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

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Basic information

Entry
Database: PDB / ID: 7rsj
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-7IH / Phosphatidylinositol 3-kinase catalytic subunit type 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.881 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)70,7318
Polymers70,0761
Non-polymers6557
Water6,089338
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)61.302, 107.386, 110.502
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121
Components on special symmetry positions
IDModelComponents
11A-1262-

HOH

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Components

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Protein , 1 types, 1 molecules A

#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.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3C3, VPS34 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Gold / References: UniProt: Q8NEB9, phosphatidylinositol 3-kinase

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Non-polymers , 5 types, 345 molecules

#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-7IH / N-{4-[(7R,8R)-4-oxo-7-(propan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]pyridin-2-yl}cyclopropanecarboxamide


Mass: 339.392 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21N5O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 338 / 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: 2.6 Å3/Da / Density % sol: 52.6 %
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: APS / Beamline: 24-ID-C / Wavelength: 0.9791 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Aug 8, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.88→110.5 Å / Num. obs: 59229 / % possible obs: 98.7 % / Redundancy: 6.3 % / Rmerge(I) obs: 0.099 / Net I/σ(I): 12.6
Reflection shellResolution: 1.88→1.92 Å / Redundancy: 5.7 % / Rmerge(I) obs: 1.45 / Num. unique obs: 32696 / % possible all: 86

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
Aimless0.5.32data scaling
PDB_EXTRACT3.27data extraction
XDSBUILT=20190315data reduction
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: APO

Resolution: 1.881→77.011 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 21.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2029 1995 3.38 %
Rwork0.1683 57099 -
obs0.1695 59094 98.43 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 125.77 Å2 / Biso mean: 42.3886 Å2 / Biso min: 24.97 Å2
Refinement stepCycle: final / Resolution: 1.881→77.011 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4409 0 66 341 4816
Biso mean--56.48 48.74 -
Num. residues----545
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.881-1.92770.3911200.3222349486
1.9277-1.97980.31491430.2674083100
1.9798-2.0380.2771440.22984066100
2.038-2.10380.24541390.195406999
2.1038-2.1790.23071400.18764092100
2.179-2.26630.21761410.17594103100
2.2663-2.36940.24821430.1694095100
2.3694-2.49440.21061410.18134083100
2.4944-2.65060.20711430.17574119100
2.6506-2.85530.24081480.18064133100
2.8553-3.14270.2071460.1794411499
3.1427-3.59740.2151480.1613415599
3.5974-4.53230.15221460.1343415199
4.5323-77.0110.17321530.1568434298
Refinement TLS params.Method: refined / Origin x: -9.8696 Å / Origin y: -12.6399 Å / Origin z: 15.8535 Å
111213212223313233
T0.3383 Å20.0032 Å2-0.0061 Å2-0.3396 Å20.0288 Å2--0.2804 Å2
L0.7551 °20.0054 °2-0.0418 °2-0.7162 °2-0.0546 °2--0.4039 °2
S0.0053 Å °-0.0509 Å °-0.0104 Å °-0.0059 Å °0.0018 Å °0.085 Å °0.0505 Å °-0.0374 Å °0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA287 - 872
2X-RAY DIFFRACTION1allM1 - 410
3X-RAY DIFFRACTION1allB1 - 3
4X-RAY DIFFRACTION1allZ1
5X-RAY DIFFRACTION1allY1 - 3

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