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- PDB-8rxr: Crystal structure of VPS34 in complex with inhibitor SB02024 -

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Basic information

Entry
Database: PDB / ID: 8rxr
TitleCrystal structure of VPS34 in complex with inhibitor SB02024
ComponentsPhosphatidylinositol 3-kinase catalytic subunit type 3
KeywordsSIGNALING PROTEIN / Inhibitor / Complex / Kinase / Autophagy / Drug Discovery / Signaling
Function / homology
Function and homology information


Toll Like Receptor 9 (TLR9) Cascade / protein lipidation / Synthesis of PIPs at the late endosome membrane / phosphatidylinositol 3-kinase complex, class III / Synthesis of PIPs at the early endosome membrane / phosphatidylinositol 3-kinase complex, class III, type II / phosphatidylinositol 3-kinase complex, class III, type I / positive regulation by host of viral genome replication / Synthesis of PIPs at the Golgi membrane / phosphatidylinositol kinase activity ...Toll Like Receptor 9 (TLR9) Cascade / protein lipidation / Synthesis of PIPs at the late endosome membrane / phosphatidylinositol 3-kinase complex, class III / Synthesis of PIPs at the early endosome membrane / phosphatidylinositol 3-kinase complex, class III, type II / phosphatidylinositol 3-kinase complex, class III, type I / positive regulation by host of viral genome replication / Synthesis of PIPs at the Golgi membrane / phosphatidylinositol kinase activity / protein localization to phagophore assembly site / protein targeting to lysosome / early endosome to late endosome transport / phagophore assembly site / Translation of Replicase and Assembly of the Replication Transcription Complex / autolysosome / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / Macroautophagy / 1-phosphatidylinositol-3-kinase activity / axoneme / phosphatidylinositol phosphate biosynthetic process / phosphatidylinositol-mediated signaling / autophagosome maturation / autophagosome assembly / PI3K Cascade / RHO GTPases Activate NADPH Oxidases / autophagosome / regulation of macroautophagy / cellular response to glucose starvation / regulation of cytokinesis / regulation of autophagy / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / macroautophagy / autophagy / endocytosis / peroxisome / phagocytic vesicle membrane / late endosome / kinase activity / Translation of Replicase and Assembly of the Replication Transcription Complex / midbody / endosome / protein kinase activity / cell cycle / phosphorylation / cell division / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP binding / membrane / cytosol / cytoplasm
Similarity search - Function
Phosphatidylinositol 3-kinase, Vps34 type / Phosphoinositide 3-kinase C2 / Phosphoinositide 3-kinase, region postulated to contain C2 domain / C2 phosphatidylinositol 3-kinase-type domain / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase ...Phosphatidylinositol 3-kinase, Vps34 type / Phosphoinositide 3-kinase C2 / Phosphoinositide 3-kinase, region postulated to contain C2 domain / C2 phosphatidylinositol 3-kinase-type domain / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / C2 domain superfamily / Armadillo-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / IMIDAZOLE / DI(HYDROXYETHYL)ETHER / Phosphatidylinositol 3-kinase catalytic subunit type 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.06 Å
AuthorsTresaugues, L. / Yu, Y. / Bogdan, M. / Parpal, S. / Silvander, C. / Lindstrom, J. / Simeon, J. / Timson, M.J. / Al-Hashimi, H. / Smith, B.D. ...Tresaugues, L. / Yu, Y. / Bogdan, M. / Parpal, S. / Silvander, C. / Lindstrom, J. / Simeon, J. / Timson, M.J. / Al-Hashimi, H. / Smith, B.D. / Flynn, D.L. / Viklund, J. / Martinsson, J. / De Milito, A. / Andersson, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol Oncol / Year: 2024
Title: Combining VPS34 inhibitors with STING agonists enhances type I interferon signaling and anti-tumor efficacy.
Authors: Yu, Y. / Bogdan, M. / Noman, M.Z. / Parpal, S. / Bartolini, E. / Van Moer, K. / Kleinendorst, S.C. / Bilgrav Saether, K. / Tresaugues, L. / Silvander, C. / Lindstrom, J. / Simeon, J. / ...Authors: Yu, Y. / Bogdan, M. / Noman, M.Z. / Parpal, S. / Bartolini, E. / Van Moer, K. / Kleinendorst, S.C. / Bilgrav Saether, K. / Tresaugues, L. / Silvander, C. / Lindstrom, J. / Simeon, J. / Timson, M.J. / Al-Hashimi, H. / Smith, B.D. / Flynn, D.L. / Alexeyenko, A. / Viklund, J. / Andersson, M. / Martinsson, J. / Pokrovskaja Tamm, K. / De Milito, A. / Janji, B.
History
DepositionFeb 7, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 20, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Phosphatidylinositol 3-kinase catalytic subunit type 3
B: Phosphatidylinositol 3-kinase catalytic subunit type 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)138,80216
Polymers137,1132
Non-polymers1,68914
Water10,629590
1
A: Phosphatidylinositol 3-kinase catalytic subunit type 3
hetero molecules


  • defined by author
  • Evidence: gel filtration
  • 69.5 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)69,5109
Polymers68,5561
Non-polymers9538
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Phosphatidylinositol 3-kinase catalytic subunit type 3
hetero molecules


  • defined by author
  • 69.3 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)69,2927
Polymers68,5561
Non-polymers7366
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)288.824, 98.65, 62.895
Angle α, β, γ (deg.)90, 92.266, 90
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1283-

HOH

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Phosphatidylinositol 3-kinase catalytic subunit type 3 / PI3-kinase type 3 / PI3K type 3 / PtdIns-3-kinase type 3 / Phosphatidylinositol 3-kinase p100 ...PI3-kinase type 3 / PI3K type 3 / PtdIns-3-kinase type 3 / Phosphatidylinositol 3-kinase p100 subunit / Phosphoinositide-3-kinase class 3 / hVps34


Mass: 68556.336 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Construct encompassing helical and catalytic domains of VPS34
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3C3, VPS34 / Plasmid: pNIC28-Bsa24 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2 / References: UniProt: Q8NEB9, phosphatidylinositol 3-kinase

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Non-polymers , 6 types, 604 molecules

#2: Chemical ChemComp-A1H4E / 4-[(3R)-3-methylmorpholin-4-yl]-2-[(2R)-2-(trifluoromethyl)piperidin-1-yl]-3H-pyridin-6-one


Mass: 345.360 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H22F3N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-IMD / IMIDAZOLE / Imidazole


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#5: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: 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
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 590 / 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: 3.6 Å3/Da / Density % sol: 65.84 % / Description: Large plates
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 22.5 % PEG3350, 0.2 M ammonium acetate, 0.1 M HEPES pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: flux of nitrogen 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.97802 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 1, 2015 / Details: TOROIDAL MIRROR
RadiationMonochromator: Si(311) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97802 Å / Relative weight: 1
ReflectionResolution: 2.06→49.374 Å / Num. obs: 108408 / % possible obs: 99.6 % / Redundancy: 4.5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.055 / Rpim(I) all: 0.043 / Rrim(I) all: 0.07 / Net I/σ(I): 12.6
Reflection shellResolution: 2.06→2.13 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.9 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 10600 / CC1/2: 0.53 / Rpim(I) all: 0.73 / Rrim(I) all: 1.164 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.06→49.374 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.95 / WRfactor Rfree: 0.22 / WRfactor Rwork: 0.177 / SU B: 4.677 / SU ML: 0.118 / Average fsc free: 0.9583 / Average fsc work: 0.9691 / Cross valid method: FREE R-VALUE / ESU R: 0.145 / ESU R Free: 0.143
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2245 5315 4.904 %
Rwork0.1816 103076 -
all0.184 --
obs-108391 99.481 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 47.699 Å2
Baniso -1Baniso -2Baniso -3
1--0.131 Å2-0 Å2-1.143 Å2
2---0.735 Å20 Å2
3---0.953 Å2
Refinement stepCycle: LAST / Resolution: 2.06→49.374 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8728 0 105 590 9423
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0129044
X-RAY DIFFRACTIONr_bond_other_d0.0010.0168795
X-RAY DIFFRACTIONr_angle_refined_deg1.3151.8612216
X-RAY DIFFRACTIONr_angle_other_deg0.4671.78220283
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.69451084
X-RAY DIFFRACTIONr_dihedral_angle_2_deg6.213552
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.685101687
X-RAY DIFFRACTIONr_dihedral_angle_6_deg13.94310429
X-RAY DIFFRACTIONr_chiral_restr0.0650.21365
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0210396
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022007
X-RAY DIFFRACTIONr_nbd_refined0.2150.21998
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1820.27884
X-RAY DIFFRACTIONr_nbtor_refined0.1790.24457
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0720.24643
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1610.2509
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1210.213
X-RAY DIFFRACTIONr_nbd_other0.1910.275
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1410.212
X-RAY DIFFRACTIONr_mcbond_it2.7314.4624321
X-RAY DIFFRACTIONr_mcbond_other2.7314.4624321
X-RAY DIFFRACTIONr_mcangle_it3.8678.0175403
X-RAY DIFFRACTIONr_mcangle_other3.8668.0175404
X-RAY DIFFRACTIONr_scbond_it3.7984.9734723
X-RAY DIFFRACTIONr_scbond_other3.7984.9744724
X-RAY DIFFRACTIONr_scangle_it5.9248.9246810
X-RAY DIFFRACTIONr_scangle_other5.9248.9246811
X-RAY DIFFRACTIONr_lrange_it7.32242.81610451
X-RAY DIFFRACTIONr_lrange_other7.32242.81810452
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.06-2.1130.3543680.31876060.3280330.910.92299.26550.319
2.113-2.1710.3073980.29873740.29878420.9360.93799.10740.294
2.171-2.2340.2843600.26671810.26675520.940.95299.85430.257
2.234-2.3030.2793370.23669790.23873490.9530.96399.5510.222
2.303-2.3780.2513320.21368060.21571620.9620.97299.66490.195
2.378-2.4610.2533430.20965760.21269560.9610.97499.46810.19
2.461-2.5540.2473720.20962610.21166690.9620.97499.46020.189
2.554-2.6580.2483420.20360650.20564560.9650.97799.2410.183
2.658-2.7760.2563360.19157980.19561450.960.97999.8210.176
2.776-2.9110.2662760.20156310.20459220.9560.97699.74670.187
2.911-3.0680.2362760.19253170.19456280.9650.97899.37810.182
3.068-3.2530.2362680.20550390.20753330.9670.97699.51250.198
3.253-3.4760.2462260.20547360.20750080.9710.97999.08150.201
3.476-3.7530.2651850.20144460.20446420.9610.98199.7630.201
3.753-4.1090.1792170.15840950.15943190.9810.98799.83790.16
4.109-4.590.1611670.12436950.12638990.9850.99199.0510.132
4.59-5.2930.1981570.13332850.13634700.980.99199.19310.142
5.293-6.4640.2031520.15827760.1629290.9830.98999.96590.164
6.464-9.0640.181250.13121640.13423030.9860.99199.39210.143
9.064-49.3740.175780.12912460.13213290.9840.9999.62380.142

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