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- PDB-6bty: Crystal structure of the PI3KC2alpha C2 domain in space group P41212 -

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Basic information

Entry
Database: PDB / ID: 6bty
TitleCrystal structure of the PI3KC2alpha C2 domain in space group P41212
ComponentsPhosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha
KeywordsTRANSFERASE / C2 domain / lipid binding / phosphoinositide / PI3-kinase
Function / homology
Function and homology information


vascular associated smooth muscle contraction / Synthesis of PIPs at the late endosome membrane / Synthesis of PIPs at the early endosome membrane / phosphatidylinositol-4-phosphate 3-kinase / Synthesis of PIPs at the Golgi membrane / clathrin coat assembly / phosphatidylinositol biosynthetic process / membrane organization / 1-phosphatidylinositol-4-phosphate 3-kinase activity / phosphatidylinositol-3-phosphate biosynthetic process ...vascular associated smooth muscle contraction / Synthesis of PIPs at the late endosome membrane / Synthesis of PIPs at the early endosome membrane / phosphatidylinositol-4-phosphate 3-kinase / Synthesis of PIPs at the Golgi membrane / clathrin coat assembly / phosphatidylinositol biosynthetic process / membrane organization / 1-phosphatidylinositol-4-phosphate 3-kinase activity / phosphatidylinositol-3-phosphate biosynthetic process / clathrin-coated vesicle / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / positive regulation of cell migration involved in sprouting angiogenesis / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / clathrin binding / Golgi Associated Vesicle Biogenesis / phosphatidylinositol-mediated signaling / platelet-derived growth factor receptor signaling pathway / Synthesis of PIPs at the plasma membrane / exocytosis / positive regulation of autophagy / phosphatidylinositol binding / phosphatidylinositol 3-kinase/protein kinase B signal transduction / trans-Golgi network / epidermal growth factor receptor signaling pathway / endocytosis / insulin receptor signaling pathway / cell migration / Clathrin-mediated endocytosis / vesicle / intracellular membrane-bounded organelle / extracellular exosome / nucleoplasm / ATP binding / membrane / plasma membrane / cytoplasm / cytosol
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. / 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 / C2 domain superfamily / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
1,4,7,10,13,16-HEXAOXACYCLOOCTADECANE / Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.678 Å
AuthorsChen, K.-E. / Collins, B.M.
CitationJournal: Structure / Year: 2018
Title: Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2α.
Authors: Kai-En Chen / Vikas A Tillu / Mintu Chandra / Brett M Collins /
Abstract: Phosphorylation of phosphoinositides by the class II phosphatidylinositol 3-kinase (PI3K) PI3K-C2α is essential for many processes, including neuroexocytosis and formation of clathrin-coated ...Phosphorylation of phosphoinositides by the class II phosphatidylinositol 3-kinase (PI3K) PI3K-C2α is essential for many processes, including neuroexocytosis and formation of clathrin-coated vesicles. A defining feature of the class II PI3Ks is a C-terminal module composed of phox-homology (PX) and C2 membrane interacting domains; however, the mechanisms that control their specific cellular localization remain poorly understood. Here we report the crystal structure of the C2 domain of PI3K-C2α in complex with the phosphoinositide head-group mimic inositol hexaphosphate, revealing two distinct pockets for membrane binding. The C2 domain preferentially binds to phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate, and low-resolution structures of the combined PX-C2 module by small-angle X-ray scattering reveal a compact conformation in which cooperative lipid binding by each domain binding can occur. Finally, we demonstrate an unexpected role for calcium in perturbing the membrane interactions of the PX-C2 module, which we speculate may be important for regulating the activity of PI3K-C2α.
History
DepositionDec 8, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 17, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 19, 2018Group: Data collection / Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.2Oct 4, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
B: Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,1533
Polymers29,8882
Non-polymers2641
Water3,315184
1
A: Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha


Theoretical massNumber of molelcules
Total (without water)14,9441
Polymers14,9441
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,2082
Polymers14,9441
Non-polymers2641
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.062, 53.062, 199.794
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11A-1797-

HOH

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Components

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


Mass: 14944.179 Da / Num. of mol.: 2 / Fragment: C2 domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3C2A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: O00443, phosphatidylinositol-4-phosphate 3-kinase
#2: Chemical ChemComp-O4B / 1,4,7,10,13,16-HEXAOXACYCLOOCTADECANE


Mass: 264.315 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H24O6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 184 / 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: 2.35 Å3/Da / Density % sol: 47.72 % / Mosaicity: 0.12 °
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.68→46.86 Å / Num. obs: 33617 / % possible obs: 99.3 % / Redundancy: 6.4 % / Biso Wilson estimate: 23.56 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.025 / Rrim(I) all: 0.064 / Net I/σ(I): 13 / Num. measured all: 215571
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.68-1.716.10.4711007016400.890.2020.5142.895.1
9.04-46.863.90.0426191600.9980.0210.04717.850.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å46.86 Å
Translation2.5 Å46.86 Å

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Processing

Software
NameVersionClassificationNB
PHENIX(phenix.refine: 1.8.4_1496)refinement
XDSdata reduction
Aimless0.5.25data scaling
PHASER2.3.0phasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2B3R

2b3r


Resolution: 1.678→37.521 Å / FOM work R set: 0.8488 / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 21.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2284 2000 5.97 %
Rwork0.1951 31518 -
obs0.1971 33518 99.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 59.56 Å2 / Biso mean: 25.8 Å2 / Biso min: 10.72 Å2
Refinement stepCycle: final / Resolution: 1.678→37.521 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2012 0 18 184 2214
Biso mean--42.27 31.8 -
Num. residues----250
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072102
X-RAY DIFFRACTIONf_angle_d1.152825
X-RAY DIFFRACTIONf_chiral_restr0.046321
X-RAY DIFFRACTIONf_plane_restr0.005351
X-RAY DIFFRACTIONf_dihedral_angle_d14.589821
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6783-1.72020.2931360.23742141227796
1.7202-1.76670.25921410.21122272368100
1.7667-1.81870.26121400.205622012341100
1.8187-1.87740.25871420.205722482390100
1.8774-1.94450.24041410.207922112352100
1.9445-2.02240.2441430.222482391100
2.0224-2.11440.27711420.19922392381100
2.1144-2.22590.22841410.19922422383100
2.2259-2.36530.25831430.212822482391100
2.3653-2.54790.26041440.211222732417100
2.5479-2.80420.24931460.226722782424100
2.8042-3.20980.27441430.20342278242199
3.2098-4.04330.19061490.17432341249099
4.0433-37.52990.18231490.17522343249293

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