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- PDB-4dk5: Crystal structure of human PI3K-gamma in complex with a pyridyl-t... -

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Basic information

Entry
Database: PDB / ID: 4dk5
TitleCrystal structure of human PI3K-gamma in complex with a pyridyl-triazine inhibitor
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTransferase/Inhibitor / phosphotransferase / cancer / p85-alpha / p85-beta / Ras / 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 / regulation of calcium ion transmembrane transport / T cell chemotaxis ...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 / regulation of calcium ion transmembrane transport / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / 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 / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / mast cell degranulation / 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-mediated signaling / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / phosphorylation / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / ephrin receptor binding / neutrophil chemotaxis / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of endothelial cell migration / T cell activation / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / kinase activity / phospholipase C-activating G protein-coupled receptor signaling pathway / 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 / inflammatory response / immune response / G protein-coupled receptor signaling pathway / innate immune response / protein serine kinase activity / protein serine/threonine 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-/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-0KO / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsWhittington, D.A. / Tang, J. / Yakowec, P.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Structure-based design of a novel series of potent, selective inhibitors of the class I phosphatidylinositol 3-kinases.
Authors: Smith, A.L. / D'Angelo, N.D. / Bo, Y.Y. / Booker, S.K. / Cee, V.J. / Herberich, B. / Hong, F.T. / Jackson, C.L. / Lanman, B.A. / Liu, L. / Nishimura, N. / Pettus, L.H. / Reed, A.B. / ...Authors: Smith, A.L. / D'Angelo, N.D. / Bo, Y.Y. / Booker, S.K. / Cee, V.J. / Herberich, B. / Hong, F.T. / Jackson, C.L. / Lanman, B.A. / Liu, L. / Nishimura, N. / Pettus, L.H. / Reed, A.B. / Tadesse, S. / Tamayo, N.A. / Wurz, R.P. / Yang, K. / Andrews, K.L. / Whittington, D.A. / McCarter, J.D. / Miguel, T.S. / Zalameda, L. / Jiang, J. / Subramanian, R. / Mullady, E.L. / Caenepeel, S. / Freeman, D.J. / Wang, L. / Zhang, N. / Wu, T. / Hughes, P.E. / Norman, M.H.
History
DepositionFeb 3, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 16, 2012Provider: repository / Type: Initial release
Revision 1.1Aug 1, 2012Group: Database references
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)110,5415
Polymers109,7671
Non-polymers7744
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)143.775, 68.233, 107.182
Angle α, β, γ (deg.)90.000, 94.990, 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: 109767.000 Da / Num. of mol.: 1 / Fragment: catalytic domain, UNP residues 114-1102
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


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-0KO / 4-(2-[(6-methoxypyridin-3-yl)amino]-5-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine


Mass: 485.563 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27N9O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / 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: 2.39 Å3/Da / Density % sol: 48.44 %
Crystal growTemperature: 273 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 21% polyethylene glycol 3350, 100 mM Tris, 245 mM ammonium sulfate, 1 mM DTT, 2 mM EDTA, pH 7.3, VAPOR DIFFUSION, HANGING DROP, temperature 273K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 7, 2009
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.95→50 Å / Num. all: 22189 / Num. obs: 22145 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 3.4 % / Rmerge(I) obs: 0.075 / Χ2: 1.096 / Net I/σ(I): 10.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.95-3.063.30.73721860.957199.6
3.06-3.183.40.57521910.979199.8
3.18-3.323.50.3822101.0061100
3.32-3.53.50.24121971.0491100
3.5-3.723.50.14721911.0221100
3.72-43.50.09422421.0441100
4-4.413.50.06721891.1241100
4.41-5.043.50.05822231.2161100
5.04-6.353.40.06822381.296199.9
6.35-503.30.02622781.259198.9

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
HKL-2000data reduction
HKL-2000data scaling
EPMRphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1E8Y

1e8y


Resolution: 2.95→50 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.874 / WRfactor Rfree: 0.3013 / WRfactor Rwork: 0.2239 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7968 / SU B: 43.851 / SU ML: 0.39 / SU R Cruickshank DPI: 0.4015 / SU Rfree: 0.5213 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.506 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2891 1584 7.2 %RANDOM
Rwork0.2188 ---
obs0.2239 21966 99.62 %-
all-22050 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 177.67 Å2 / Biso mean: 87.3493 Å2 / Biso min: 40.56 Å2
Baniso -1Baniso -2Baniso -3
1--1.85 Å20 Å20.77 Å2
2--2.85 Å20 Å2
3----0.86 Å2
Refinement stepCycle: LAST / Resolution: 2.95→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6757 0 49 14 6820
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0226950
X-RAY DIFFRACTIONr_angle_refined_deg1.0021.9669404
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1675824
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.75824.317322
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.067151258
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3271540
X-RAY DIFFRACTIONr_chiral_restr0.0670.21057
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025141
X-RAY DIFFRACTIONr_nbd_refined0.1940.23071
X-RAY DIFFRACTIONr_nbtor_refined0.3020.24710
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1330.2199
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1270.228
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0680.22
X-RAY DIFFRACTIONr_mcbond_it0.52124265
X-RAY DIFFRACTIONr_mcangle_it0.93736747
X-RAY DIFFRACTIONr_scbond_it0.65733033
X-RAY DIFFRACTIONr_scangle_it1.0714.52657
LS refinement shellResolution: 2.95→3.026 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.33 102 -
Rwork0.266 1452 -
all-1554 -
obs--97.98 %
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)
15.7549-0.6153-0.28431.1264-0.29382.5877-0.06180.0281-1.37410.00810.21940.42530.1922-0.5009-0.1576-0.2276-0.0064-0.0072-0.27040.09950.089221.3871-14.388828.0077
24.2687-1.30390.43553.41942.39198.27760.1147-0.5609-1.05880.08810.53780.38720.0425-0.8694-0.6525-0.3501-0.09160.0832-0.0050.30710.190812.5597-12.511631.6954
33.10860.3632-1.60354.0404-2.28044.4060.0790.1661-0.08670.1111-0.0116-0.1512-0.23590.4269-0.0674-0.23270.03620.04440.2134-0.1208-0.178766.5871-5.428514.8342
43.9652-0.1067-0.34844.5095-1.20862.7886-0.0280.6406-0.17140.01860.0143-0.0487-0.08460.36250.0137-0.19160.05570.0330.2223-0.1277-0.227757.0587-7.818713.6528
54.1135-0.53452.1060.2313-0.10442.15360.0084-0.1465-0.39610.01540.0410.13230.00690.0756-0.0493-0.03710.02630.0256-0.14010.0314-0.020445.9888-9.949234.244
63.3808-1.35350.51222.1457-0.4622.06750.05020.5264-0.0686-0.05140.06410.211-0.3262-0.1583-0.1143-0.08050.09110.003-0.02830.0623-0.088220.24485.061117.6521
75.3242-1.9381.54752.7882-0.64312.0262-0.7443-0.49180.81840.47940.3124-0.2657-0.6554-0.1440.43180.22990.1838-0.1384-0.2207-0.1607-0.044929.52719.4737.7785
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A144 - 250
2X-RAY DIFFRACTION2A269 - 321
3X-RAY DIFFRACTION3A352 - 436
4X-RAY DIFFRACTION4A457 - 532
5X-RAY DIFFRACTION5A547 - 725
6X-RAY DIFFRACTION6A726 - 885
7X-RAY DIFFRACTION7A886 - 1088

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