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- PDB-7kke: Phosphoinositide 3-Kinase gamma bound to a thiazole inhibitor -

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Basic information

Entry
Database: PDB / ID: 7kke
TitlePhosphoinositide 3-Kinase gamma bound to a thiazole inhibitor
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/Inhibitor / KINASE / INHIBITOR / 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- 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 / C2 domain superfamily / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-WJV / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.81 Å
AuthorsJacobs, M.D. / Griffith, J.P.
Funding support United States, 1items
OrganizationGrant numberCountry
Department of Energy (DOE, United States)DE-AC02-05CH11231 United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Discovery of a Novel Series of Potent and Selective Alkynylthiazole-Derived PI3K gamma Inhibitors.
Authors: Bandarage, U.K. / Aronov, A.M. / Cao, J. / Come, J.H. / Cottrell, K.M. / Davies, R.J. / Giroux, S. / Jacobs, M. / Mahajan, S. / Messersmith, D. / Moody, C.S. / Swett, R. / Xu, J.
History
DepositionOct 27, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 24, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)111,6552
Polymers111,2691
Non-polymers3871
Water41423
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)141.456, 67.050, 107.398
Angle α, β, γ (deg.)90.000, 97.050, 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: 111268.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Plasmid: pBev12 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-WJV / N-[2-(3,3-dimethylbutoxy)ethyl]-N'-{4-methyl-5-[(pyridin-4-yl)ethynyl]-1,3-thiazol-2-yl}urea


Mass: 386.511 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H26N4O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 2.27 Å3/Da / Density % sol: 45.85 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 8.5
Details: 25% PEG3350, 200MM LITHIUM SULFATE, 10 REMARK 280 MM DTT, 10 MM EDTA, 100 MM TRIS, PH 8.5, VAPOR DIFFUSION, REMARK 280 HANGING DROP, TEMPERATURE 298K

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Data collection

DiffractionMean temperature: 110 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 1, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.81→62.24 Å / Num. obs: 19864 / % possible obs: 87.3 % / Redundancy: 3.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.07 / Rpim(I) all: 0.044 / Rrim(I) all: 0.083 / Net I/σ(I): 13.1
Reflection shell

Num. unique obs: 993 / Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.81-2.993.71.15436880.5470.6921.3481.142.7
8.086-62.2373.30.0232770.9990.0120.02342.490.3

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTERrefinement
PDB_EXTRACT3.25data extraction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6C1S

6c1s


Resolution: 2.81→62.24 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.884 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.449
RfactorNum. reflection% reflectionSelection details
Rfree0.2637 937 4.72 %RANDOM
Rwork0.1936 ---
obs0.1967 19864 80.8 %-
Displacement parametersBiso max: 158.52 Å2 / Biso mean: 86.79 Å2 / Biso min: 26.37 Å2
Baniso -1Baniso -2Baniso -3
1-1.885 Å20 Å2-6.8064 Å2
2--3.6709 Å20 Å2
3----5.5559 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: final / Resolution: 2.81→62.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6775 0 27 23 6825
Biso mean--66.68 52.92 -
Num. residues----842
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2444SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1161HARMONIC5
X-RAY DIFFRACTIONt_it6967HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion911SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5409SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6967HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg9433HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion2.7
X-RAY DIFFRACTIONt_other_torsion21.85
LS refinement shellResolution: 2.81→2.93 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2941 21 4.86 %
Rwork0.2419 411 -
obs--24.1 %
Refinement TLS params.Method: refined / Origin x: 32.4077 Å / Origin y: -20.6799 Å / Origin z: 27.0153 Å
111213212223313233
T-0.0099 Å2-0.0047 Å2-0.0775 Å2--0.1722 Å2-0.0206 Å2---0.1804 Å2
L3.4169 °2-0.9612 °20.414 °2-0.3901 °2-0.0089 °2--1.5661 °2
S-0.1462 Å °0.0134 Å °-0.2156 Å °0.0715 Å °0.0944 Å °0.0962 Å °-0.2282 Å °-0.0395 Å °0.0518 Å °
Refinement TLS groupSelection details: { A|* }

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