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- PDB-7jto: Crystal structure of Protac MS33 in complex with the WD repeat-co... -

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Entry
Database: PDB / ID: 7jto
TitleCrystal structure of Protac MS33 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 / 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 / elongin 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 / elongin complex / Set1C/COMPASS 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 / negative regulation of autophagy / transcription initiation-coupled chromatin remodeling / protein serine/threonine kinase binding / transcription corepressor binding / gluconeogenesis / skeletal system development / 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 / 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 / HATs acetylate histones / Neddylation / 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 / ubiquitin-dependent protein catabolic process / Replication of the SARS-CoV-2 genome / protein-macromolecule adaptor activity / histone binding / molecular adaptor activity / cellular response to hypoxia / 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
THIOCYANATE ION / Chem-VKA / 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: 1.7 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
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)77,32916
Polymers75,4634
Non-polymers1,86612
Water11,241624
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7610 Å2
ΔGint-48 kcal/mol
Surface area27010 Å2
Unit cell
Length a, b, c (Å)47.380, 187.830, 49.150
Angle α, β, γ (deg.)90.000, 116.960, 90.000
Int Tables number4
Space group name H-MP1211

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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: 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: pET28a / Production host: Escherichia coli BL21(DE3) (bacteria) / 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 / Plasmid: pCDF Duet / Production host: Escherichia coli BL21(DE3) (bacteria) / 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: 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
#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 BL21(DE3) (bacteria) / References: UniProt: P40337

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Non-polymers , 6 types, 636 molecules

#5: Chemical
ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: CNS
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-VKA / 3-methyl-N-(11-{[2-(4-{[4'-(4-methylpiperazin-1-yl)-3'-{[6-oxo-4-(trifluoromethyl)-5,6-dihydropyridine-3-carbonyl]amino}[1,1'-biphenyl]-3-yl]methyl}piperazin-1-yl)ethyl]amino}-11-oxoundecanoyl)-L-valyl-(4R)-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-L-prolinamide / Protac MS33


Mass: 1208.481 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C64H84F3N11O7S / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#9: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 624 / 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: 52.38 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1 M HEPES sodium, pH 7.5-8.0, 1.3-1.6 M sodium thiocyanate, 15-20% PEG3350
PH range: 7.5-8.0

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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: 0.97928 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 30, 2019
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97928 Å / Relative weight: 1
ReflectionResolution: 1.7→93.915 Å / Num. all: 83626 / Num. obs: 83626 / % possible obs: 99.9 % / Redundancy: 3.6 % / Biso Wilson estimate: 20.23 Å2 / Rpim(I) all: 0.047 / Rrim(I) all: 0.091 / Rsym value: 0.077 / Net I/av σ(I): 6.4 / Net I/σ(I): 7.3 / Num. measured all: 296910
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
1.7-1.793.30.4051.940641121720.2580.4820.4052.7100
1.79-1.93.40.3622.139727115660.2280.430.362399.9
1.9-2.033.70.3052.339512108100.1860.3590.3053.699.8
2.03-2.193.60.2292.636748100960.1410.270.2294.799.9
2.19-2.43.40.16443141392900.1040.1950.1645.899.8
2.4-2.693.50.1175.62947284030.0730.1380.1177.8100
2.69-3.13.90.0768.62879074380.0450.0880.07611.6100
3.1-3.83.80.05511.22381162840.0320.0640.05516.8100
3.8-5.383.40.04113.91671448690.0250.0480.04119.799.9
5.38-93.9153.70.03514.21008226980.0210.0410.03518.6100

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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: 1.7→46.958 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 26.69 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2253 4161 4.98 %
Rwork0.1996 79383 -
obs0.2009 83544 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 66.07 Å2 / Biso mean: 28.3267 Å2 / Biso min: 11.86 Å2
Refinement stepCycle: final / Resolution: 1.7→46.958 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4981 0 125 624 5730
Biso mean--32.2 37.66 -
Num. residues----641
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.7-1.71930.37281250.37282620100
1.7193-1.73960.40421450.37952651100
1.7396-1.76080.3431490.3432664100
1.7608-1.78310.37051540.34762570100
1.7831-1.80650.35361310.33092694100
1.8065-1.83130.35191420.30792639100
1.8313-1.85740.31071220.29252608100
1.8574-1.88520.34091440.27872683100
1.8852-1.91460.31461340.2547261699
1.9146-1.9460.30311380.24962645100
1.946-1.97960.26161450.24242657100
1.9796-2.01560.25861370.2342615100
2.0156-2.05430.28931370.23062661100
2.0543-2.09630.27511410.22022613100
2.0963-2.14180.26711430.22112672100
2.1418-2.19170.2731660.21392611100
2.1917-2.24650.24761400.21012638100
2.2465-2.30720.23991490.20792614100
2.3072-2.37510.26661390.20062654100
2.3751-2.45180.25611220.20862651100
2.4518-2.53940.22381400.20642648100
2.5394-2.6410.2431320.20842680100
2.641-2.76120.21551690.19372597100
2.7612-2.90680.23581410.18542659100
2.9068-3.08890.19851080.18322672100
3.0889-3.32730.21721100.17912704100
3.3273-3.6620.18961380.15872649100
3.662-4.19160.14951460.14482650100
4.1916-5.27990.15211450.1342662100
5.2799-46.9580.15731290.15732686100

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