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- PDB-7z74: PI3KC2a core in complex with PITCOIN2 -

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Basic information

Entry
Database: PDB / ID: 7z74
TitlePI3KC2a core in complex with PITCOIN2
ComponentsPhosphatidylinositol 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 / clathrin-coated vesicle / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / clathrin binding / 1-phosphatidylinositol-3-kinase activity / 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
Chem-IKC / 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: 2.5 Å
AuthorsLo, W.T. / Roske, Y. / Daumke, O. / Haucke, V.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat.Chem.Biol. / Year: 2023
Title: Development of selective inhibitors of phosphatidylinositol 3-kinase C2 alpha.
Authors: Lo, W.T. / Belabed, H. / Kucukdisli, M. / Metag, J. / Roske, Y. / Prokofeva, P. / Ohashi, Y. / Horatscheck, A. / Cirillo, D. / Krauss, M. / Schmied, C. / Neuenschwander, M. / von Kries, J.P. ...Authors: Lo, W.T. / Belabed, H. / Kucukdisli, M. / Metag, J. / Roske, Y. / Prokofeva, P. / Ohashi, Y. / Horatscheck, A. / Cirillo, D. / Krauss, M. / Schmied, C. / Neuenschwander, M. / von Kries, J.P. / Medard, G. / Kuster, B. / Perisic, O. / Williams, R.L. / Daumke, O. / Payrastre, B. / Severin, S. / Nazare, M. / Haucke, V.
History
DepositionMar 15, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 31, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 28, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 11, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.3Jan 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,3137
Polymers102,4861
Non-polymers8276
Water1,33374
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.309, 135.151, 151.916
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 / PI3K-C2-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 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, phosphatidylinositol-4-phosphate 3-kinase
#2: Chemical ChemComp-IKC / ~{N}-[4-(3-hydroxyphenyl)-1,3-thiazol-2-yl]-2-[4-oxidanylidene-3-(2-phenylethyl)pteridin-2-yl]sulfanyl-ethanamide


Mass: 516.595 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H20N6O3S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 74 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.82 Å3/Da / Density % sol: 56.5 %
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: Apr 7, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.5→43.26 Å / Num. obs: 41035 / % possible obs: 99.67 % / Redundancy: 5.5 % / CC1/2: 0.998 / Net I/σ(I): 9.02
Reflection shellResolution: 2.5→2.589 Å / Num. unique obs: 4007 / CC1/2: 0.172 / % possible all: 99.68

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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: 7BI4

7bi4


Resolution: 2.5→43.26 Å / SU ML: 0.54 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 35.07 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2699 2048 5 %RANDOM
Rwork0.2258 38907 --
obs0.2281 40955 99.66 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 210.34 Å2 / Biso mean: 86.8764 Å2 / Biso min: 30 Å2
Refinement stepCycle: final / Resolution: 2.5→43.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6476 0 56 74 6606
Biso mean--96.86 78.84 -
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 (%)
2.5-2.560.45781350.42912568270399
2.56-2.620.4171320.413325082640100
2.62-2.690.41131350.372925652700100
2.69-2.770.36031350.366125612696100
2.77-2.860.36351350.338825592694100
2.86-2.960.42581360.34225852721100
2.96-3.080.39331340.300625482682100
3.08-3.220.33551360.284525822718100
3.22-3.390.32821370.265125962733100
3.39-3.60.25161360.236425852721100
3.6-3.880.26681360.20625952731100
3.88-4.270.21851380.178526112749100
4.27-4.890.18341380.16312619275799
4.89-6.150.25711390.195726562795100
6.16-43.260.24141460.19092769291599
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)
10.8893-0.1404-0.84092.84161.90793.82020.1929-0.2193-0.080.1070.2092-0.4085-0.01820.8081-0.43340.627-0.021-0.09410.8213-0.1390.635724.4776-1.4694-15.7735
20.79970.14510.5411.58151.38632.98540.04470.0879-0.1268-0.08570.184-0.09980.04220.1267-0.14310.5728-0.00770.04430.52970.04160.45965.0426-16.039-48.8184
31.61130.52150.00433.26441.96731.88140.15820.19160.2011-0.5590.199-0.4534-0.69180.351-0.29920.985-0.06010.21010.8261-0.02950.559716.72790.0692-56.4806
41.6227-0.1266-0.91141.62690.16142.73160.0737-0.183-0.18410.1260.10650.1070.3821-0.1654-0.13410.5934-0.0706-0.10630.5875-0.0220.43995.3258-8.6008-25.2712
52.55710.7367-0.69683.7557-0.33653.51040.262-0.42160.39430.58-0.11610.7488-0.4145-0.54020.05990.68410.01940.1130.7326-0.04680.6256-8.080313.7001-15.498
61.0157-0.9212-0.63193.86572.06043.01260.33320.18490.1482-0.7571-0.33080.3502-0.7754-0.51350.02790.77560.0131-0.02140.6201-0.02660.529-4.413516.7523-31.7212
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 3 through 117 )A3 - 117
2X-RAY DIFFRACTION2chain 'A' and (resid 118 through 412 )A118 - 412
3X-RAY DIFFRACTION3chain 'A' and (resid 413 through 570 )A413 - 570
4X-RAY DIFFRACTION4chain 'A' and (resid 571 through 795 )A571 - 795
5X-RAY DIFFRACTION5chain 'A' and (resid 796 through 864 )A796 - 864
6X-RAY DIFFRACTION6chain 'A' and (resid 865 through 1006 )A865 - 1006

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