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- PDB-6xrm: Crystal structure of human PI3K-gamma in complex with Compound 4 -

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Basic information

Entry
Database: PDB / ID: 6xrm
TitleCrystal structure of human PI3K-gamma in complex with Compound 4
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


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-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 ...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. / 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 3/4-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-V81 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.88 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)109,4194
Polymers108,7461
Non-polymers6743
Water50428
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.711, 68.649, 106.718
Angle α, β, γ (deg.)90.000, 95.380, 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-V81 / 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one


Mass: 481.473 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H22F3N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 28 / 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: 2.43 Å3/Da / Density % sol: 49.31 %
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: 0.999 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: 0.999 Å / Relative weight: 1
ReflectionResolution: 2.88→106.25 Å / Num. obs: 23191 / % possible obs: 97.2 % / Redundancy: 2.915 % / Biso Wilson estimate: 75.538 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.042 / Rrim(I) all: 0.051 / Χ2: 0.978 / Net I/σ(I): 20.8 / Num. measured all: 67612
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
2.88-3.132.9390.4382.9915102522951380.8230.53398.3
3.13-3.452.9030.1786.9213452472046340.9630.21798.2
3.45-3.962.8920.06616.2713194468045620.9940.08197.5
3.96-4.842.8830.0332.7611393408839520.9980.03696.7
4.84-6.123.0450.02539.747578258224890.9990.0396.4
6.12-7.872.8420.02143.973584133412610.9990.02694.5
7.87-11.482.9480.01565.4823238327880.9990.01994.7
11.48-18.382.6520.01269.147322992760.9990.01692.3
18.38-106.252.7910.01269.232541059110.01586.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSdata reduction
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.88→106.25 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.863 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.482 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.3049 610 2.6 %RANDOM
Rwork0.2411 ---
obs0.2427 22579 97.14 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 304.72 Å2 / Biso mean: 133.485 Å2 / Biso min: 45.87 Å2
Baniso -1Baniso -2Baniso -3
1-1.58 Å20 Å23.88 Å2
2---0.91 Å2-0 Å2
3----1.38 Å2
Refinement stepCycle: final / Resolution: 2.88→106.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6731 0 67 28 6826
Biso mean--82.58 63.49 -
Num. residues----828
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0196672
X-RAY DIFFRACTIONr_bond_other_d00.026323
X-RAY DIFFRACTIONr_angle_refined_deg1.271.9589069
X-RAY DIFFRACTIONr_angle_other_deg3.891314419
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5135817
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.52323.891293
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.02115.0181102
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.8141537
X-RAY DIFFRACTIONr_chiral_restr0.0650.21037
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0217473
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021547
LS refinement shellResolution: 2.88→2.955 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.441 43 -
Rwork0.402 1672 -
all-1715 -
obs--97.39 %
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)
14.59460.17661.42621.3498-0.07132.89110.07630.0389-0.58340.10880.0677-0.11560.1868-0.138-0.14410.1668-0.0225-0.14870.01440.00550.2042-42.03-12.712-29.552
24.2926-0.00721.65454.0263-1.2457.69520.07740.6536-0.18-0.5303-0.0702-0.9424-0.00181.3528-0.00720.3003-0.04440.04240.6383-0.20760.6864-8.334-8.255-39.67
36.38270.0387-0.93772.43180.41764.75840.072-0.32060.06280.2180.00740.3287-0.0765-0.5118-0.07930.2656-0.0082-0.02640.41620.13360.1744-62.312-6.597-13.671
43.6859-0.0531.36372.8932-0.52233.46790.0044-0.1620.59750.09030.1185-0.2137-0.6430.179-0.1230.4324-0.1023-0.11950.2086-0.0940.331-25.913.382-27.885
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A144 - 200
2X-RAY DIFFRACTION1A311 - 323
3X-RAY DIFFRACTION1A543 - 726
4X-RAY DIFFRACTION2A201 - 310
5X-RAY DIFFRACTION3A351 - 522
6X-RAY DIFFRACTION4A727 - 1091

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