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- PDB-6xrl: Crystal structure of human PI3K-gamma in complex with inhibitor I... -

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Basic information

Entry
Database: PDB / ID: 6xrl
TitleCrystal structure of human PI3K-gamma in complex with inhibitor IPI-549
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE inhibitor / Phosphoinositide 3-kinase gamma / inhibitor / immunosuppression / cancer / Proteros / TRANSFERASE / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / regulation of calcium ion transmembrane transport / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis ...secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / regulation of calcium ion transmembrane transport / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / 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-kinase complex, class IA / 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 / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / T cell activation / ephrin receptor binding / neutrophil chemotaxis / positive regulation of endothelial cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / Signaling by CSF1 (M-CSF) in myeloid cells / kinase activity / 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 / immune response / inflammatory response / G protein-coupled receptor signaling pathway / phosphorylation / protein serine kinase activity / innate immune response / protein serine/threonine kinase activity / ATP binding / membrane / identical protein binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding 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. / Phosphoinositide 3-kinase C2 / Phosphoinositide 3-kinase, region postulated to contain C2 domain ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding 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. / Phosphoinositide 3-kinase C2 / Phosphoinositide 3-kinase, region postulated to contain C2 domain / C2 phosphatidylinositol 3-kinase-type domain / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / 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 / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-V7Y / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.99 Å
AuthorsWalker, N.P. / Jeffrey, J.L.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of Potent and Selective PI3K gamma Inhibitors.
Authors: Drew, S.L. / Thomas-Tran, R. / Beatty, J.W. / Fournier, J. / Lawson, K.V. / Miles, D.H. / Mata, G. / Sharif, E.U. / Yan, X. / Mailyan, A.K. / Ginn, E. / Chen, J. / Wong, K. / Soni, D. / ...Authors: Drew, S.L. / Thomas-Tran, R. / Beatty, J.W. / Fournier, J. / Lawson, K.V. / Miles, D.H. / Mata, G. / Sharif, E.U. / Yan, X. / Mailyan, A.K. / Ginn, E. / Chen, J. / Wong, K. / Soni, D. / Dhanota, P. / Chen, P.Y. / Shaqfeh, S.G. / Meleza, C. / Pham, A.T. / Chen, A. / Zhao, X. / Banuelos, J. / Jin, L. / Schindler, U. / Walters, M.J. / Young, S.W. / Walker, N.P. / Leleti, M.R. / Powers, J.P. / Jeffrey, J.L.
History
DepositionJul 13, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 16, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 21, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 6, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
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)109,4674
Polymers108,7461
Non-polymers7213
Water724
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)146.368, 68.370, 107.433
Angle α, β, γ (deg.)90.000, 94.520, 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: 108745.875 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-V7Y / 2-amino-N-[(1S)-1-{8-[(1-methyl-1H-pyrazol-4-yl)ethynyl]-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl}ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 528.564 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H24N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.51 Å3/Da / Density % sol: 51.07 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: PEG 4000, (NH4)2SO4, Na Form, Tris / PH range: 6.75-7.75

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99997 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 28, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99997 Å / Relative weight: 1
ReflectionResolution: 2.99→44.93 Å / Num. obs: 21106 / % possible obs: 97.2 % / Redundancy: 2.92 % / Biso Wilson estimate: 79.012 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.046 / Rrim(I) all: 0.057 / Χ2: 0.982 / Net I/σ(I): 18.6 / Num. measured all: 61623 / Scaling rejects: 5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.99-3.242.9640.4352.9813347459945030.8250.53197.9
3.24-3.432.7850.2016.247288268626170.9380.24997.4
3.43-3.792.9680.11810.4410618364335770.9810.14498.2
3.79-4.352.9480.05120.7710418363035340.9960.06297.4
4.35-5.32.9330.0331.529004316230700.9980.03797.1
5.3-6.722.880.0332.045530200819200.9980.03795.6
6.72-8.632.9430.02143.08290510219870.9990.02596.7
8.63-12.592.7930.01755.7816876396040.9990.0294.5
12.59-20.142.850.01660.586472382270.9990.01995.4
20.14-44.932.6720.01755.8217982670.9990.02181.7

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: none

Resolution: 2.99→44.93 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.912 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.466 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2694 494 2.3 %RANDOM
Rwork0.2023 ---
obs0.2038 20560 97.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 304.13 Å2 / Biso mean: 127.957 Å2 / Biso min: 43.9 Å2
Baniso -1Baniso -2Baniso -3
1-3.29 Å2-0 Å21.75 Å2
2---1.9 Å20 Å2
3----1.65 Å2
Refinement stepCycle: final / Resolution: 2.99→44.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6773 0 72 4 6849
Biso mean--79.85 50.53 -
Num. residues----835
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0136775
X-RAY DIFFRACTIONr_bond_other_d0.0350.0176315
X-RAY DIFFRACTIONr_angle_refined_deg1.7121.6449193
X-RAY DIFFRACTIONr_angle_other_deg2.2881.5714553
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3095824
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.57822.576330
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.855151138
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.71535
X-RAY DIFFRACTIONr_chiral_restr0.1160.2900
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.027462
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021410
LS refinement shellResolution: 2.99→3.068 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.512 46 -
Rwork0.349 1490 -
all-1536 -
obs--98.4 %
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)
14.0568-0.15571.07461.4661-0.1452.56840.183-0.0178-0.43450.09920.0345-0.02090.2404-0.0809-0.21750.0544-0.0559-0.04520.1444-0.01460.2241-43.535-12.613-30.347
26.3454-0.88931.1864.5867-0.57666.26010.07850.5002-0.0792-0.4163-0.1152-1.08260.02591.28510.03670.125-0.07140.18180.7295-0.18450.7261-10.068-8.408-40.498
35.2987-0.924-0.71452.11940.63235.13630.0696-0.27990.14020.29370.00870.4266-0.2239-0.6093-0.07840.1882-0.06930.09140.55930.0820.2697-63.49-6.121-14.081
43.22250.07350.90563.5797-0.33842.8884-0.0286-0.21370.48760.19310.1512-0.3702-0.70890.1152-0.12260.226-0.13810.0560.3319-0.14830.3011-27.3413.5-28.347
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A144 - 200
2X-RAY DIFFRACTION1A311 - 322
3X-RAY DIFFRACTION1A543 - 726
4X-RAY DIFFRACTION2A201 - 310
5X-RAY DIFFRACTION3A357 - 530
6X-RAY DIFFRACTION4A727 - 1091

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