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- PDB-4wwn: Crystal structure of human PI3K-gamma in complex with (S)-N-(1-(7... -

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Basic information

Entry
Database: PDB / ID: 4wwn
TitleCrystal structure of human PI3K-gamma in complex with (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine AMG319 inhibitor
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 / 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 / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / phosphorylation / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / neutrophil chemotaxis / ephrin receptor binding / 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-3VC / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.7 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)110,3454
Polymers109,7671
Non-polymers5783
Water70339
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area370 Å2
ΔGint-26 kcal/mol
Surface area35880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)143.873, 68.213, 106.690
Angle α, β, γ (deg.)90.000, 94.810, 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.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-3VC / N-{(1S)-1-[7-fluoro-2-(pyridin-2-yl)quinolin-3-yl]ethyl}-9H-purin-6-amine


Mass: 385.397 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16FN7 / Comment: anticancer, antiinflammatory, inhibitor*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / 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: 2.38 Å3/Da / Density % sol: 48.24 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 21% PEG 3350, 100 mM Tris (pH 7.3), 245 mM ammonium sulfate, 1 mM dithiothreitol, 1 mM EDTA

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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: May 19, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.7→30 Å / Num. all: 28575 / Num. obs: 27232 / % possible obs: 95.3 % / Observed criterion σ(I): -3 / Redundancy: 2.4 % / Biso Wilson estimate: 83.6 Å2 / Rmerge(I) obs: 0.076 / Χ2: 1.598 / Net I/av σ(I): 15.06 / Net I/σ(I): 16 / Num. measured all: 64610
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.7-2.82.20.39927281.20296.4
2.8-2.912.40.32327661.26298.2
2.91-3.042.40.24428471.24898.8
3.04-3.22.40.18527801.39598.4
3.2-3.42.40.13527831.5698.5
3.4-3.662.40.10127911.79897.9
3.66-4.032.40.0827181.78695.2
4.03-4.612.30.06625691.64189.7
4.61-5.82.30.05926131.55891
5.8-302.40.0526372.54689.4

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Processing

Software
NameVersionClassification
CrystalCleardata collection
DENZOdata reduction
PDB_EXTRACT3.15data extraction
SCALEPACKdata scaling
REFMACrefinement
RefinementResolution: 2.7→30 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.898 / WRfactor Rfree: 0.3098 / WRfactor Rwork: 0.2286 / FOM work R set: 0.7779 / SU B: 32.607 / SU ML: 0.316 / SU R Cruickshank DPI: 0.3627 / SU Rfree: 0.4244 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.424 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2907 1951 7.2 %RANDOM
Rwork0.216 25280 --
obs0.2213 27231 95.21 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 166.83 Å2 / Biso mean: 71.3 Å2 / Biso min: 39.1 Å2
Baniso -1Baniso -2Baniso -3
1--3.05 Å20 Å20.06 Å2
2--2.55 Å20 Å2
3---0.52 Å2
Refinement stepCycle: final / Resolution: 2.7→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6729 0 39 39 6807
Biso mean--69.84 64.05 -
Num. residues----831
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.026913
X-RAY DIFFRACTIONr_bond_other_d0.0010.024727
X-RAY DIFFRACTIONr_angle_refined_deg1.1391.9659355
X-RAY DIFFRACTIONr_angle_other_deg0.821311524
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9835821
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.11624.33321
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.153151252
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7721540
X-RAY DIFFRACTIONr_chiral_restr0.0620.21053
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0217490
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021377
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.427 142 -
Rwork0.289 1775 -
all-1917 -
obs--95.61 %
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)
14.60650.6292-0.3091.626-0.43792.01160.1120.1923-0.76510.05050.0570.64280.0932-0.6261-0.1690.30630.0329-0.02050.32180.09430.595423.1757-13.879927.826
21.18750.52890.91242.9781.80236.65520.201-0.2849-0.51060.10470.31160.6145-0.0128-0.7456-0.51260.2418-0.00580.07540.59810.2620.726313.0058-11.867332.3165
32.77070.7473-1.37195.3046-2.3416.67690.13420.24930.1423-0.1287-0.0536-0.4187-0.19090.5709-0.08060.18490.02220.06020.5761-0.07760.187866.8007-6.364815.2389
47.2903-0.1472-0.68896.997-1.73685.13070.02960.6103-0.1316-0.00610.0716-0.46570.07970.3343-0.10120.23690.03130.03220.444-0.12940.076757.3304-9.059814.2145
55.0142-0.23882.67150.74510.08443.19160.1005-0.3017-0.390.15870.06180.06740.06440.118-0.16230.18290.05870.06060.16250.03210.142546.2439-9.98234.6023
64.5775-0.71731.63273.06050.35242.47230.03780.8259-0.0238-0.51530.0360.5059-0.4446-0.2944-0.07380.36170.13040.01610.42960.0860.265520.72025.034317.6387
74.6986-1.77931.57734.3406-0.74452.4145-0.4034-0.42961.03810.45570.2327-0.0188-0.8747-0.2210.17070.6390.15990.03490.3084-0.07520.354530.257319.878236.9995
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A144 - 244
2X-RAY DIFFRACTION2A269 - 321
3X-RAY DIFFRACTION3A351 - 436
4X-RAY DIFFRACTION4A457 - 533
5X-RAY DIFFRACTION5A546 - 725
6X-RAY DIFFRACTION6A726 - 885
7X-RAY DIFFRACTION7A886 - 1088

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