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- PDB-4fjy: Crystal structure of PI3K-gamma in complex with quinoline-indolin... -

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Basic information

Entry
Database: PDB / ID: 4fjy
TitleCrystal structure of PI3K-gamma in complex with quinoline-indoline inhibitor 24f
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTransferase/Inhibitor / inflammation / cancer / p110 / C2 domain / leukocytes / kinase / p85 / phosphotransferase / Transferase-Inhibitor complex
Function / homology
Function and homology information


secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / regulation of calcium ion transmembrane transport / 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 ...secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / regulation of calcium ion transmembrane transport / 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 / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / dendritic cell chemotaxis / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / hepatocyte apoptotic process / positive regulation of Rac protein signal transduction / regulation of cell adhesion mediated by integrin / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / ephrin receptor binding / T cell activation / neutrophil chemotaxis / positive regulation of endothelial cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / Signaling by CSF1 (M-CSF) in myeloid cells / kinase activity / positive regulation of cytosolic calcium ion concentration / angiogenesis / adaptive immune response / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / protein kinase activity / immune response / inflammatory response / G protein-coupled receptor signaling pathway / phosphorylation / protein serine kinase activity / innate immune response / protein serine/threonine kinase activity / ATP binding / membrane / identical protein binding / plasma membrane / cytosol / 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. / 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. / 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
Chem-FJY / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.9 Å
AuthorsWhittington, D.A. / Tang, J. / Yakowec, P.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery and in Vivo Evaluation of Dual PI3K-beta/delta inhibitors
Authors: Gonzalez-Lopez de Turiso, F. / Shin, Y. / Brown, M. / Cardozo, M. / Chen, Y. / Fong, D. / Hao, X. / He, X. / Henne, K. / Hu, Y.L. / Johnson, M.G. / Kohn, T. / Lohman, J. / McBride, H.J. / ...Authors: Gonzalez-Lopez de Turiso, F. / Shin, Y. / Brown, M. / Cardozo, M. / Chen, Y. / Fong, D. / Hao, X. / He, X. / Henne, K. / Hu, Y.L. / Johnson, M.G. / Kohn, T. / Lohman, J. / McBride, H.J. / McGee, L.R. / Medina, J.C. / Metz, D. / Miner, K. / Mohn, D. / Pattaropong, V. / Seganish, J. / Simard, J.L. / Wannberg, S. / Whittington, D.A. / Yu, G. / Cushing, T.D.
History
DepositionJun 12, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 24, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)110,5815
Polymers109,8241
Non-polymers7574
Water23413
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.223, 67.711, 106.772
Angle α, β, γ (deg.)90.000, 95.080, 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 / PI3-kinase subunit gamma / PI3K-gamma / PI3Kgamma / PtdIns-3-kinase subunit gamma / ...PI3-kinase subunit gamma / PI3K-gamma / PI3Kgamma / PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / PtdIns-3-kinase subunit p110-gamma / p110gamma / Phosphoinositide-3-kinase catalytic gamma polypeptide / Serine/threonine protein kinase PIK3CG / p120-PI3K


Mass: 109824.055 Da / Num. of mol.: 1 / Fragment: catalytic domain, UNP residues 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-FJY / 4-[3,3-dimethyl-6-(morpholin-4-yl)-2,3-dihydro-1H-indol-1-yl]-7-fluoro-3-methyl-2-(pyridin-3-yl)quinoline


Mass: 468.565 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H29FN4O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 13 / 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: 2.36 Å3/Da / Density % sol: 47.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 22% PEG 3350, 250 mM ammonium sulfate, 10 mM EDTA, 100 mM Tris, pH 7.3, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jun 11, 2008 / Details: Varimax HR
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.9→30 Å / Num. all: 23009 / Num. obs: 22917 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 3.3 % / Biso Wilson estimate: 99.7 Å2 / Rmerge(I) obs: 0.071 / Χ2: 1.309 / Net I/σ(I): 16.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.9-32.90.56322341.381198.2
3-3.123.20.47922951.279199.8
3.12-3.273.40.33222661.2581100
3.27-3.443.40.21722811.291199.9
3.44-3.653.40.13923001.295199.9
3.65-3.933.40.09822621.3261100
3.93-4.333.40.07323071.2751100
4.33-4.953.40.05923081.242199.6
4.95-6.233.40.05723101.206199.8
6.23-303.30.04123541.548199.2

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
DENZOdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.9→30 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.913 / WRfactor Rfree: 0.2853 / WRfactor Rwork: 0.2009 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7994 / SU B: 41.619 / SU ML: 0.37 / SU R Cruickshank DPI: 0.3755 / SU Rfree: 0.4645 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.465 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2745 1661 7.2 %RANDOM
Rwork0.197 ---
obs0.2026 22913 99.5 %-
all-23028 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 226.91 Å2 / Biso mean: 101.7433 Å2 / Biso min: 49.3 Å2
Baniso -1Baniso -2Baniso -3
1--1.1 Å20 Å21.8 Å2
2--2.61 Å20 Å2
3----1.19 Å2
Refinement stepCycle: LAST / Resolution: 2.9→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6795 0 50 13 6858
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.026990
X-RAY DIFFRACTIONr_angle_refined_deg1.1451.9679462
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6445829
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.83724.338325
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.682151265
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2231541
X-RAY DIFFRACTIONr_chiral_restr0.0770.21065
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0215183
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.348 113 -
Rwork0.282 1469 -
all-1582 -
obs--97.71 %
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)
18.1184-0.37340.36562.4106-0.59653.25970.28860.1326-1.61440.04230.09920.94380.1499-0.7324-0.38770.2291-0.0093-0.06850.21150.0970.745122.664-13.945727.2018
24.8834-3.90761.07745.68462.410410.02420.3531-0.7203-1.3007-0.16150.43430.8218-0.1068-1.5137-0.78740.1988-0.09120.10250.74470.47020.995112.648-12.282431.5899
34.34552.2968-2.69725.6032-4.05018.11480.22960.25530.1288-0.3153-0.0279-0.2899-0.0880.8374-0.20170.20190.0770.08220.6747-0.15550.221666.7406-5.6414.8804
48.8963-0.168-0.16756.51490.60286.02470.10261.0101-0.32030.12130.3261-0.4114-0.19150.4507-0.42860.25290.12490.0790.5988-0.17310.130657.1671-7.820813.6767
57.0665-1.0523.87730.5595-0.20234.50980.1917-0.3584-0.71920.10710.10420.10540.0670.118-0.2960.15110.00180.04390.06350.05420.217446.2334-10.01534.3202
66.1637-1.27562.62193.9646-0.61154.2247-0.12730.84850.1056-0.55690.12430.5726-0.6523-0.32660.0030.31520.0857-0.00690.29640.06380.29620.56945.348817.4677
77.8601-2.11653.02995.1729-0.97423.0978-1.0176-0.88991.72280.71530.4301-0.3-1.2681-0.44750.58740.85040.2819-0.1520.2265-0.20290.440529.880819.32337.4508
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A144 - 245
2X-RAY DIFFRACTION2A269 - 321
3X-RAY DIFFRACTION3A351 - 436
4X-RAY DIFFRACTION4A457 - 532
5X-RAY DIFFRACTION5A546 - 725
6X-RAY DIFFRACTION6A726 - 885
7X-RAY DIFFRACTION7A886 - 1088

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