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- PDB-8bb2: Structure of human WDR5 and pVHL:ElonginC:ElonginB bound to PROTA... -

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Basic information

Entry
Database: PDB / ID: 8bb2
TitleStructure of human WDR5 and pVHL:ElonginC:ElonginB bound to PROTAC with PEG linker (conformation #2)
Components
  • Elongin-B
  • Elongin-C
  • WD repeat-containing protein 5
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / E3-Ligase / WDR5 / VHL / Elongin
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 / MLL3/4 complex / elongin complex / VCB complex / Set1C/COMPASS complex / MLL1/2 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 / MLL3/4 complex / elongin complex / VCB complex / Set1C/COMPASS complex / MLL1/2 complex / ATAC complex / NSL complex / histone H3K4 methyltransferase activity / Replication of the SARS-CoV-1 genome / Cardiogenesis / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / histone methyltransferase complex / regulation of tubulin deacetylation / intracellular membraneless organelle / SUMOylation of ubiquitinylation proteins / Formation of WDR5-containing histone-modifying complexes / negative regulation of transcription elongation by RNA polymerase II / regulation of cell division / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / regulation of embryonic development / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / MLL1 complex / histone acetyltransferase complex / Tat-mediated elongation of the HIV-1 transcript / ubiquitin-like ligase-substrate adaptor activity / 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 / positive regulation of gluconeogenesis / negative regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / methylated histone binding / negative regulation of autophagy / transcription initiation-coupled chromatin remodeling / transcription corepressor binding / skeletal system development / gluconeogenesis / 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 / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / cell morphogenesis / Inactivation of CSF3 (G-CSF) signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Evasion by RSV of host interferon responses / mitotic spindle / PKMTs methylate histone lysines / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / 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 / HATs acetylate histones / protein-macromolecule adaptor activity / histone binding / 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 / regulation of cell cycle / 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 / 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, 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 / G-protein beta WD-40 repeat / Ubiquitin-like domain superfamily / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Chem-Q3X / THIOCYANATE ION / von Hippel-Lindau disease tumor suppressor / WD repeat-containing protein 5 / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.05 Å
AuthorsKraemer, A. / Doelle, A. / Knapp, S. / Structural Genomics Consortium (SGC)
Funding support Canada, 1items
OrganizationGrant numberCountry
The Structural Genomics Consortium (SGC) Canada
CitationJournal: To Be Published
Title: Structure of human WDR5 and pVHL:ElonginC:ElonginB bound to PROTAC with PEG linker (conformation #2)
Authors: Kraemer, A. / Doelle, A. / Knapp, S. / Structural Genomics Consortium (SGC)
History
DepositionOct 12, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: WD repeat-containing protein 5
J: Elongin-B
K: Elongin-C
L: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,67617
Polymers76,7914
Non-polymers1,88513
Water5,188288
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7910 Å2
ΔGint-30 kcal/mol
Surface area27700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.262, 85.731, 197.670
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 4 types, 4 molecules BJKL

#1: Protein WD repeat-containing protein 5 / BMP2-induced 3-kb gene protein


Mass: 35296.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR5, BIG3 / Production host: Escherichia coli (E. coli) / References: UniProt: P61964
#2: 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.: 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
#3: 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: 11043.678 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
#4: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18702.291 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

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Non-polymers , 4 types, 301 molecules

#5: Chemical
ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: CNS
#6: Chemical ChemComp-Q3X / ~{N}-[5-[4-[2-[2-[2-[2-[3-[[3,3-dimethyl-1-[(2~{S},4~{R})-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]-4-oxidanyl-pyrrolidin-1-yl]-1-oxidanylidene-butan-2-yl]amino]-3-oxidanylidene-propoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxidanylidene-4-(trifluoromethyl)-3~{H}-pyridine-3-carboxamide


Mass: 1160.306 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C58H72F3N9O11S / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 288 / 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: 2.61 Å3/Da / Density % sol: 52.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.8 / Details: 21-28% PEG 3350 0.4-1 M KSCN 0.1 M HEPES 6.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.999995 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Feb 10, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999995 Å / Relative weight: 1
ReflectionResolution: 2.05→47.26 Å / Num. obs: 51530 / % possible obs: 100 % / Redundancy: 13.2 % / CC1/2: 0.998 / Rmerge(I) obs: 0.168 / Rpim(I) all: 0.048 / Rrim(I) all: 0.175 / Net I/σ(I): 13.6 / Num. measured all: 680581
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.05-2.1113.21.5415152938960.7790.4351.6021.9100
8.94-47.2611.80.03987737410.9990.0120.04150.699.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.456
Highest resolutionLowest resolution
Rotation45.97 Å2.2 Å

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0352refinement
XDSdata reduction
Aimless0.7.9data scaling
MOLREPphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7Q2J

7q2j


Resolution: 2.05→46.01 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.938 / SU B: 5.194 / SU ML: 0.133 / SU R Cruickshank DPI: 0.1867 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.187 / ESU R Free: 0.165 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2373 2551 5 %RANDOM
Rwork0.1992 ---
obs0.2011 48901 99.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 93.09 Å2 / Biso mean: 33.616 Å2 / Biso min: 19.9 Å2
Baniso -1Baniso -2Baniso -3
1-0.08 Å20 Å2-0 Å2
2--2.71 Å20 Å2
3----2.79 Å2
Refinement stepCycle: final / Resolution: 2.05→46.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5045 0 125 288 5458
Biso mean--41.76 40.82 -
Num. residues----644
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0125285
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164815
X-RAY DIFFRACTIONr_angle_refined_deg1.5011.6457160
X-RAY DIFFRACTIONr_angle_other_deg0.4931.58511235
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.9115640
X-RAY DIFFRACTIONr_dihedral_angle_2_deg6.926527
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.21610865
X-RAY DIFFRACTIONr_chiral_restr0.0660.2802
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.026040
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021024
LS refinement shellResolution: 2.05→2.103 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.311 185 -
Rwork0.294 3511 -
all-3696 -
obs--100 %

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