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- PDB-7bi2: PI3KC2aDeltaN and DeltaC-C2 -

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Entry
Database: PDB / ID: 7bi2
TitlePI3KC2aDeltaN and DeltaC-C2
ComponentsPhosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha,Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha
KeywordsTRANSFERASE / PI3KC2 alpha / kinase
Function / homology
Function and homology information


negative regulation of zinc ion transmembrane transport / Synthesis of PIPs at the early endosome membrane / Synthesis of PIPs at the late endosome membrane / Synthesis of PIPs at the Golgi membrane / Synthesis of PIPs at the plasma membrane / autophagosome organization / Golgi Associated Vesicle Biogenesis / phosphatidylinositol-4-phosphate 3-kinase / Clathrin-mediated endocytosis / 1-phosphatidylinositol-4-phosphate 3-kinase activity ...negative regulation of zinc ion transmembrane transport / Synthesis of PIPs at the early endosome membrane / Synthesis of PIPs at the late endosome membrane / Synthesis of PIPs at the Golgi membrane / Synthesis of PIPs at the plasma membrane / autophagosome organization / Golgi Associated Vesicle Biogenesis / phosphatidylinositol-4-phosphate 3-kinase / Clathrin-mediated endocytosis / 1-phosphatidylinositol-4-phosphate 3-kinase activity / phosphatidylinositol-3-phosphate biosynthetic process / clathrin-coated vesicle / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / clathrin binding / exocytosis / phosphatidylinositol binding / cellular response to starvation / macroautophagy / trans-Golgi network / endocytosis / vesicle / ATP binding / nucleus / plasma membrane / cytoplasm
Similarity search - Function
PI3K-C2-alpha, catalytic domain / Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha, PX domain / PhoX homologous domain, present in p47phox and p40phox. / PX domain profile. / PX domain / Phox homology / PX domain superfamily / Phosphatidylinositol 3-kinase, accessory domain (PIK) / PI3-kinase family, Ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain ...PI3K-C2-alpha, catalytic domain / Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha, PX domain / PhoX homologous domain, present in p47phox and p40phox. / PX domain profile. / PX domain / Phox homology / PX domain superfamily / Phosphatidylinositol 3-kinase, accessory domain (PIK) / PI3-kinase family, Ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain / PI3-kinase family, ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain profile. / 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 / C2 domain / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Protein kinase C conserved region 2 (CalB) / C2 domain / C2 domain / C2 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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / C2 domain superfamily / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Ubiquitin-like (UB roll) / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Roll / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-17G / IODIDE ION / Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.25 Å
AuthorsLo, W.T. / Roske, Y. / Daumke, O. / Haucke, V.
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: Structural basis of phosphatidylinositol 3-kinase C2α function.
Authors: Wen-Ting Lo / Yingyi Zhang / Oscar Vadas / Yvette Roske / Federico Gulluni / Maria Chiara De Santis / Andreja Vujicic Zagar / Heike Stephanowitz / Emilio Hirsch / Fan Liu / Oliver Daumke / ...Authors: Wen-Ting Lo / Yingyi Zhang / Oscar Vadas / Yvette Roske / Federico Gulluni / Maria Chiara De Santis / Andreja Vujicic Zagar / Heike Stephanowitz / Emilio Hirsch / Fan Liu / Oliver Daumke / Misha Kudryashev / Volker Haucke /
Abstract: Phosphatidylinositol 3-kinase type 2α (PI3KC2α) is an essential member of the structurally unresolved class II PI3K family with crucial functions in lipid signaling, endocytosis, angiogenesis, ...Phosphatidylinositol 3-kinase type 2α (PI3KC2α) is an essential member of the structurally unresolved class II PI3K family with crucial functions in lipid signaling, endocytosis, angiogenesis, viral replication, platelet formation and a role in mitosis. The molecular basis of these activities of PI3KC2α is poorly understood. Here, we report high-resolution crystal structures as well as a 4.4-Å cryogenic-electron microscopic (cryo-EM) structure of PI3KC2α in active and inactive conformations. We unravel a coincident mechanism of lipid-induced activation of PI3KC2α at membranes that involves large-scale repositioning of its Ras-binding and lipid-binding distal Phox-homology and C-C2 domains, and can serve as a model for the entire class II PI3K family. Moreover, we describe a PI3KC2α-specific helical bundle domain that underlies its scaffolding function at the mitotic spindle. Our results advance our understanding of PI3K biology and pave the way for the development of specific inhibitors of class II PI3K function with wide applications in biomedicine.
History
DepositionJan 12, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 9, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2022Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 30, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Apr 27, 2022Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.4Jan 31, 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 4-phosphate 3-kinase C2 domain-containing subunit alpha,Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,4918
Polymers131,3621
Non-polymers1,1297
Water34219
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area990 Å2
ΔGint1 kcal/mol
Surface area49900 Å2
Unit cell
Length a, b, c (Å)82.557, 115.887, 144.365
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha,Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha / PtdIns-3-kinase C2 subunit alpha / Cpk-m / Phosphoinositide 3-kinase-C2-alpha / p170


Mass: 131361.906 Da / Num. of mol.: 1 / Mutation: 533-544/GSGS
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Pik3c2a, Cpk / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q61194, phosphatidylinositol-4-phosphate 3-kinase
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-17G / 9-(6-aminopyridin-3-yl)-1-[3-(trifluoromethyl)phenyl]benzo[h][1,6]naphthyridin-2(1H)-one


Mass: 432.397 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H15F3N4O
#4: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: I
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 19 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.63 Å3/Da / Density % sol: 53.21 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1MTris, 8% PEG20000, 10% ethylene glycol, 10% formamide

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 12, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 3.25→49.2 Å / Num. obs: 22257 / % possible obs: 99.1 % / Redundancy: 4.9 % / CC1/2: 0.998 / Rrim(I) all: 0.152 / Net I/σ(I): 9.73
Reflection shellResolution: 3.25→3.45 Å / Redundancy: 4.9 % / Mean I/σ(I) obs: 0.84 / Num. unique obs: 3455 / CC1/2: 0.443 / Rrim(I) all: 2.294 / % possible all: 97.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1E8X, 2IWL

1e8x

2iwl


Resolution: 3.25→49.2 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.889 / SU B: 110.025 / SU ML: 0.748 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.647 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.3118 1113 5 %RANDOM
Rwork0.2664 ---
obs0.2687 21143 99.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 545.73 Å2 / Biso mean: 137.09 Å2 / Biso min: 72.4 Å2
Baniso -1Baniso -2Baniso -3
1--2.34 Å2-0 Å20 Å2
2--4.7 Å2-0 Å2
3----2.37 Å2
Refinement stepCycle: final / Resolution: 3.25→49.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8219 0 41 19 8279
Biso mean--231.63 139.07 -
Num. residues----1021
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0138437
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177962
X-RAY DIFFRACTIONr_angle_refined_deg1.1661.6411412
X-RAY DIFFRACTIONr_angle_other_deg1.0851.57418475
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.58251008
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.47922.642424
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.626151515
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.2461545
X-RAY DIFFRACTIONr_chiral_restr0.040.21092
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.029173
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021756
LS refinement shellResolution: 3.25→3.334 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.356 76 -
Rwork0.415 1450 -
all-1526 -
obs--94.43 %
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)
12.0344-0.42011.09070.4664-1.10772.9628-0.0688-0.2928-0.1648-0.03310.26480.1062-0.0548-0.2393-0.1960.62710.05640.0880.55970.13610.0512-21.363-7.3072-7.7284
21.4838-0.96840.81490.6414-0.57971.41010.31840.0642-0.1226-0.2223-0.0040.1023-0.03330.2215-0.31440.6264-0.1350.09860.37310.03130.1152-41.238416.9354-46.9942
31.55940.08350.39940.9874-0.74421.2393-0.0084-0.01760.12890.111-0.0819-0.046-0.33660.01020.09030.64790.03720.06160.24340.06130.0386-12.04769.9377-20.5694
40.7101-0.3849-0.5591.8275-0.98561.56540.6142-0.375-0.1497-0.35670.0820.9274-0.38120.4515-0.69620.755-0.1966-0.26990.8756-0.01320.588814.689118.4438-63.6121
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 147
2X-RAY DIFFRACTION2A148 - 538
3X-RAY DIFFRACTION3A539 - 981
4X-RAY DIFFRACTION4A982 - 1157

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