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- PDB-4f1s: Crystal structure of human PI3K-gamma in complex with a pyridyl-t... -

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Basic information

Entry
Database: PDB / ID: 4f1s
TitleCrystal structure of human PI3K-gamma in complex with a pyridyl-triazine-sulfonamide inhibitor
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTransferase/Inhibitor / phosphotransferase / lipid kinase / p85 / Transferase-Inhibitor complex
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 / 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 / phosphatidylinositol 3-kinase / dendritic cell chemotaxis / 1-phosphatidylinositol-3-kinase activity / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / hepatocyte apoptotic process / phosphatidylinositol-mediated signaling / 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 / regulation of angiogenesis / T cell proliferation / GPVI-mediated activation cascade / cellular response to cAMP / ephrin receptor binding / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of endothelial cell migration / neutrophil chemotaxis / positive regulation of MAP kinase activity / T cell activation / positive regulation of cytokine production / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / positive regulation of cytosolic calcium ion concentration / 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / histone H3T11 kinase activity / histone H3T45 kinase activity / 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-F1S / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / difference Fourier / Resolution: 3 Å
AuthorsWhittington, D.A. / Tang, J. / Yakowec, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold.
Authors: Wurz, R.P. / Liu, L. / Yang, K. / Nishimura, N. / Bo, Y. / Pettus, L.H. / Caenepeel, S. / Freeman, D.J. / McCarter, J.D. / Mullady, E.L. / Miguel, T.S. / Wang, L. / Zhang, N. / Andrews, K.L. ...Authors: Wurz, R.P. / Liu, L. / Yang, K. / Nishimura, N. / Bo, Y. / Pettus, L.H. / Caenepeel, S. / Freeman, D.J. / McCarter, J.D. / Mullady, E.L. / Miguel, T.S. / Wang, L. / Zhang, N. / Andrews, K.L. / Whittington, D.A. / Jiang, J. / Subramanian, R. / Hughes, P.E. / Norman, M.H.
History
DepositionMay 7, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 8, 2012Provider: repository / Type: Initial release
Revision 1.1Sep 5, 2012Group: Database references
Revision 1.2Feb 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)110,8918
Polymers109,8241
Non-polymers1,0677
Water41423
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)146.701, 69.079, 107.623
Angle α, β, γ (deg.)90.000, 94.870, 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: p110 catalytic domain, UNP 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) / Strain (production host): Sf9
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-F1S / N-(5-{[3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl]amino}-2-chloropyridin-3-yl)methanesulfonamide


Mass: 490.966 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23ClN8O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 2.47 Å3/Da / Density % sol: 50.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 20% PEG 3350, 100 mM Tris, 250 mM ammonium sulfate, 2 mM dithiothreitol, pH 7.3, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jan 15, 2010
RadiationMonochromator: Double-crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. all: 21730 / Num. obs: 21187 / % possible obs: 97.5 % / Observed criterion σ(I): -3 / Redundancy: 3.6 % / Biso Wilson estimate: 88.6 Å2 / Rmerge(I) obs: 0.085 / Χ2: 1.062 / Net I/σ(I): 11.22
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2% possible all
3-3.112.60.452.317581.03182
3.11-3.2330.3553.420331.12694.5
3.23-3.383.40.2625.221311.05498.8
3.38-3.563.70.1997.121331.07399.6
3.56-3.783.80.1439.521621.13799.9
3.78-4.073.80.10711.621891.11799.8
4.07-4.483.80.08514.221641.182100
4.48-5.133.80.06715.821650.99799.9
5.13-6.463.80.06315.821980.909100
6.46-503.70.03627.222540.994100

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
REFMACphasing
RefinementMethod to determine structure: difference Fourier / Resolution: 3→41.58 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.896 / WRfactor Rfree: 0.2574 / WRfactor Rwork: 0.1854 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7987 / SU B: 45.051 / SU ML: 0.378 / SU R Cruickshank DPI: 0.3451 / SU Rfree: 0.4798 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.48 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS, U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2649 1268 6 %RANDOM
Rwork0.1918 ---
obs0.1964 21185 97.42 %-
all-21746 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 133.45 Å2 / Biso mean: 65.8402 Å2 / Biso min: 29.08 Å2
Baniso -1Baniso -2Baniso -3
1--0.55 Å20 Å21.35 Å2
2--0.84 Å20 Å2
3----0.05 Å2
Refinement stepCycle: LAST / Resolution: 3→41.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6761 0 63 23 6847
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.026965
X-RAY DIFFRACTIONr_bond_other_d0.0010.024757
X-RAY DIFFRACTIONr_angle_refined_deg1.0061.9689426
X-RAY DIFFRACTIONr_angle_other_deg0.805311592
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6685823
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.98124.317322
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.821151259
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6381540
X-RAY DIFFRACTIONr_chiral_restr0.0570.21062
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0217514
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021389
LS refinement shellResolution: 3→3.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.474 68 -
Rwork0.336 1126 -
all-1194 -
obs--78.45 %
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)
12.5788-0.4194-0.0360.7511-0.08541.06530.07720.0236-0.7190.0430.1140.34760.012-0.1726-0.19120.1266-0.00560.03030.07670.06890.323222.2144-13.831729.5202
21.4448-1.057-0.251.1057-0.67883.14560.0916-0.2239-0.50380.06340.34330.6052-0.1307-0.4164-0.43490.08560.01920.08180.23520.19290.394114.2446-12.833531.6069
31.0722-0.0432-0.72512.7092-1.85122.41890.04950.03150.05490.0170.011-0.1265-0.02370.2357-0.06050.1319-0.02070.01620.3708-0.07040.091968.1481-6.277715.204
42.0344-0.2970.47631.2185-0.89630.7349-0.0260.4223-0.10730.0250.11440.074-0.02760.0717-0.08840.20920.03680.04210.3272-0.0810.11258.2291-9.042414.2794
51.8476-0.24730.82890.12020.07521.06880.0299-0.0488-0.18280.00830.04390.0718-0.05540.0998-0.07380.25030.0220.0010.16610.02370.171847.147-10.202834.9433
61.8891-0.65790.14330.8238-0.19730.71420.14430.36720.020.0501-0.04860.1742-0.2492-0.1478-0.09570.22950.12150.01780.26470.09570.147320.7824.852917.5527
71.12450.1410.0631.1361-0.22640.7479-0.1072-0.12410.25670.34370.0770.0542-0.32570.01230.03020.45750.12040.07120.1044-0.03570.143230.934320.215737.2228
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A147 - 248
2X-RAY DIFFRACTION2A269 - 323
3X-RAY DIFFRACTION3A352 - 436
4X-RAY DIFFRACTION4A457 - 533
5X-RAY DIFFRACTION5A545 - 725
6X-RAY DIFFRACTION6A726 - 885
7X-RAY DIFFRACTION7A886 - 1091

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