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- PDB-4ph4: The crystal structure of Human VPS34 in complex with PIK-III -

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Basic information

Entry
Database: PDB / ID: 4ph4
TitleThe crystal structure of Human VPS34 in complex with PIK-III
ComponentsPhosphatidylinositol 3-kinase catalytic subunit type 3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / VPS34 / autophagy / class III / phosphatidylinositol-3-kinase / PIK3C3 / 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 / 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 / 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 ...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 / 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 / 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-2UG / Phosphatidylinositol 3-kinase catalytic subunit type 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.8 Å
AuthorsKnapp, M.S. / Elling, R.A.
CitationJournal: Nat.Cell Biol. / Year: 2014
Title: Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo.
Authors: Dowdle, W.E. / Nyfeler, B. / Nagel, J. / Elling, R.A. / Liu, S. / Triantafellow, E. / Menon, S. / Wang, Z. / Honda, A. / Pardee, G. / Cantwell, J. / Luu, C. / Cornella-Taracido, I. / ...Authors: Dowdle, W.E. / Nyfeler, B. / Nagel, J. / Elling, R.A. / Liu, S. / Triantafellow, E. / Menon, S. / Wang, Z. / Honda, A. / Pardee, G. / Cantwell, J. / Luu, C. / Cornella-Taracido, I. / Harrington, E. / Fekkes, P. / Lei, H. / Fang, Q. / Digan, M.E. / Burdick, D. / Powers, A.F. / Helliwell, S.B. / D'Aquin, S. / Bastien, J. / Wang, H. / Wiederschain, D. / Kuerth, J. / Bergman, P. / Schwalb, D. / Thomas, J. / Ugwonali, S. / Harbinski, F. / Tallarico, J. / Wilson, C.J. / Myer, V.E. / Porter, J.A. / Bussiere, D.E. / Finan, P.M. / Labow, M.A. / Mao, X. / Hamann, L.G. / Manning, B.D. / Valdez, R.A. / Nicholson, T. / Schirle, M. / Knapp, M.S. / Keaney, E.P. / Murphy, L.O.
History
DepositionMay 4, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 29, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 5, 2014Group: Database references
Revision 1.2Nov 12, 2014Group: Database references
Revision 1.3Feb 4, 2015Group: Derived calculations
Revision 1.4Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_oper_list / refine_hist / struct_keywords
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein / _struct_keywords.text

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)72,2573
Polymers71,8451
Non-polymers4112
Water1,63991
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)114.532, 114.532, 146.257
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

#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.: 1 / Fragment: UNP residues 293-887
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3C3, VPS34 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8NEB9, phosphatidylinositol 3-kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-2UG / 4'-(cyclopropylmethyl)-N~2~-(pyridin-4-yl)-4,5'-bipyrimidine-2,2'-diamine


Mass: 319.364 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17N7
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 91 / 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: 3.6 Å3/Da / Density % sol: 65.84 %
Crystal growTemperature: 303.15 K / Method: vapor diffusion, hanging drop
Details: VPS34 protein and PIK-III were mixed and incubated on ice for 1 hr (final PIK-III concentration was 1 mM). Prior to crystallization, the mixture was passed through a 0.2 um filter. The ...Details: VPS34 protein and PIK-III were mixed and incubated on ice for 1 hr (final PIK-III concentration was 1 mM). Prior to crystallization, the mixture was passed through a 0.2 um filter. The protein:ligand complex was crystallized using the hanging drop vapor diffusion method in Nextal plates: 6 uL of protein solution was mixed with 4 uL of precipitant, which consisted of 20% (w/v) PEG 3350, 100 mM bis-tris propane, and 200 mM Na-K-phosphate. The resulting drop was suspended over a reservoir of 0.3 mL of precipitant and sealed with a screw cap. The crystals grew at 30 degC in approximately 12-24 hr.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 21, 2009
RadiationMonochromator: Double-crystal, Si(111) liquid N2 cooled / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 1.98→48.75 Å / Num. obs: 29404 / % possible obs: 100 % / Redundancy: 15.4 % / Biso Wilson estimate: 85.63 Å2 / Net I/σ(I): 20.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDSdata reduction
BUSTER-TNTBUSTER 2.11.4refinement
PDB_EXTRACT3.14data extraction
PHASERphasing
BUSTER2.11.4refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→48.34 Å / Cor.coef. Fo:Fc: 0.9466 / Cor.coef. Fo:Fc free: 0.9285 / SU R Cruickshank DPI: 0.423 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.438 / SU Rfree Blow DPI: 0.262 / SU Rfree Cruickshank DPI: 0.263
RfactorNum. reflection% reflectionSelection details
Rfree0.2232 1237 5.03 %RANDOM
Rwork0.1938 ---
obs0.1953 24604 100 %-
Displacement parametersBiso max: 155.58 Å2 / Biso mean: 75.22 Å2 / Biso min: 33.33 Å2
Baniso -1Baniso -2Baniso -3
1--2.0558 Å20 Å20 Å2
2---2.0558 Å20 Å2
3---4.1115 Å2
Refinement stepCycle: final / Resolution: 2.8→48.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4228 0 30 91 4349
Biso mean--56.97 63.37 -
Num. residues----529
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1557SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes121HARMONIC2
X-RAY DIFFRACTIONt_gen_planes639HARMONIC5
X-RAY DIFFRACTIONt_it4365HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion558SEMIHARMONIC5
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_contact5143SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4365HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg5912HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion2.46
X-RAY DIFFRACTIONt_other_torsion19.35
LS refinement shellResolution: 2.8→2.92 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2792 147 5 %
Rwork0.2479 2791 -
all0.2498 2938 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 9.3866 Å / Origin y: 14.1087 Å / Origin z: -22.8495 Å
111213212223313233
T0 Å20 Å20 Å2-0 Å20 Å2--0 Å2
L0 °20 °20 °2-0 °20 °2--0 °2
S0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °0 Å °
Refinement TLS groupSelection details: { B|* }

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