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- PDB-7rsp: Structure of the VPS34 kinase domain with compound 14 -

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Basic information

Entry
Database: PDB / ID: 7rsp
TitleStructure of the VPS34 kinase domain with compound 14
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 / autophagy of peroxisome / positive regulation by host of viral genome replication / Synthesis of PIPs at the Golgi membrane ...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 / autophagy of peroxisome / 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 / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / Macroautophagy / autolysosome / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / axoneme / PI3K Cascade / autophagosome assembly / autophagosome maturation / RHO GTPases Activate NADPH Oxidases / regulation of macroautophagy / cellular response to glucose starvation / autophagosome / regulation of cytokinesis / regulation of autophagy / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / macroautophagy / autophagy / endocytosis / phagocytic vesicle membrane / late endosome / peroxisome / kinase activity / Translation of Replicase and Assembly of the Replication Transcription Complex / midbody / protein kinase activity / endosome / 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 / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase ...Phosphatidylinositol 3-kinase, Vps34 type / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / C2 domain superfamily / Armadillo-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-7IK / Phosphatidylinositol 3-kinase catalytic subunit type 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.67 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 1.2Mar 13, 2024Group: Data collection / Source and taxonomy / Category: chem_comp_atom / chem_comp_bond / entity_src_gen
Revision 1.3Apr 3, 2024Group: Refinement description / Category: 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)140,9857
Polymers140,1522
Non-polymers8335
Water12,124673
1
A: Phosphatidylinositol 3-kinase catalytic subunit type 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,4463
Polymers70,0761
Non-polymers3702
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Phosphatidylinositol 3-kinase catalytic subunit type 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,5384
Polymers70,0761
Non-polymers4633
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.320, 117.910, 90.400
Angle α, β, γ (deg.)90.000, 109.540, 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C3H8O3
#3: Chemical ChemComp-7IK / (7R,8R)-2-[(3R)-3-methylmorpholin-4-yl]-7-(propan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one


Mass: 278.350 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H22N4O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 673 / 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: 2.31 Å3/Da / Density % sol: 46.64 %
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: SSRL / Beamline: BL12-2 / Wavelength: 0.977 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 3, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977 Å / Relative weight: 1
ReflectionResolution: 1.67→43.054 Å / Num. obs: 145165 / % possible obs: 98.8 % / Redundancy: 3.419 % / Biso Wilson estimate: 34.479 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.047 / Rrim(I) all: 0.056 / Χ2: 1.019 / Net I/σ(I): 18.06 / Num. measured all: 496296 / Scaling rejects: 79
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.67-1.713.4891.5161.053704010828106150.4871.78898
1.71-1.763.4291.1321.373554510558103670.5741.3498.2
1.76-1.813.2820.8661.683327110303101370.6611.03598.4
1.81-1.873.460.6812.2533962995798150.7840.80598.6
1.87-1.933.3890.4942.9332425968895680.8590.58798.8
1.93-23.4060.362431489936192460.9120.42998.8
2-2.073.5320.2755.3931600904989480.9470.32498.9
2.07-2.163.490.1947.330070870186160.9750.2399
2.16-2.253.330.1399.3927410830882310.9840.16599.1
2.25-2.363.4010.10712.1826830798078880.9910.12798.8
2.36-2.493.4150.08314.9125674761075190.9940.09998.8
2.49-2.643.4250.06518.7524310715870970.9960.07899.1
2.64-2.823.5430.0524.0123826677267240.9980.05999.3
2.82-3.053.4360.03730.721493631062560.9980.04499.1
3.05-3.343.280.02540.7218735577357120.9990.0398.9
3.34-3.733.3520.01756.72174585259520910.0299
3.73-4.313.4760.01373.91159864627459910.01699.4
4.31-5.283.4860.01286.33136663938392010.01499.5
5.28-7.473.2970.01376.999873057302910.01599.1
7.47-43.0543.3070.009101.2555191699166910.01198.2

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
XSCALEBUILT=20161205data scaling
PDB_EXTRACT3.27data extraction
XDSBUILT=20190315data reduction
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: APO

Resolution: 1.67→43.054 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 29.89 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2246 1890 1.3 %
Rwork0.2078 143205 -
obs0.208 145095 98.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 109.96 Å2 / Biso mean: 34.0671 Å2 / Biso min: 21.79 Å2
Refinement stepCycle: final / Resolution: 1.67→43.054 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8531 0 82 696 9309
Biso mean--38.27 41.13 -
Num. residues----1062
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.67-1.71520.441450.41321085998
1.7152-1.76560.36841420.36041092798
1.7656-1.82260.35461380.34151092098
1.8226-1.88780.3211540.30071099799
1.8878-1.96330.2751370.2751097199
1.9633-2.05270.26831510.25761100999
2.0527-2.16090.28151440.23771101699
2.1609-2.29630.25331440.2181103099
2.2963-2.47360.28081480.2151100999
2.4736-2.72250.23081440.2141104499
2.7225-3.11630.22731460.20181109899
3.1163-3.92580.1891500.17091108499
3.9258-43.0540.1531470.15251124199
Refinement TLS params.Method: refined / Origin x: 42.9795 Å / Origin y: 13.3457 Å / Origin z: 92.8537 Å
111213212223313233
T0.2521 Å20.0097 Å20.0267 Å2-0.2659 Å20.0113 Å2--0.3331 Å2
L0.0868 °20.0327 °20.1843 °2-0.0127 °20.066 °2--0.3966 °2
S0.01 Å °0.0024 Å °-0.019 Å °-0.0073 Å °0.0125 Å °0.0058 Å °0.0115 Å °-0.0094 Å °-0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA286 - 1001
2X-RAY DIFFRACTION1allA901
3X-RAY DIFFRACTION1allB282 - 901
4X-RAY DIFFRACTION1allB901
5X-RAY DIFFRACTION1allM1 - 694

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