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- PDB-7jtp: Crystal structure of Protac MS67 in complex with the WD repeat-co... -

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Basic information

Entry
Database: PDB / ID: 7jtp
TitleCrystal structure of Protac MS67 in complex with the WD repeat-containing protein 5 and pVHL:ElonginC:ElonginB
Components
  • Elongin-B
  • Elongin-C
  • WD repeat-containing protein 5
  • von Hippel-Lindau disease tumor suppressor
KeywordsPROTEIN BINDING / Protac / protein degradation / ubiquitination
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 / MLL3/4 complex / elongin complex / Set1C/COMPASS complex / VCB complex / MLL1/2 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 / MLL3/4 complex / elongin complex / Set1C/COMPASS complex / VCB 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 non-membrane-bounded organelle / SUMOylation of ubiquitinylation proteins / Formation of WDR5-containing histone-modifying complexes / regulation of cell division / negative regulation of transcription elongation by RNA polymerase II / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / regulation of embryonic development / MLL1 complex / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / ubiquitin-like ligase-substrate adaptor activity / histone acetyltransferase complex / 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 / positive regulation of gluconeogenesis / negative regulation of TORC1 signaling / transcription initiation-coupled chromatin remodeling / methylated histone binding / RNA Polymerase II Pre-transcription Events / negative regulation of autophagy / transcription corepressor binding / skeletal system development / gluconeogenesis / 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 / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / cell morphogenesis / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / mitotic spindle / PKMTs methylate histone lysines / RMTs methylate histone arginines / Regulation of expression of SLITs and ROBOs / Activation of anterior HOX genes in hindbrain development during early embryogenesis / ubiquitin-protein transferase activity / transcription corepressor activity / protein-macromolecule adaptor 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 / histone binding / ubiquitin-dependent protein catabolic process / cellular response to hypoxia / regulation of gene expression / proteasome-mediated ubiquitin-dependent protein catabolic process / protein-containing complex assembly / DNA-binding transcription factor binding / amyloid fibril formation / protein stabilization / molecular adaptor activity / protein ubiquitination / regulation of cell cycle / 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-like domain / Ubiquitin domain profile. / G-protein beta WD-40 repeat / Ubiquitin-like domain superfamily / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Chem-X6M / 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 / Resolution: 2.12 Å
AuthorsKottur, J. / Jain, R. / Aggarwal, A.K.
CitationJournal: Sci Transl Med / Year: 2021
Title: A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models.
Authors: Yu, X. / Li, D. / Kottur, J. / Shen, Y. / Kim, H.S. / Park, K.S. / Tsai, Y.H. / Gong, W. / Wang, J. / Suzuki, K. / Parker, J. / Herring, L. / Kaniskan, H.U. / Cai, L. / Jain, R. / Liu, J. / ...Authors: Yu, X. / Li, D. / Kottur, J. / Shen, Y. / Kim, H.S. / Park, K.S. / Tsai, Y.H. / Gong, W. / Wang, J. / Suzuki, K. / Parker, J. / Herring, L. / Kaniskan, H.U. / Cai, L. / Jain, R. / Liu, J. / Aggarwal, A.K. / Wang, G.G. / Jin, J.
History
DepositionAug 18, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 18, 2023Group: 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
J: Elongin-B
K: Elongin-C
L: von Hippel-Lindau disease tumor suppressor
A: WD repeat-containing protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,5856
Polymers75,4634
Non-polymers1,1222
Water7,945441
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6510 Å2
ΔGint-40 kcal/mol
Surface area26400 Å2
Unit cell
Length a, b, c (Å)63.831, 98.611, 127.629
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 JKLA

#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 / Plasmid: pCDF Duet / Production host: Escherichia coli BL21(DE3) (bacteria) / 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.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Plasmid: pCDF Duet / Production host: Escherichia coli BL21(DE3) (bacteria) / 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 BL21(DE3) (bacteria) / References: UniProt: P40337
#4: Protein WD repeat-containing protein 5 / BMP2-induced 3-kb gene protein


Mass: 34037.641 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR5, BIG3 / Plasmid: pET28 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P61964

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Non-polymers , 3 types, 443 molecules

#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-X6M / N-(6-fluoro-3'-{[6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carbonyl]amino}-4'-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl][1,1'-biphenyl]-3-carbonyl)glycyl-3-methyl-L-valyl-(4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide / Protac MS67


Mass: 1030.140 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C52H59F4N9O7S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 441 / 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: 2.66 Å3/Da / Density % sol: 53.78 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 0.1 M Tris, pH 8.5, 30% PEG300 / PH range: 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.97936 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 17, 2019
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97936 Å / Relative weight: 1
ReflectionResolution: 2.05→78.033 Å / Num. all: 46516 / Num. obs: 46516 / % possible obs: 100 % / Redundancy: 7.1 % / Biso Wilson estimate: 35.02 Å2 / Rpim(I) all: 0.038 / Rrim(I) all: 0.102 / Rsym value: 0.095 / Net I/av σ(I): 4.7 / Net I/σ(I): 11.7 / Num. measured all: 331442
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs
2.12-2.237.20.5671.34815666810.2260.6110.5673.4
2.23-2.376.80.4271.74306763590.1770.4630.4274.2
2.37-2.536.90.2942.64121359520.120.3180.2945.7
2.53-2.7470.2033.63906455810.0830.220.2037.9
2.74-37.70.1375.33964851300.0530.1470.13711.6
3-3.357.60.0977.13581646900.0370.1040.09716.3
3.35-3.877.30.0758.83024941380.030.0810.07521.2
3.87-4.746.70.06110.22384435520.0250.0670.06124
4.74-6.76.90.05411.11935828000.0220.0590.05423.9
6.7-78.0336.80.0545.51102716330.0240.060.05425.3

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Processing

Software
NameVersionClassification
SCALA3.3.22data scaling
PHENIX1.13refinement
PDB_EXTRACT3.25data extraction
iMOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entries 2GNQ & 1VCB

2gnq

1vcb


Resolution: 2.12→57.089 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 22.85 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2238 2344 5.05 %
Rwork0.1908 44104 -
obs0.1924 46448 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 93.47 Å2 / Biso mean: 40.2234 Å2 / Biso min: 16.96 Å2
Refinement stepCycle: final / Resolution: 2.12→57.089 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4957 0 79 441 5477
Biso mean--28.21 44.05 -
Num. residues----634
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.12-2.16330.32551310.25482539
2.1633-2.21030.27191370.23592576
2.2103-2.26180.29281280.24072546
2.2618-2.31830.29931330.2332558
2.3183-2.3810.27921300.22742566
2.381-2.45110.27591410.22112576
2.4511-2.53020.28871310.2152564
2.5302-2.62060.2821650.21762539
2.6206-2.72550.24851340.20722575
2.7255-2.84960.25391360.20562576
2.8496-2.99980.25881430.20232580
2.9998-3.18770.22761370.20782616
3.1877-3.43380.23041400.19762593
3.4338-3.77930.21641490.18452607
3.7793-4.32610.16461190.16042644
4.3261-5.44970.1661310.14772661
5.4497-57.0890.18941590.18012788

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