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- PDB-4wwp: Crystal structure of human PI3K-gamma in complex with pyridinylqu... -

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Entry
Database: PDB / ID: 4wwp
TitleCrystal structure of human PI3K-gamma in complex with pyridinylquinoline inhibitor N-{(1S)-1-[8-chloro-2-(2-methylpyridin-3-yl)quinolin-3-yl]ethyl}-9H-purin-6-amine
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / phosphotransfer / PIP2 / 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-3VE / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.4 Å
AuthorsWhittington, D.A. / Tang, J. / Yakowec, P.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3K delta Inhibitors for Inflammation and Autoimmune Disease.
Authors: Cushing, T.D. / Hao, X. / Shin, Y. / Andrews, K. / Brown, M. / Cardozo, M. / Chen, Y. / Duquette, J. / Fisher, B. / Gonzalez-Lopez de Turiso, F. / He, X. / Henne, K.R. / Hu, Y.L. / Hungate, ...Authors: Cushing, T.D. / Hao, X. / Shin, Y. / Andrews, K. / Brown, M. / Cardozo, M. / Chen, Y. / Duquette, J. / Fisher, B. / Gonzalez-Lopez de Turiso, F. / He, X. / Henne, K.R. / Hu, Y.L. / Hungate, R. / Johnson, M.G. / Kelly, R.C. / Lucas, B. / McCarter, J.D. / McGee, L.R. / Medina, J.C. / San Miguel, T. / Mohn, D. / Pattaropong, V. / Pettus, L.H. / Reichelt, A. / Rzasa, R.M. / Seganish, J. / Tasker, A.S. / Wahl, R.C. / Wannberg, S. / Whittington, D.A. / Whoriskey, J. / Yu, G. / Zalameda, L. / Zhang, D. / Metz, D.P.
History
DepositionNov 11, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 17, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 28, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list / software / struct_keywords
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _software.classification / _struct_keywords.text
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)110,5636
Polymers109,7671
Non-polymers7965
Water1,67593
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area920 Å2
ΔGint-48 kcal/mol
Surface area35720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)143.013, 67.633, 105.981
Angle α, β, γ (deg.)90.000, 95.270, 90.000
Int Tables number5
Space group name H-MC121
Detailsbiological unit is the same as asym.

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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
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-3VE / N-{(1S)-1-[8-chloro-2-(2-methylpyridin-3-yl)quinolin-3-yl]ethyl}-9H-purin-6-amine


Mass: 415.878 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18ClN7
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 93 / 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: 2.32 Å3/Da / Density % sol: 47.09 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 21% PEG 3350, 100 mM Tris (pH 7.3), 250 mM ammonium sulfate, 1 mM dithiothreitol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.9793 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Oct 29, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.4→30 Å / Num. all: 39658 / Num. obs: 39103 / % possible obs: 98.6 % / Observed criterion σ(I): -3 / Redundancy: 3.8 % / Biso Wilson estimate: 70 Å2 / Rmerge(I) obs: 0.057 / Χ2: 1.073 / Net I/av σ(I): 22.124 / Net I/σ(I): 17.3 / Num. measured all: 148533
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.4-2.493.60.66737811.15696.5
2.49-2.593.80.45938941.11898.7
2.59-2.73.90.33338871.11498.6
2.7-2.853.90.21438831.07399.1
2.85-3.023.90.13639351.04999.3
3.02-3.263.90.08839130.98999
3.26-3.583.80.05939500.94899.3
3.58-4.13.80.04839440.92799.6
4.1-5.163.80.04239780.8699.5
5.16-303.60.04639381.54596.5

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.15data extraction
DENZOdata reduction
REFMACphasing
RefinementResolution: 2.4→30 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.938 / WRfactor Rfree: 0.2841 / WRfactor Rwork: 0.2309 / FOM work R set: 0.814 / SU B: 19.805 / SU ML: 0.217 / SU R Cruickshank DPI: 0.4277 / SU Rfree: 0.2646 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.428 / ESU R Free: 0.265 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.252 1954 5 %RANDOM
Rwork0.2109 37119 --
obs0.213 39073 98.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 196.67 Å2 / Biso mean: 69.7 Å2 / Biso min: 33.51 Å2
Baniso -1Baniso -2Baniso -3
1--1.93 Å20 Å20.28 Å2
2--3.34 Å20 Å2
3----1.36 Å2
Refinement stepCycle: final / Resolution: 2.4→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6649 0 51 93 6793
Biso mean--70.31 62.75 -
Num. residues----820
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.026839
X-RAY DIFFRACTIONr_bond_other_d0.0010.024681
X-RAY DIFFRACTIONr_angle_refined_deg1.1331.9679251
X-RAY DIFFRACTIONr_angle_other_deg0.802311412
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7575810
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.28924.304316
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.844151246
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3981540
X-RAY DIFFRACTIONr_chiral_restr0.0630.21044
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0217387
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021361
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.44 134 -
Rwork0.372 2537 -
all-2671 -
obs--95.84 %
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)
16.2551-0.307-0.61141.9789-0.12093.26850.0547-0.1902-1.18870.14130.10850.78450.1283-0.8947-0.16320.25140.0133-0.06280.33420.17110.641621.9534-13.621128.3319
25.3024-1.2873-1.4264.3462.75839.36170.0985-0.3935-0.96630.03170.17520.87760.0685-1.0151-0.27370.1475-0.0354-0.01250.74590.37760.803413.5025-12.090530.9646
34.14491.6214-1.8836.6528-4.69659.48190.04640.12280.0511-0.2915-0.0246-0.4372-0.08950.8366-0.02180.14760.01570.05460.6086-0.1250.186666.1983-5.684914.8789
48.4705-0.86910.50344.9707-1.22835.88170.130.9968-0.0323-0.3812-0.0476-0.3474-0.23420.4344-0.08250.17630.01820.06490.5968-0.12390.064956.177-5.971312.3412
55.9145-0.86613.05090.7711-0.25633.79440.1229-0.2952-0.6270.14030.11080.12220.05580.0986-0.23360.13170.04130.03410.08560.02480.192445.6342-9.949134.0204
66.0369-1.34692.28163.10020.07992.93510.00720.7451-0.1309-0.36870.09180.5687-0.4901-0.4498-0.0990.31290.1438-0.01810.44150.06530.262420.25385.403617.3374
76.5346-2.47312.32644.8192-0.21373.2258-0.8416-0.80481.52120.58590.3458-0.1514-1.2959-0.49560.49580.83610.2997-0.11140.3109-0.16950.433129.416819.877937.0049
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A148 - 247
2X-RAY DIFFRACTION2A271 - 322
3X-RAY DIFFRACTION3A351 - 437
4X-RAY DIFFRACTION4A457 - 523
5X-RAY DIFFRACTION5A546 - 725
6X-RAY DIFFRACTION6A726 - 885
7X-RAY DIFFRACTION7A886 - 1090

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