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- PDB-3l54: Structure of Pi3K gamma with inhibitor -

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Basic information

Entry
Database: PDB / ID: 3l54
TitleStructure of Pi3K gamma with inhibitor
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / Pi3K / Pi3K gamma / phosphatidylinositol / Pi3 / ATP-binding / Kinase / Nucleotide-binding
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-LXX / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsElkins, P.A. / Smallwood, A.M.
CitationJournal: ACS Med Chem Lett / Year: 2010
Title: Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin.
Authors: Knight, S.D. / Adams, N.D. / Burgess, J.L. / Chaudhari, A.M. / Darcy, M.G. / Donatelli, C.A. / Luengo, J.I. / Newlander, K.A. / Parrish, C.A. / Ridgers, L.H. / Sarpong, M.A. / Schmidt, S.J. ...Authors: Knight, S.D. / Adams, N.D. / Burgess, J.L. / Chaudhari, A.M. / Darcy, M.G. / Donatelli, C.A. / Luengo, J.I. / Newlander, K.A. / Parrish, C.A. / Ridgers, L.H. / Sarpong, M.A. / Schmidt, S.J. / Van Aller, G.S. / Carson, J.D. / Diamond, M.A. / Elkins, P.A. / Gardiner, C.M. / Garver, E. / Gilbert, S.A. / Gontarek, R.R. / Jackson, J.R. / Kershner, K.L. / Luo, L. / Raha, K. / Sherk, C.S. / Sung, C.M. / Sutton, D. / Tummino, P.J. / Wegrzyn, R.J. / Auger, K.R. / Dhanak, D.
History
DepositionDec 21, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 30, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 24, 2014Group: Database references
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)111,1353
Polymers110,7151
Non-polymers4192
Water48627
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)145.262, 68.406, 106.724
Angle α, β, γ (deg.)90.00, 94.76, 90.00
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 / PI3-kinase p110 subunit gamma / PtdIns-3-kinase subunit p110 / PI3Kgamma / PI3K / p120-PI3K


Mass: 110715.109 Da / Num. of mol.: 1 / Fragment: catalytic subunit
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Production host: unidentified baculovirus
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-LXX / 6-(1H-pyrazolo[3,4-b]pyridin-5-yl)-4-pyridin-4-ylquinoline


Mass: 323.351 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H13N5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 27 / 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: 2.39 Å3/Da / Density % sol: 48.46 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: Protein at 7.9mg/ml in 20mM Tris, pH 7.2, 50mM ammonium sulfate, 1% ethylene glycol, 1% betaine, 0.02% CHAPS, 5mM DTT with 1mM inhbitor reacted overnight at 4C. 2 microliter protein solution ...Details: Protein at 7.9mg/ml in 20mM Tris, pH 7.2, 50mM ammonium sulfate, 1% ethylene glycol, 1% betaine, 0.02% CHAPS, 5mM DTT with 1mM inhbitor reacted overnight at 4C. 2 microliter protein solution plus 2 microliters well in sitting drops. Well consisted of 20% PEG 3350, 0.1M Tris, pH 8.0, 3% 1,6 hexanediol, 0.2M ammonium sulfate. Crystals grew from dilution seeding from apo seeds. Cryo was 25% ethylene glycol mixed with the well, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 46614 / Num. obs: 37850 / % possible obs: 81.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Biso Wilson estimate: 52 Å2 / Rsym value: 0.046 / Net I/σ(I): 19.4
Reflection shellResolution: 2.3→2.38 Å / Mean I/σ(I) obs: 2.3 / Rsym value: 0.437 / % possible all: 78.2

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Processing

Software
NameVersionClassification
DENZOdata reduction
PHENIXmodel building
PHENIX(phenix.refine: 1.5_2)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→39.431 Å / SU ML: 0.42 / σ(F): 1.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2798 1895 5.02 %random 5%
Rwork0.216 ---
obs0.2192 37786 81.07 %-
all-46614 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 57.716 Å2 / ksol: 0.353 e/Å3
Refinement stepCycle: LAST / Resolution: 2.3→39.431 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6779 0 30 27 6836
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0046957
X-RAY DIFFRACTIONf_angle_d0.7799417
X-RAY DIFFRACTIONf_dihedral_angle_d14.7522555
X-RAY DIFFRACTIONf_chiral_restr0.0541061
X-RAY DIFFRACTIONf_plane_restr0.0031201
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.35760.3641120.26852316X-RAY DIFFRACTION74
2.3576-2.42130.38371220.27112532X-RAY DIFFRACTION80
2.4213-2.49260.34711320.26542471X-RAY DIFFRACTION80
2.4926-2.5730.31961560.25382585X-RAY DIFFRACTION82
2.573-2.6650.40031350.25712641X-RAY DIFFRACTION83
2.665-2.77160.2911430.25452642X-RAY DIFFRACTION84
2.7716-2.89770.30851430.23072659X-RAY DIFFRACTION85
2.8977-3.05050.30461500.23682663X-RAY DIFFRACTION85
3.0505-3.24150.34531290.23752674X-RAY DIFFRACTION84
3.2415-3.49160.29031480.21722631X-RAY DIFFRACTION83
3.4916-3.84280.23681440.19852599X-RAY DIFFRACTION82
3.8428-4.39820.21991150.16562585X-RAY DIFFRACTION81
4.3982-5.53880.21461240.16362578X-RAY DIFFRACTION80
5.5388-39.43650.24221420.18782315X-RAY DIFFRACTION71
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)
13.09260.49861.87471.16740.8961.48730.14231.2117-0.6825-0.27980.1006-0.10870.23130.5573-0.24910.37820.1796-0.14210.4801-0.17060.232237.9001-19.106812.7292
21.3885-1.1477-0.25591.0907-0.1651.8070.28850.0738-0.74050.05780.1350.77750.0914-0.7975-0.0550.09250.03220.27760.47320.19430.542711.7177-10.470837.2309
30.80140.1659-0.26080.53520.16890.5160.08110.28270.0419-0.357-0.0536-0.2901-0.00220.5958-0.03260.36530.13480.08610.6219-0.00590.242964.4508-6.010513.9928
41.4214-0.0397-0.03890.7485-0.45930.2973-0.00040.67080.163-0.1665-0.0492-0.17940.2651-0.03710.05130.33580.18730.07430.545-0.01980.237256.181-7.844112.6625
52.1988-0.46830.8090.27710.16220.83310.1680.0535-0.16320.0085-0.01550.01590.00860.1549-0.12090.17730.0582-0.0260.17320.03180.167346.9278-10.061534.6559
62.485-0.26010.06781.27010.40240.3215-0.02510.7414-0.1459-0.50920.13670.4502-0.1952-0.2744-0.15910.2240.1767-0.07510.48240.11750.165917.39784.485612.1818
70.908-0.026-0.21830.32110.37780.53970.08540.79330.0559-0.13-0.3815-0.20990.39370.3990.17410.50690.284-0.040.55360.08270.327327.49995.140918.6316
80.8067-0.65380.25661.99410.3830.3356-0.05580.1625-0.19260.49450.12980.52010.3214-0.2501-0.03720.50650.16930.10110.2310.10570.211330.69825.584734.912
91.0970.01950.12651.36270.25790.39570.0885-0.03620.420.34260.02780.0751-0.369-0.0651-0.1320.45640.18420.15750.19280.09930.313131.026319.789736.3211
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A and resid 144:190
2X-RAY DIFFRACTION2chain A and resid 191:321
3X-RAY DIFFRACTION3chain A and resid 350:488
4X-RAY DIFFRACTION4chain A and resid 495:533
5X-RAY DIFFRACTION5chain A and resid 544:725
6X-RAY DIFFRACTION6chain A and resid 726:836
7X-RAY DIFFRACTION7chain A and resid 867:881
8X-RAY DIFFRACTION8chain A and resid 837:866
9X-RAY DIFFRACTION9chain A and resid 882:1090

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