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- PDB-1e8w: Structure determinants of phosphoinositide 3-kinase inhibition by... -

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Basic information

Entry
Database: PDB / ID: 1e8w
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 / QUERCETIN
Function / homology
Function and homology information


phosphatidylinositol-4-phosphate 3-kinase / phosphatidylinositol 3-kinase complex, class IB / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 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 / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / phosphatidylinositol-mediated signaling ...phosphatidylinositol-4-phosphate 3-kinase / phosphatidylinositol 3-kinase complex, class IB / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 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 / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / immune system process / phosphatidylinositol 3-kinase/protein kinase B signal transduction / endocytosis / chemotaxis / cell migration / angiogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / non-specific serine/threonine protein kinase / inflammatory response / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / plasma membrane / 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 / C2 domain / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical 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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / C2 domain superfamily / 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
3,5,7,3',4'-PENTAHYDROXYFLAVONE / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesSUS SCROFA (pig)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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 1.3Oct 24, 2018Group: Data collection / Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.gene_src_strain / _entity_src_gen.pdbx_host_org_strain
Revision 1.4Dec 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,2552
Polymers109,9531
Non-polymers3021
Water00
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)144.162, 67.435, 106.701
Angle α, β, γ (deg.)90.00, 95.87, 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: 109952.555 Da / Num. of mol.: 1 / Fragment: PI3-KINASE P110 SUBUNIT GAMMA / Mutation: YES
Source method: isolated from a genetically manipulated source
Details: QUERCETIN / Source: (gene. exp.) SUS SCROFA (pig) / Cell: NEUTROPHIL / Gene: P120S144C / Plasmid: PACHLT-C / Gene (production host): P120S144C / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): Sf9 / References: UniProt: O02697, phosphatidylinositol 3-kinase
#2: Chemical ChemComp-QUE / 3,5,7,3',4'-PENTAHYDROXYFLAVONE / QUERCETIN


Mass: 302.236 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H10O7
Sequence detailsTHE NATIVE PROTEIN WAS MUTATED BY DELETION OF RESIDUES 1-143. THE RESIDUE 143 LISTED HERE IS FROM ...THE NATIVE PROTEIN WAS MUTATED BY DELETION OF RESIDUES 1-143. THE RESIDUE 143 LISTED HERE IS FROM THE HIS-TAG, AFTER THROMBIN CLEAVAGE. ALSO RESEQUENCING OF THE ORIGINAL CLONE SHOWED THAT RESIDUE 505 IS REALLY ALA, NOT ARG AS REPORTED IN THE SWS DATABASE.

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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: 2.829 Å3/Da / Density % sol: 54.85 %
Crystal growpH: 7.25 / Details: 14% PEG 4000, 0.2 M LI2SO4, 0.1 M TRIS PH 7.25
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: Sep 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: 2.5→62.45 Å / Num. obs: 34614 / % possible obs: 97.5 % / Observed criterion σ(I): 0 / Redundancy: 3.37 % / Biso Wilson estimate: 57.3 Å2 / Rmerge(I) obs: 0.059 / Net I/σ(I): 22.55
Reflection shellResolution: 2.5→2.64 Å / Redundancy: 2.9 % / Mean I/σ(I) obs: 2.51 / Rsym value: 0.397 / % possible all: 83.1
Reflection
*PLUS
Num. measured all: 116715
Reflection shell
*PLUS
% possible obs: 83.1 %

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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: 2.5→62.45 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 1791131.55 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.33 1706 4.9 %RANDOM
Rwork0.265 ---
obs0.265 34614 98.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 49.5134 Å2 / ksol: 0.337475 e/Å3
Displacement parametersBiso mean: 68.2 Å2
Baniso -1Baniso -2Baniso -3
1--11.94 Å20 Å20.57 Å2
2--17.21 Å20 Å2
3----5.27 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.58 Å0.45 Å
Luzzati d res low-5 Å
Luzzati sigma a0.57 Å0.49 Å
Refinement stepCycle: LAST / Resolution: 2.5→62.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6893 0 22 0 6915
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.021
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_deg1.9
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d23.8
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d1.2
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.6671.5
X-RAY DIFFRACTIONc_mcangle_it2.0252
X-RAY DIFFRACTIONc_scbond_it2.8222
X-RAY DIFFRACTIONc_scangle_it2.9932.5
LS refinement shellResolution: 2.5→2.66 Å / Rfactor Rfree error: 0.028 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.416 225 4.5 %
Rwork0.406 4724 -
obs--84.1 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2QUE.PARQUE.TOP
Software
*PLUS
Name: CNS / Version: 1 / Classification: refinement
Refinement
*PLUS
Rfactor Rfree: 0.33
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg23.8
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg1.2

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