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- PDB-1e8y: Structure determinants of phosphoinositide 3-kinase inhibition by... -

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Basic information

Entry
Database: PDB / ID: 1e8y
TitleStructure determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin and staurosporine
ComponentsPHOSPHATIDYLINOSITOL 3-KINASE CATALYTIC SUBUNIT
KeywordsPHOSPHOINOSITIDE 3-KINASE GAMMA / SECONDARY MESSENGER GENERATION / PI3K / PI 3K
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
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 Å
AuthorsWalker, E.H. / Pacold, M.E. / Perisic, O. / Stephens, L. / Hawkins, P.T. / Wymann, M.P. / Williams, R.L.
Citation
Journal: Mol.Cell / Year: 2000
Title: Structural Determinations of Phosphoinositide 3-Kinase Inhibition by Wortmannin, Ly294002, Quercetin, Myricetin and Staurosporine
Authors: Walker, E.H. / Pacold, M.E. / Perisic, O. / Stephens, L. / Hawkins, P.T. / Whymann, M.P. / Williams, R.L.
#1: Journal: Nature / Year: 1999
Title: Structural Insights Into Phosphoinositide 3-Kinase Catalysis and Signalling
Authors: Walker, E.H. / Perisic, O. / Ried, C. / Stephens, L. / Williams, R.L.
History
DepositionOct 3, 2000Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 17, 2000Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: PHOSPHATIDYLINOSITOL 3-KINASE CATALYTIC SUBUNIT


Theoretical massNumber of molelcules
Total (without water)110,7561
Polymers110,7561
Non-polymers00
Water2,666148
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)139.227, 66.255, 102.642
Angle α, β, γ (deg.)90.00, 97.85, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein PHOSPHATIDYLINOSITOL 3-KINASE CATALYTIC SUBUNIT / PTDINS-3-KINASE P110 / PI3K


Mass: 110756.164 Da / Num. of mol.: 1 / Fragment: PI3-KINASE P110 SUBUNIT GAMMA / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PVL1393 / Gene (production host): H144 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9 / References: UniProt: P48736, phosphatidylinositol 3-kinase
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 148 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE NATIVE PROTEIN WAS MUTATED BY DELETION OF RESIDUES 1-143. A C-TERMINAL 6-HIS TAG WAS ATTACHED ...THE NATIVE PROTEIN WAS MUTATED BY DELETION OF RESIDUES 1-143. A C-TERMINAL 6-HIS TAG WAS ATTACHED AS WAS A N-TERMINAL METHIONINE.

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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: 2.61 Å3/Da / Density % sol: 52.91 %
Crystal growpH: 7.25 / Details: 19% PEG 4000, 0.25 M (NH4)2SO4, 0.1 M TRIS PH 7.2
Crystal grow
*PLUS
Temperature: 17 ℃ / pH: 7.2 / Method: vapor diffusion, hanging drop / Details: used hair seeding
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
10.1 MTris1reservoir
2250 mMammonium sulfate1reservoir
319 %PEG40001reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.93
DetectorType: MARRESEARCH / Detector: CCD / Date: Nov 15, 1999 / Details: BENT MIRROR
RadiationMonochromator: DIAMOND C(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.93 Å / Relative weight: 1
ReflectionResolution: 2→68.96 Å / Num. obs: 58245 / % possible obs: 92.8 % / Observed criterion σ(I): 0 / Redundancy: 3.02 % / Biso Wilson estimate: 21.7 Å2 / Rmerge(I) obs: 0.079 / Net I/σ(I): 16.5
Reflection shellResolution: 2→2.13 Å / Redundancy: 1.6 % / Mean I/σ(I) obs: 2.32 / Rsym value: 0.345 / % possible all: 72.9
Reflection
*PLUS
Num. measured all: 176129
Reflection shell
*PLUS
% possible obs: 72.9 %

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Processing

Software
NameVersionClassification
CNS1refinement
MOSFLMdata reduction
SCALAdata scaling
CNS1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1QMM

1qmm
PDB Unreleased entry


Resolution: 2→68.96 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 2721990.51 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.305 2284 3.9 %RANDOM
Rwork0.245 ---
obs0.245 58196 92.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 54.6281 Å2 / ksol: 0.360018 e/Å3
Displacement parametersBiso mean: 41.8 Å2
Baniso -1Baniso -2Baniso -3
1--7.79 Å20 Å22.09 Å2
2--5.47 Å20 Å2
3---2.32 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.37 Å0.31 Å
Luzzati d res low-5 Å
Luzzati sigma a0.42 Å0.46 Å
Refinement stepCycle: LAST / Resolution: 2→68.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6815 0 0 148 6963
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.016
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d23
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d1.08
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.6371.5
X-RAY DIFFRACTIONc_mcangle_it2.2862
X-RAY DIFFRACTIONc_scbond_it2.7732
X-RAY DIFFRACTIONc_scangle_it3.3852.5
LS refinement shellResolution: 2→2.13 Å / Rfactor Rfree error: 0.018 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.358 393 5.2 %
Rwork0.372 7220 -
obs--73.4 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION4WATER.PARAM
Software
*PLUS
Name: CNS / Version: 1 / Classification: refinement
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg23
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg1.08

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