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- PDB-7bi4: PI3KC2a core apo -

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Basic information

Entry
Database: PDB / ID: 7bi4
TitlePI3KC2a core apo
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 / phosphatidylinositol 3-kinase complex ...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 / phosphatidylinositol 3-kinase complex / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / clathrin-coated vesicle / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / clathrin binding / positive regulation of cell migration involved in sprouting angiogenesis / exocytosis / positive regulation of autophagy / cellular response to starvation / phosphatidylinositol binding / phosphatidylinositol 3-kinase/protein kinase B signal transduction / macroautophagy / trans-Golgi network / endocytosis / vesicle / phosphorylation / intracellular membrane-bounded organelle / nucleoplasm / ATP binding / plasma membrane / cytosol / 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 / PI3-kinase family, Ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain / PI3-kinase family, ras-binding 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 / 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. / 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. / C2 domain / Protein kinase C conserved region 2 (CalB) / 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 / C2 domain superfamily / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
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: 2.42 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

Downloads & links

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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)102,7064
Polymers102,4861
Non-polymers2203
Water1,53185
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area650 Å2
ΔGint-4 kcal/mol
Surface area37280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)135.193, 151.570, 56.044
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: 102486.023 Da / Num. of mol.: 1 / Mutation: 533-544/GSGS;550-665/SGAGSGA; F735A;F736A;L809A
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 / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 18.015 Da / Num. of mol.: 85 / 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: 2.8 Å3/Da / Density % sol: 56.09 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.5 / Details: 0.1MTris, 8-6% PEG3350, 0.2-0.1M MgSO4

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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: Jan 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.42→45.06 Å / Num. obs: 44453 / % possible obs: 99.8 % / Redundancy: 4.4 % / CC1/2: 0.998 / Rrim(I) all: 0.122 / Net I/σ(I): 10.55
Reflection shellResolution: 2.42→2.51 Å / Num. unique obs: 6969 / CC1/2: 0.279 / % possible all: 97.4

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7BI2

7bi2


Resolution: 2.42→45.06 Å / SU ML: 0.53 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 34.79 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2768 2100 4.73 %
Rwork0.2293 42342 -
obs0.2316 44442 98.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 152.25 Å2 / Biso mean: 71.6442 Å2 / Biso min: 30 Å2
Refinement stepCycle: final / Resolution: 2.42→45.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6546 0 13 85 6644
Biso mean--101.83 61.92 -
Num. residues----822
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.42-2.470.4271300.43952630276094
2.47-2.530.45361400.387428192959100
2.53-2.60.431380.377527982936100
2.6-2.680.39131390.33932800293999
2.68-2.770.37841400.322528072947100
2.77-2.860.38611410.302628412982100
2.86-2.980.33431390.292228072946100
2.98-3.110.38241410.29732838297999
3.11-3.280.31511380.27042784292299
3.28-3.480.2911400.2432842298299
3.48-3.750.27511420.22392857299999
3.75-4.130.2571400.19432826296699
4.13-4.730.2391420.17252858300098
4.73-5.950.21151420.19292873301598
5.96-45.060.22141480.18982962311096

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