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- PDB-5jha: Structure of Phosphoinositide 3-kinase gamma (PI3K) bound to the ... -

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Basic information

Entry
Database: PDB / ID: 5jha
TitleStructure of Phosphoinositide 3-kinase gamma (PI3K) bound to the potent inhibitor PIKin2
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / Inhibitor / Lipid kinase / PI3K
Function / homology
Function and homology information


negative regulation of triglyceride catabolic process / secretory granule localization / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis / regulation of calcium ion transmembrane transport ...negative regulation of triglyceride catabolic process / secretory granule localization / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis / regulation of calcium ion transmembrane transport / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Co-stimulation by ICOS / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / dendritic cell chemotaxis / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / phosphatidylinositol-mediated signaling / hepatocyte apoptotic process / regulation of cell adhesion mediated by integrin / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / positive regulation of Rac protein signal transduction / CD28 dependent PI3K/Akt signaling / regulation of angiogenesis / T cell proliferation / GPVI-mediated activation cascade / cellular response to cAMP / ephrin receptor binding / neutrophil chemotaxis / positive regulation of endothelial cell migration / positive regulation of MAP kinase activity / T cell activation / positive regulation of cytokine production / phosphatidylinositol 3-kinase/protein kinase B signal transduction / platelet aggregation / endocytosis / Constitutive Signaling by Aberrant PI3K in Cancer / G beta:gamma signalling through PI3Kgamma / cell migration / PIP3 activates AKT signaling / positive regulation of cytosolic calcium ion concentration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / phospholipase C-activating G protein-coupled receptor signaling pathway / angiogenesis / adaptive immune response / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / protein kinase activity / immune response / G protein-coupled receptor signaling pathway / inflammatory response / innate immune response / protein serine kinase activity / ATP binding / identical protein binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / PI3-kinase family, Ras-binding domain ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / 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 / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / C2 domain / 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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-6K7 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsBurke, J.E. / Inglis, A.J. / Williams, R.L.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)U105184308 United Kingdom
CitationJournal: Nat Commun / Year: 2017
Title: Deconvolution of Buparlisib's mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention.
Authors: Bohnacker, T. / Prota, A.E. / Beaufils, F. / Burke, J.E. / Melone, A. / Inglis, A.J. / Rageot, D. / Sele, A.M. / Cmiljanovic, V. / Cmiljanovic, N. / Bargsten, K. / Aher, A. / Akhmanova, A. / ...Authors: Bohnacker, T. / Prota, A.E. / Beaufils, F. / Burke, J.E. / Melone, A. / Inglis, A.J. / Rageot, D. / Sele, A.M. / Cmiljanovic, V. / Cmiljanovic, N. / Bargsten, K. / Aher, A. / Akhmanova, A. / Diaz, J.F. / Fabbro, D. / Zvelebil, M. / Williams, R.L. / Steinmetz, M.O. / Wymann, M.P.
History
DepositionApr 20, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Mar 15, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2017Group: Database references
Revision 1.2Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 10, 2024Group: 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
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 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,7416
Polymers109,8981
Non-polymers8435
Water1,26170
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area840 Å2
ΔGint-63 kcal/mol
Surface area35120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.560, 68.040, 106.730
Angle α, β, γ (deg.)90.000, 95.360, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform / PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / p110gamma / Phosphoinositide-3-kinase catalytic gamma polypeptide / Serine/threonine protein kinase PIK3CG / p120-PI3K


Mass: 109898.203 Da / Num. of mol.: 1 / Mutation: Fragment: Residues 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-6K7 / [1-{4-[6-amino-4-(trifluoromethyl)pyridin-3-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}-3-(chloromethyl)azetidin-3-yl]methanol


Mass: 458.865 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22ClF3N6O2
#3: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 70 / 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: 2.38 Å3/Da / Density % sol: 48.27 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 17% PEG 4000, 250 mM (NH4)2SO4, and 100mM Tris pH-7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 21, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.51→61.51 Å / Num. obs: 34660 / % possible obs: 97.8 % / Redundancy: 3.4 % / Biso Wilson estimate: 73.53 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.059 / Rpim(I) all: 0.038 / Rrim(I) all: 0.07 / Net I/σ(I): 17.7 / Num. measured all: 116517
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.51-2.583.50.652198.3
11.23-61.513.10.026188.9

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Processing

Software
NameVersionClassification
Aimless0.1.29data scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3sd5

3sd5


Resolution: 2.51→61.51 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.11
RfactorNum. reflection% reflection
Rfree0.246 1745 5.03 %
Rwork0.2019 --
obs0.2042 34658 97.43 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 228.55 Å2 / Biso mean: 100.9621 Å2 / Biso min: 42.25 Å2
Refinement stepCycle: final / Resolution: 2.51→61.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6531 0 73 70 6674
Biso mean--106.34 74.3 -
Num. residues----803
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0036718
X-RAY DIFFRACTIONf_angle_d0.5319088
X-RAY DIFFRACTIONf_chiral_restr0.0211018
X-RAY DIFFRACTIONf_plane_restr0.0021140
X-RAY DIFFRACTIONf_dihedral_angle_d10.7642492
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.51-2.58390.32351500.28962732288298
2.5839-2.66730.36181280.28162795292398
2.6673-2.76260.33951610.28092707286898
2.7626-2.87320.32531440.28892747289198
2.8732-3.0040.31411380.26062740287898
3.004-3.16240.3251340.25942774290898
3.1624-3.36050.29041220.25232796291898
3.3605-3.61990.27421670.22682745291298
3.6199-3.98420.26151440.19212746289097
3.9842-4.56050.19591480.16722712286096
4.5605-5.74510.2051650.17592706287196
5.7451-61.53130.2241440.17522713285793
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)
12.6696-0.64421.75280.7936-0.67512.70150.25660.4946-0.8708-0.00060.16420.29480.11890.32890.05170.4650.00720.01610.2551-0.08010.693436.5754-28.353123.3205
22.9781-0.99321.07550.9301-0.11971.5910.06090.1714-0.61210.06170.1580.1292-0.17120.54180.00040.5502-0.00950.01750.5758-0.02990.604848.3687-26.327532.5709
34.2349-1.06451.00192.219-0.7210.9146-0.29650.15020.50270.47460.25050.1728-0.5006-0.2245-0.00660.76510.14690.04490.40320.08440.531326.0398-6.007427.3605
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 145 through 483 )A145 - 483
2X-RAY DIFFRACTION2chain 'A' and (resid 484 through 705 )A484 - 705
3X-RAY DIFFRACTION3chain 'A' and (resid 706 through 1088 )A706 - 1088

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