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- PDB-7rsv: Structure of the VPS34 kinase domain with compound 5 -

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Basic information

Entry
Database: PDB / ID: 7rsv
TitleStructure of the VPS34 kinase domain with compound 5
ComponentsPhosphatidylinositol 3-kinase catalytic subunit type 3
KeywordsTRANSFERASE/TRANSFERASE inhibitor / VPS34 inhibitor / endosomal trafficking / authophagy / ONCOPROTEIN / TRANSFERASE-TRANSFERASE inhibitor complex
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 / phosphatidylinositol-mediated signaling / 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 / autophagosome maturation / phosphatidylinositol phosphate biosynthetic process / autophagosome assembly / PI3K Cascade / RHO GTPases Activate NADPH Oxidases / regulation of macroautophagy / cellular response to glucose starvation / regulation of cytokinesis / regulation of autophagy / macroautophagy / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / autophagy / peroxisome / endocytosis / phagocytic vesicle membrane / late endosome / Translation of Replicase and Assembly of the Replication Transcription Complex / kinase activity / midbody / endosome / protein kinase activity / cell cycle / cell division / phosphorylation / 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
Chem-7IQ / Phosphatidylinositol 3-kinase catalytic subunit type 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.78 Å
AuthorsHu, D.X. / Patel, S. / Chen, H. / Wang, S. / Staben, S. / Dimitrova, Y.N. / Wallweber, H.A. / Lee, J.Y. / Chan, G.K.Y. / Sneeringer, C.J. ...Hu, D.X. / Patel, S. / Chen, H. / Wang, S. / Staben, S. / Dimitrova, Y.N. / Wallweber, H.A. / Lee, J.Y. / Chan, G.K.Y. / Sneeringer, C.J. / Prangley, M.S. / Moffat, J.G. / Wu, C. / Schutt, L.K. / Salphati, L. / Pang, J. / McNamara, E. / Huang, H. / Chen, Y. / Wang, Y. / Zhao, W. / Lim, J. / Murthy, A. / Siu, M.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2022
Title: Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase Inhibitors.
Authors: Hu, D.X. / Patel, S. / Chen, H. / Wang, S. / Staben, S.T. / Dimitrova, Y.N. / Wallweber, H.A. / Lee, J.Y. / Chan, G.K.Y. / Sneeringer, C.J. / Prangley, M.S. / Moffat, J.G. / Wu, K.C. / ...Authors: Hu, D.X. / Patel, S. / Chen, H. / Wang, S. / Staben, S.T. / Dimitrova, Y.N. / Wallweber, H.A. / Lee, J.Y. / Chan, G.K.Y. / Sneeringer, C.J. / Prangley, M.S. / Moffat, J.G. / Wu, K.C. / Schutt, L.K. / Salphati, L. / Pang, J. / McNamara, E. / Huang, H. / Chen, Y. / Wang, Y. / Zhao, W. / Lim, J. / Murthy, A. / Siu, M.
History
DepositionAug 11, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 24, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 14, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.2Apr 3, 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
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)141,09612
Polymers140,1522
Non-polymers94410
Water15,061836
1
A: Phosphatidylinositol 3-kinase catalytic subunit type 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,6288
Polymers70,0761
Non-polymers5527
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Phosphatidylinositol 3-kinase catalytic subunit type 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,4674
Polymers70,0761
Non-polymers3913
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)64.706, 119.027, 91.287
Angle α, β, γ (deg.)90.000, 108.950, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#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: 70075.930 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3C3, VPS34 / Production host: Escherichia coli (E. coli) / References: UniProt: Q8NEB9, phosphatidylinositol 3-kinase
#2: Chemical ChemComp-7IQ / (5aS,8aR,9S)-2-[(3R)-3-methylmorpholin-4-yl]-5,5a,6,7,8,8a-hexahydro-4H-cyclopenta[e]pyrazolo[1,5-a]pyrazin-4-one


Mass: 276.334 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H20N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 836 / Source method: isolated from a natural source / Formula: H2O
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: 2.37 Å3/Da / Density % sol: 48.15 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop
Details: 0.2M Potassium/Sodium tartrate 0.1M Bis-Tris propane pH7.5, 20% PEG3350 0.7% v/v 1-butanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.34→39.68 Å / Num. obs: 238821 / % possible obs: 69.2 % / Redundancy: 3.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.048 / Rrim(I) all: 0.088 / Net I/σ(I): 6.7
Reflection shellResolution: 1.34→1.36 Å / Redundancy: 1.9 % / Rmerge(I) obs: 9.9 / Num. unique obs: 594 / CC1/2: 0.042 / Rpim(I) all: 23.86 / Rrim(I) all: 34.198 / % possible all: 4.1

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
XDSBUILT=20190315data reduction
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: apo

Resolution: 1.78→34.502 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 22.71 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2143 2363 1 %
Rwork0.1794 236458 -
obs0.1797 238821 96.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 156.54 Å2 / Biso mean: 34.5956 Å2 / Biso min: 20.47 Å2
Refinement stepCycle: final / Resolution: 1.78→34.502 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8520 0 71 844 9435
Biso mean--36.94 44.41 -
Num. residues----1063
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.78-1.81630.28961420.28961401198
1.8163-1.85580.29231380.28221410497
1.8558-1.8990.29491470.26791368495
1.899-1.94650.28891220.25871255687
1.9465-1.99910.30351330.24081410398
1.9991-2.05790.27741400.22731416499
2.0579-2.12430.2771480.20691426899
2.1243-2.20020.22591410.19941401298
2.2002-2.28830.22081440.19271386496
2.2883-2.39240.19651360.18231310491
2.3924-2.51850.20941400.17781425199
2.5185-2.67630.21631440.18151423899
2.6763-2.88280.2171470.18231418299
2.8828-3.17280.23281290.17811347594
3.1728-3.63140.19311340.1631433199
3.6314-4.57350.18891430.13811390497
Refinement TLS params.Method: refined / Origin x: 8.7642 Å / Origin y: -22.9118 Å / Origin z: 7.3062 Å
111213212223313233
T0.2599 Å20.0083 Å20.0172 Å2-0.2592 Å20.0062 Å2--0.2875 Å2
L0.1147 °20.0451 °20.2363 °2--0.0039 °20.0948 °2--0.4685 °2
S0.0221 Å °-0.002 Å °-0.0361 Å °-0.0048 Å °0.0099 Å °-0.0004 Å °-0.0021 Å °-0.0096 Å °-0.0001 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA287 - 871
2X-RAY DIFFRACTION1allA901
3X-RAY DIFFRACTION1allZ2 - 3
4X-RAY DIFFRACTION1allB282 - 871
5X-RAY DIFFRACTION1allB901
6X-RAY DIFFRACTION1allX2
7X-RAY DIFFRACTION1allM1 - 876
8X-RAY DIFFRACTION1allC1 - 5

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