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- PDB-6xrn: Crystal structure of human PI3K-gamma in complex with Compound 17 -

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Basic information

Entry
Database: PDB / ID: 6xrn
TitleCrystal structure of human PI3K-gamma in complex with Compound 17
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE inhibitor / Phosphoinositide 3-kinase gamma / inhibitor / AB610 / 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 complex, class IA / 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 / 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 / ephrin receptor binding / T cell activation / 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-V84 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.96 Å
AuthorsWalker, N.P. / Jeffrey, J.L.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Design, Synthesis, and Structure-Activity Relationship Optimization of Pyrazolopyrimidine Amide Inhibitors of Phosphoinositide 3-Kinase gamma (PI3K gamma ).
Authors: Mata, G. / Miles, D.H. / Drew, S.L. / Fournier, J. / Lawson, K.V. / Mailyan, A.K. / Sharif, E.U. / Yan, X. / Beatty, J.W. / Banuelos, J. / Chen, J. / Ginn, E. / Chen, A. / Gerrick, K.Y. / ...Authors: Mata, G. / Miles, D.H. / Drew, S.L. / Fournier, J. / Lawson, K.V. / Mailyan, A.K. / Sharif, E.U. / Yan, X. / Beatty, J.W. / Banuelos, J. / Chen, J. / Ginn, E. / Chen, A. / Gerrick, K.Y. / Pham, A.T. / Wong, K. / Soni, D. / Dhanota, P. / Shaqfeh, S.G. / Meleza, C. / Narasappa, N. / Singh, H. / Zhao, X. / 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 1.0Nov 3, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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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)109,2062
Polymers108,7461
Non-polymers4611
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.205, 68.173, 106.800
Angle α, β, γ (deg.)90.000, 95.260, 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-V84 / 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(trans-3-hydroxycyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 460.528 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H28N6O3 / Feature type: SUBJECT OF INVESTIGATION
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: 2.45 Å3/Da / Density % sol: 49.8 %
Crystal growTemperature: 277 K / Method: small tubes / 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: 1.00002 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 2.96→44.78 Å / Num. obs: 21184 / % possible obs: 97.3 % / Redundancy: 2.871 % / Biso Wilson estimate: 74.071 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.046 / Rrim(I) all: 0.057 / Χ2: 0.975 / Net I/σ(I): 18.51 / Num. measured all: 60822 / Scaling rejects: 6
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
2.96-3.212.7560.4442.6812528463345450.7940.55198.1
3.21-3.542.9840.1736.8212683432242500.9640.2198.3
3.54-4.072.8650.06715.4611967429441770.9930.08397.3
4.07-4.962.9370.03229.8310833378936890.9980.03997.4
4.96-6.282.8120.0330.426371236922660.9980.03795.7
6.28-8.072.9610.02142.143532123111930.9990.02696.9
8.07-11.772.7010.01752.0819187517100.9990.0294.5
11.77-18.842.8120.01756.917482802660.9990.02195
18.84-44.782.750.01457.77242101880.9990.01887.1

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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: 2.96→44.78 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.914 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.451 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2695 531 2.5 %RANDOM
Rwork0.224 ---
obs0.2252 20653 97.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 313.3 Å2 / Biso mean: 129.132 Å2 / Biso min: 39.81 Å2
Baniso -1Baniso -2Baniso -3
1-1.28 Å2-0 Å21.21 Å2
2---1.92 Å2-0 Å2
3---0.41 Å2
Refinement stepCycle: final / Resolution: 2.96→44.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6696 0 59 0 6755
Biso mean--92.85 --
Num. residues----824
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0136514
X-RAY DIFFRACTIONr_bond_other_d0.0360.0176036
X-RAY DIFFRACTIONr_angle_refined_deg1.6641.6458854
X-RAY DIFFRACTIONr_angle_other_deg2.3441.5713864
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4245812
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.01522.896297
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.92315.0341043
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.4731529
X-RAY DIFFRACTIONr_chiral_restr0.1130.2889
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.027211
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021326
LS refinement shellResolution: 2.96→3.037 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.371 40 -
Rwork0.371 1495 -
all-1535 -
obs--98.33 %
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)
14.40090.42541.82091.35760.23592.7870.1960.0037-0.72380.03060.1159-0.16410.273-0.0312-0.3120.115-0.0332-0.01750.1515-0.00650.142525.256-12.67323.625
25.26240.08840.85584.53230.88064.59250.07920.8742-0.4628-0.43840.1956-0.7201-0.03671.4617-0.27470.2993-0.01010.18641.0336-0.35550.582958.988-8.86213.823
36.0548-0.4545-0.47913.18381.27224.29390.0523-0.44470.01550.1526-0.00090.3249-0.0162-0.5979-0.05150.2202-0.0150.05030.60820.160.08745.098-6.15939.287
43.83730.21391.86872.18080.01362.3121-0.40470.05090.7217-0.0320.1765-0.1878-0.87590.24610.22830.5245-0.1355-0.03990.4644-0.01320.305441.44513.09324.922
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A144 - 200
2X-RAY DIFFRACTION1A311 - 321
3X-RAY DIFFRACTION1A544 - 726
4X-RAY DIFFRACTION2A201 - 310
5X-RAY DIFFRACTION3A357 - 530
6X-RAY DIFFRACTION4A727 - 1091

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