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- PDB-5kae: Crystal structure of human PI3K-gamma in complex with quinoline-c... -

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Basic information

Entry
Database: PDB / ID: 5kae
TitleCrystal structure of human PI3K-gamma in complex with quinoline-containing inhibitor 5g
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTransferase/Transferase Inhibitor / phosphotransferase / inhibitor / inflammatory disease / Transferase-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-6RF / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.65 Å
AuthorsWhittington, D.A. / Tang, J. / Yakowec, P.
CitationJournal: To Be Published
Title: Discovery and in vivo evaluation of the potent and selective PI3K-delta inhibitors AM-0687 and AM-1430
Authors: Gonzalez-Lopez de Turiso, F. / Hao, X. / Shin, Y. / Bui, M. / Campuzano, I. / Cardozo, M. / Dunn, M.C. / Duquette, J. / Fisher, B. / Foti, R.S. / Henne, K. / He, X. / Hu, Y.-L. / Kelly, R.C. ...Authors: Gonzalez-Lopez de Turiso, F. / Hao, X. / Shin, Y. / Bui, M. / Campuzano, I. / Cardozo, M. / Dunn, M.C. / Duquette, J. / Fisher, B. / Foti, R.S. / Henne, K. / He, X. / Hu, Y.-L. / Kelly, R.C. / Johnson, M.G. / Lucas, B.S. / McCarter, J. / McGee, L.R. / Medina, J.C. / Metz, D. / San Miguel, T. / Mohn, D. / Tran, T. / Vissinga, C. / Wannberg, S. / Whittington, D.A. / Whoriskey, J. / Yu, G. / Zalameda, L. / Zhang, X. / Cushing, T.D.
History
DepositionJun 1, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 21, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)110,5525
Polymers109,7671
Non-polymers7854
Water97354
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)143.578, 67.661, 106.197
Angle α, β, γ (deg.)90.000, 95.050, 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 / PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / p110gamma / Phosphoinositide-3-kinase catalytic gamma polypeptide / Serine/threonine protein kinase PIK3CG / p120-PI3K


Mass: 109767.000 Da / Num. of mol.: 1 / Fragment: 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)
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-6RF / 4-azanyl-6-[[(1~{S})-1-(6-fluoranyl-3-phenyl-4-piperazin-1-ylcarbonyl-quinolin-2-yl)ethyl]amino]pyrimidine-5-carbonitrile


Mass: 496.539 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H25FN8O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 54 / 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: 2.34 Å3/Da / Density % sol: 47.45 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.3
Details: 20% PEG 3350, 250 mM ammonium sulfate, 100 mM Tris (pH 7.3), 2 mM dithiothreitol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jan 15, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.65→50 Å / Num. obs: 28948 / % possible obs: 97.3 % / Observed criterion σ(I): -3 / Redundancy: 3.6 % / Biso Wilson estimate: 73.2 Å2 / Rmerge(I) obs: 0.053 / Net I/av σ(I): 20.3 / Net I/σ(I): 13.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
2.65-2.742.50.4212.5180
2.74-2.853.10.336193.4
2.85-2.983.50.242199.6
2.98-3.143.70.1841100
3.14-3.343.80.1171100
3.34-3.63.80.0731100
3.6-3.963.80.0531100
3.96-4.533.80.0441100
4.53-5.713.80.0391100
5.71-503.70.033199.9

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.6.0117refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4WWN

4wwn


Resolution: 2.65→45 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.931 / SU B: 27.415 / SU ML: 0.276 / SU R Cruickshank DPI: 0.305 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.346
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2519 1699 5.9 %RANDOM
Rwork0.2007 ---
obs0.2039 27245 97.27 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 202.41 Å2 / Biso mean: 66.35 Å2 / Biso min: 28.87 Å2
Baniso -1Baniso -2Baniso -3
1--2.11 Å20 Å20.47 Å2
2--3.12 Å20 Å2
3----0.93 Å2
Refinement stepCycle: final / Resolution: 2.65→45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6802 0 52 54 6908
Biso mean--63.57 54.18 -
Num. residues----840
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.027000
X-RAY DIFFRACTIONr_bond_other_d0.0010.024790
X-RAY DIFFRACTIONr_angle_refined_deg1.1821.9679472
X-RAY DIFFRACTIONr_angle_other_deg0.8193.00111665
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0865830
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.54324.224322
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.256151266
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5681541
X-RAY DIFFRACTIONr_chiral_restr0.0650.21068
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0217570
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021400
LS refinement shellResolution: 2.65→2.719 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.402 91 -
Rwork0.322 1496 -
all-1587 -
obs--75.86 %
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)
17.5592-0.33770.62861.9303-0.21933.66440.1278-0.2774-1.70430.11420.19920.79640.1729-1.0517-0.3270.28210.0054-0.03230.34840.2110.771721.1206-14.073828.2955
23.7554-0.46921.03884.68452.93399.97070.2665-0.7606-1.1571-0.06830.32660.74060.0607-1.2927-0.59310.1991-0.05430.07550.76670.39880.965312.7899-12.488431.0519
34.3232.1104-1.43645.7081-2.49547.4382-0.020.58520.1184-0.15470.0265-0.4887-0.19481.1296-0.00650.19860.03260.0770.9812-0.12780.253166.5737-5.464614.7858
49.4282-0.86550.64625.4835-1.30986.89820.11171.4505-0.3544-0.16-0.0489-0.3207-0.08541.0483-0.06280.17390.02880.06780.9713-0.25680.121156.8079-7.666113.506
57.4399-0.70954.20770.9011-0.23164.48110.2026-0.2917-0.7730.19480.11920.13530.14720.1663-0.32180.22140.04260.05890.1319-0.00980.239446.2235-10.215134.2486
65.553-1.09011.94543.023-0.34453.1997-0.04010.7949-0.0924-0.37480.13630.4955-0.538-0.489-0.09620.37070.11780.01040.42590.01510.293520.37375.300817.398
77.3897-3.31382.81715.0458-0.98492.8971-1.099-0.83111.5950.77760.4602-0.42-1.2474-0.45670.63890.90630.3173-0.18920.3282-0.22290.468929.675219.617837.0095
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A147 - 250
2X-RAY DIFFRACTION2A269 - 321
3X-RAY DIFFRACTION3A352 - 436
4X-RAY DIFFRACTION4A457 - 532
5X-RAY DIFFRACTION5A543 - 725
6X-RAY DIFFRACTION6A726 - 885
7X-RAY DIFFRACTION7A886 - 1092

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