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- PDB-8bb4: Structure of human WDR5 and pVHL:ElonginC:ElonginB bound to PROTA... -

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Basic information

Entry
Database: PDB / ID: 8bb4
TitleStructure of human WDR5 and pVHL:ElonginC:ElonginB bound to PROTAC with C3 linker
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 / histone H3Q5ser reader activity / histone H3K4me1 reader activity / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / Epigenetic regulation of gene expression by MLL3 and MLL4 complexes / MLL3/4 complex / transcription elongation factor activity / target-directed miRNA degradation / Set1C/COMPASS complex ...regulation of cellular response to hypoxia / histone H3Q5ser reader activity / histone H3K4me1 reader activity / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / Epigenetic regulation of gene expression by MLL3 and MLL4 complexes / MLL3/4 complex / transcription elongation factor activity / target-directed miRNA degradation / Set1C/COMPASS complex / elongin complex / MLL1/2 complex / ATAC complex / NSL complex / histone H3K4 methyltransferase activity / Replication of the SARS-CoV-1 genome / Cardiogenesis / VCB complex / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / intracellular membraneless organelle / SUMOylation of ubiquitinylation proteins / Formation of WDR5-containing histone-modifying complexes / histone methyltransferase complex / regulation of cell division / MLL1 complex / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / negative regulation of transcription elongation by RNA polymerase II / regulation of embryonic development / histone acetyltransferase complex / 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 / positive regulation of gluconeogenesis / transcription initiation-coupled chromatin remodeling / negative regulation of autophagy / protein serine/threonine kinase binding / transcription corepressor binding / gluconeogenesis / skeletal system development / 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 / Inactivation of CSF3 (G-CSF) signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Evasion by RSV of host interferon responses / PKMTs methylate histone lysines / Regulation of expression of SLITs and ROBOs / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / cell morphogenesis / ubiquitin-protein transferase activity / mitotic spindle / transcription corepressor activity / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / HATs acetylate histones / microtubule cytoskeleton / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / regulation of gene expression / protein-containing complex assembly / Replication of the SARS-CoV-2 genome / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / histone binding / cellular response to hypoxia / molecular adaptor activity / DNA-binding transcription factor binding / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of cell cycle / 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
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 / WDR5 beta-propeller domain / 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 / WDR5 beta-propeller 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 / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Roll / Alpha Beta
Similarity search - Domain/homology
Chem-Q3R / 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: 2.8 Å
AuthorsKraemer, A. / Doelle, A. / 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
DepositionOct 12, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 9, 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
Revision 1.2Jan 31, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
I: Elongin-B
O: Elongin-C
P: von Hippel-Lindau disease tumor suppressor
Q: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,7895
Polymers76,7914
Non-polymers9981
Water1,04558
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5750 Å2
ΔGint-38 kcal/mol
Surface area27210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.786, 184.506, 47.951
Angle α, β, γ (deg.)90.000, 102.780, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 4 types, 4 molecules IOPQ

#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.: 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: 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
#3: 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
#4: 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

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Non-polymers , 2 types, 59 molecules

#5: Chemical ChemComp-Q3R / ~{N}-[5-[4-[[4-[[(2~{S})-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]-4-oxidanylidene-butyl]carbamoyl]phenyl]-2-(4-methylpiperazin-1-yl)phenyl]-6-oxidanyl-4-(trifluoromethyl)pyridine-3-carboxamide


Mass: 998.123 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C51H58F3N9O7S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 58 / 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: 2.63 Å3/Da / Density % sol: 53.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.8 / Details: 21-28% PEG 3350 0.4 M KSCN 0.1 M HEPES pH 6.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.999998 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: 0.999998 Å / Relative weight: 1
ReflectionResolution: 2.8→184.51 Å / Num. obs: 19494 / % possible obs: 100 % / Redundancy: 2 % / CC1/2: 0.984 / Rmerge(I) obs: 0.105 / Rpim(I) all: 0.105 / Rrim(I) all: 0.149 / Net I/σ(I): 6 / Num. measured all: 38524
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
2.8-2.9520.459561928320.7070.4590.651.2100
8.85-184.511.90.02612466460.9970.0260.03724.199.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.416
Highest resolutionLowest resolution
Rotation92.25 Å2.95 Å

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Processing

Software
NameVersionClassification
Aimless0.7.9data scaling
MOLREPphasing
REFMAC5.8.0352refinement
PDB_EXTRACT3.27data extraction
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7Q2J

7q2j


Resolution: 2.8→92.25 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.863 / SU B: 43.624 / SU ML: 0.388 / SU R Cruickshank DPI: 0.3222 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.415 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.279 888 4.6 %RANDOM
Rwork0.2027 ---
obs0.2062 18571 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: 111.62 Å2 / Biso mean: 48.286 Å2 / Biso min: 7.31 Å2
Baniso -1Baniso -2Baniso -3
1-2.81 Å20 Å22.42 Å2
2---2.27 Å20 Å2
3----1.49 Å2
Refinement stepCycle: final / Resolution: 2.8→92.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4948 0 71 58 5077
Biso mean--43.55 31.5 -
Num. residues----636
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0125140
X-RAY DIFFRACTIONr_bond_other_d0.0040.0164647
X-RAY DIFFRACTIONr_angle_refined_deg1.1991.646996
X-RAY DIFFRACTIONr_angle_other_deg0.4331.58110828
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.3115630
X-RAY DIFFRACTIONr_dihedral_angle_2_deg6.423525
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.410832
X-RAY DIFFRACTIONr_chiral_restr0.0520.2792
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025940
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021012
LS refinement shellResolution: 2.8→2.873 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.384 65 -
Rwork0.331 1344 -
all-1409 -
obs--99.93 %
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)
11.9093-1.2510.31563.7171-0.63692.0493-0.05510.07540.43670.0366-0.0226-0.1177-0.26240.11910.07770.2537-0.06550.02880.0471-0.01720.2959.629744.268930.646
24.8208-1.06271.90336.9918-1.37854.73070.0352-0.35930.4903-0.22370.03330.8242-0.1103-0.5807-0.06860.26720.03130.08320.0795-0.02190.2256-0.907731.031837.4508
32.9518-0.0194-1.96342.8480.94536.40810.04370.08640.1830.0859-0.06050.1152-0.1426-0.23550.01680.13980.00840.04760.00940.00630.13128.01325.316931.9467
40.99050.10151.19151.39630.98245.92190.1014-0.0864-0.19140.0697-0.00510.13850.3311-0.233-0.09630.230.00680.10070.01680.01750.14999.02549.143813.7636
52.07530.6453-0.19613.5987-0.27261.3364-0.05550.0802-0.1411-0.35690.018-0.305-0.1648-0.00020.03750.4334-0.01630.08050.017-0.05940.244912.9261-22.7646-11.7505
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1I1 - 104
2X-RAY DIFFRACTION2O17 - 48
3X-RAY DIFFRACTION3O57 - 112
4X-RAY DIFFRACTION4P62 - 208
5X-RAY DIFFRACTION5Q33 - 334

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