444694

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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: 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
#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 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
#4: Chemical ChemComp-A1H6O / (2S,4R)-1-[(2R)-2-[(1-fluoranylcyclopropyl)carbonylamino]-3-methyl-3-[[cis-4-(morpholin-4-ylmethyl)cyclohexyl]methylsulfanyl]butanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide


Mass: 729.968 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C37H52FN5O5S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 283 / 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: 2.57 Å3/Da / Density % sol: 52.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.2 NaCl, 0.1M HEPES pH 7.5, and 25% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.6702 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 2, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.6702 Å / Relative weight: 1
ReflectionResolution: 2.05→40.02 Å / Num. obs: 48840 / % possible obs: 95.1 % / Redundancy: 3.6 % / Biso Wilson estimate: 37.34 Å2 / CC1/2: 0.976 / Net I/σ(I): 15.7
Reflection shellResolution: 2.05→2.09 Å / Num. unique obs: 1638 / CC1/2: 0.924

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
DIALSdata reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.05→31.64 Å / SU ML: 0.216 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 24.606
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2163 2508 5.14 %
Rwork0.1833 46277 -
obs0.185 48785 94.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.8 Å2
Refinement stepCycle: LAST / Resolution: 2.05→31.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5301 0 100 283 5684
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01365531
X-RAY DIFFRACTIONf_angle_d1.12597525
X-RAY DIFFRACTIONf_chiral_restr0.0662852
X-RAY DIFFRACTIONf_plane_restr0.0101966
X-RAY DIFFRACTIONf_dihedral_angle_d15.08182069
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS0.79955500585
ens_2d_2BBX-RAY DIFFRACTIONTorsion NCS0.410204141126
ens_3d_2CCX-RAY DIFFRACTIONTorsion NCS0.705960270798
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.090.31731150.25961711X-RAY DIFFRACTION65.78
2.09-2.140.3179920.2482058X-RAY DIFFRACTION74.68
2.14-2.180.30621350.23682267X-RAY DIFFRACTION83.17
2.18-2.230.28131330.21912654X-RAY DIFFRACTION98.27
2.23-2.290.23811350.20842672X-RAY DIFFRACTION98.7
2.29-2.350.25321320.19472711X-RAY DIFFRACTION98.58
2.35-2.420.22581540.20062611X-RAY DIFFRACTION98.68
2.42-2.50.24781560.20312746X-RAY DIFFRACTION98.94
2.5-2.590.24021420.20642649X-RAY DIFFRACTION99.01
2.59-2.690.2621510.2172640X-RAY DIFFRACTION98.59
2.69-2.810.25171280.21272741X-RAY DIFFRACTION99.14
2.81-2.960.24991300.20382705X-RAY DIFFRACTION99.13
2.96-3.150.20811650.1952684X-RAY DIFFRACTION99.3
3.15-3.390.21881650.18842662X-RAY DIFFRACTION99.26
3.39-3.730.22481430.17692669X-RAY DIFFRACTION99.5
3.73-4.270.18091440.15362702X-RAY DIFFRACTION99.34
4.27-5.370.17131450.14392686X-RAY DIFFRACTION99.68
5.37-31.640.19671430.18032709X-RAY DIFFRACTION99.55

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