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- PDB-1e7u: Structure determinants of phosphoinositide 3-kinase inhibition by... -

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Basic information

Entry
Database: PDB / ID: 1e7u
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 / WORTMANNIN
Function / homology
Function and homology information


phosphatidylinositol-4-phosphate 3-kinase / phosphatidylinositol 3-kinase complex, class IB / phosphatidylinositol 3-kinase complex, class IA / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / immune system process ...phosphatidylinositol-4-phosphate 3-kinase / phosphatidylinositol 3-kinase complex, class IB / phosphatidylinositol 3-kinase complex, class IA / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / immune system process / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / phosphatidylinositol 3-kinase/protein kinase B signal transduction / endocytosis / chemotaxis / phospholipase C-activating G protein-coupled receptor signaling pathway / angiogenesis / 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-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / C2 domain / 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. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / 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
Chem-KWT / 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 Å
AuthorsWalker, E.H. / Perisic, O. / Ried, C. / Stephens, L. / 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
DepositionSep 8, 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 / Derived calculations / Other / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_database_status / pdbx_entity_nonpoly / pdbx_initial_refinement_model / struct_conn
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_leaving_atom_flag

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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)110,3812
Polymers109,9531
Non-polymers4281
Water2,954164
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)145.327, 67.664, 106.650
Angle α, β, γ (deg.)90.00, 95.05, 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 / PI 3K


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: WORTMANNIN / 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-KWT / (1S,6BR,9AS,11R,11BR)-9A,11B-DIMETHYL-1-[(METHYLOXY)METHYL]-3,6,9-TRIOXO-1,6,6B,7,8,9,9A,10,11,11B-DECAHYDRO-3H-FURO[4, 3,2-DE]INDENO[4,5-H][2]BENZOPYRAN-11-YL ACETATE / [1S-(1A,6BA,9AB,11A,11BB)]-11-(ACETYLOXY)-1,6B,7,8,9A,10,11,11B-OCTAHYDRO-1-(METHOXYMETHLY) -9A,11B-DIMETHYL-3H-FURO[4,3,2-DE]INDENL[4,5-H]-2-BENZOPYRAN-3,6,9,TRIONE / WORTMANNIN


Mass: 428.432 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24O8 / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 164 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsFUTHER DATA COLLECTION AND REFINEMENT AFTER THE ORIGINAL DEPOSITION OF 1QMM SUGGESTED A REGISTER ...FUTHER DATA COLLECTION AND REFINEMENT AFTER THE ORIGINAL DEPOSITION OF 1QMM SUGGESTED A REGISTER SHIFT IN THE ELECTRON DENSITY IN THE RAS BINDING DOMAIN. THEREFORE THE ELECTRON DENSITY THAT USED TO CORRESPOND TO RESIDUES 231 TO 256 NOW CORRESPONDS TO RESIDUES 228 TO 253. 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: 2.796 Å3/Da / Density % sol: 56.96 %
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→72.38 Å / Num. obs: 68705 / % possible obs: 97.4 % / Observed criterion σ(I): 0 / Redundancy: 3.3 % / Biso Wilson estimate: 30.8 Å2 / Rmerge(I) obs: 0.083 / Net I/σ(I): 16.01
Reflection shellResolution: 2→2.11 Å / Redundancy: 3 % / Mean I/σ(I) obs: 1.6 / Rsym value: 0.575 / % possible all: 94.2
Reflection
*PLUS
Num. measured all: 227525
Reflection shell
*PLUS
Rmerge(I) obs: 94.2 / Mean I/σ(I) obs: 1.1

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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→72.38 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 2435589.98 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.298 2686 3.9 %RANDOM
Rwork0.254 ---
obs0.254 68048 94.3 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 44.0509 Å2 / ksol: 0.341002 e/Å3
Displacement parametersBiso mean: 49.9 Å2
Baniso -1Baniso -2Baniso -3
1--0.46 Å20 Å21.89 Å2
2--1.8 Å20 Å2
3----1.34 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.38 Å0.31 Å
Luzzati d res low-5 Å
Luzzati sigma a0.3 Å0.27 Å
Refinement stepCycle: LAST / Resolution: 2→72.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7054 0 31 164 7249
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
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_deg1.1
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d21.7
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.8
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.4481.5
X-RAY DIFFRACTIONc_mcangle_it2.0322
X-RAY DIFFRACTIONc_scbond_it2.282
X-RAY DIFFRACTIONc_scangle_it2.9512.5
LS refinement shellResolution: 2→2.13 Å / Rfactor Rfree error: 0.014 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.341 565 5.2 %
Rwork0.316 10312 -
obs--94.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2KWT.PARKWT.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_deg21.7
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.8

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