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- PDB-5enn: The crystal structure of Human VPS34 in complex with a selective ... -

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Basic information

Entry
Database: PDB / ID: 5enn
TitleThe crystal structure of Human VPS34 in complex with a selective and potent inhibitor
ComponentsPhosphatidylinositol 3-kinase catalytic subunit type 3
KeywordsTransferase/Transferase Inhibitor / VPS34 / 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 / Translation of Replicase and Assembly of the Replication Transcription Complex / phagophore assembly site / autolysosome / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / Macroautophagy / 1-phosphatidylinositol-3-kinase activity / axoneme / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / 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 / macroautophagy / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / autophagy / endocytosis / phagocytic vesicle membrane / peroxisome / late endosome / kinase activity / Translation of Replicase and Assembly of the Replication Transcription Complex / midbody / protein kinase activity / endosome / cell cycle / phosphorylation / cell division / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP binding / membrane / cytoplasm / cytosol
Similarity search - Function
Phosphatidylinositol 3-kinase, Vps34 type / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / 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. ...Phosphatidylinositol 3-kinase, Vps34 type / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / 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 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Armadillo-type fold / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-5QS / Phosphatidylinositol 3-kinase catalytic subunit type 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsKearney, E.P.
CitationJournal: To Be Published
Title: Potent, selective, and orally bioavailable inhibitors of VPS34 provide chemical tools to modulate autophagy in vivo
Authors: Kearney, E.P.
History
DepositionNov 9, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 16, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)144,7078
Polymers143,6902
Non-polymers1,0176
Water5,026279
1
A: Phosphatidylinositol 3-kinase catalytic subunit type 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,2603
Polymers71,8451
Non-polymers4142
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)72,4485
Polymers71,8451
Non-polymers6034
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)113.726, 114.481, 143.903
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 71845.047 Da / Num. of mol.: 2 / Fragment: UNP residues 293-887
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3C3, VPS34 / Production host: unidentified baculovirus / References: UniProt: Q8NEB9, phosphatidylinositol 3-kinase

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Non-polymers , 5 types, 285 molecules

#2: Chemical ChemComp-5QS / 1-[[4-(cyclopropylmethyl)-5-[2-(pyridin-4-ylamino)pyrimidin-4-yl]pyrimidin-2-yl]amino]-2-methyl-propan-2-ol


Mass: 391.470 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H25N7O
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 279 / Source method: isolated from a natural source / Formula: H2O

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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: 3.26 Å3/Da / Density % sol: 62.27 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 200nL:200nL well to protein 0.2M Sodium Acetate 0.1M HEPES 7.5 20% PEG 3000
Temp details: 20% ethylene glycol and 80% well solution used as cryo-protectant

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 10, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.55→48.01 Å / Num. obs: 61540 / % possible obs: 99.6 % / Redundancy: 4.8 % / Biso Wilson estimate: 74.01 Å2 / Net I/σ(I): 15.1
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2.55-2.6950.572.54436888970.7690.28299.4
8.07-48.014.60.02334956921030.9990.01298.6

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
Aimlessdata scaling
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→48.01 Å / Cor.coef. Fo:Fc: 0.9488 / Cor.coef. Fo:Fc free: 0.9329 / SU R Cruickshank DPI: 0.34 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.343 / SU Rfree Blow DPI: 0.221 / SU Rfree Cruickshank DPI: 0.223
RfactorNum. reflection% reflectionSelection details
Rfree0.2007 2615 5.03 %RANDOM
Rwork0.1735 ---
obs0.1749 51995 99.5 %-
Displacement parametersBiso mean: 73.98 Å2
Baniso -1Baniso -2Baniso -3
1--0.881 Å20 Å20 Å2
2--1.4693 Å20 Å2
3----0.5883 Å2
Refine analyzeLuzzati coordinate error obs: 0.316 Å
Refinement stepCycle: LAST / Resolution: 2.7→48.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8473 0 71 279 8823
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018721HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1211810HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3120SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes238HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1272HARMONIC5
X-RAY DIFFRACTIONt_it8721HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.69
X-RAY DIFFRACTIONt_other_torsion18.62
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1113SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact10371SEMIHARMONIC4
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2562 166 4.36 %
Rwork0.2143 3644 -
all0.2163 3810 -
obs--99.92 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.6787-0.5545-0.68242.6568-0.95562.949-0.1947-0.10560.17760.44690.1437-0.43430.05940.50650.051-0.19930.0868-0.0071-0.2443-0.0326-0.2759-19.6368-13.79364.4511
22.59470.31161.82631.50640.91824.0612-0.05190.26290.3231-0.0864-0.0312-0.0825-0.5780.0570.0831-0.20650.0510.0066-0.3244-0.0368-0.2703-42.17459.64831.2272
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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