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- PDB-3l08: Structure of Pi3K gamma with a potent inhibitor: GSK2126458 -

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Basic information

Entry
Database: PDB / ID: 3l08
TitleStructure of Pi3K gamma with a potent inhibitor: GSK2126458
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / Pi3K gamma / lipid kinase / phosphoinositide / inhibitor / GSK2126458 / signaling / kinase / ATP-binding / Nucleotide-binding
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-/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. / 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 / 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-ZIG / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsElkins, P.A. / Marrero, E.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 9, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 23, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Apr 18, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
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
Revision 1.4Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)111,4254
Polymers110,7271
Non-polymers6983
Water1,02757
1
A: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
hetero molecules

A: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)222,8498
Polymers221,4542
Non-polymers1,3956
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_656-x+1,y,-z+11
Buried area2000 Å2
ΔGint-73 kcal/mol
Surface area71750 Å2
MethodPISA
2


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)145.617, 68.410, 107.470
Angle α, β, γ (deg.)90.00, 94.72, 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: 110727.102 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Production host: Escherichia coli (E. coli)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-ZIG / 2,4-difluoro-N-[2-methoxy-5-(4-pyridazin-4-ylquinolin-6-yl)pyridin-3-yl]benzenesulfonamide


Mass: 505.496 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H17F2N5O3S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 57 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.41 Å3/Da / Density % sol: 48.94 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: Protein was 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 ...Details: Protein was 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: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jul 1, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. all: 29208 / Num. obs: 28636 / % possible obs: 98 % / Observed criterion σ(F): 1.5 / Observed criterion σ(I): 1.5 / Biso Wilson estimate: 75 Å2 / Rsym value: 0.078 / Net I/σ(I): 10.4
Reflection shellResolution: 2.7→2.8 Å / Mean I/σ(I) obs: 1.9 / Rsym value: 0.411 / % possible all: 83.1

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHENIXmodel building
PHENIX(phenix.refine: 1.4_87)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Proprietary pi3K gamma structure

Resolution: 2.7→41.215 Å / SU ML: 0.4 / σ(F): 1.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2614 1396 4.88 %random
Rwork0.1976 ---
obs0.2008 28588 97.88 %-
all-29208 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 38.668 Å2 / ksol: 0.276 e/Å3
Refinement stepCycle: LAST / Resolution: 2.7→41.215 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6711 0 46 57 6814
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0046926
X-RAY DIFFRACTIONf_angle_d0.7319375
X-RAY DIFFRACTIONf_dihedral_angle_d14.3352550
X-RAY DIFFRACTIONf_chiral_restr0.0511051
X-RAY DIFFRACTIONf_plane_restr0.0031194
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.79650.32691130.26012295X-RAY DIFFRACTION84
2.7965-2.90840.3071500.23412643X-RAY DIFFRACTION97
2.9084-3.04080.32321270.2212748X-RAY DIFFRACTION100
3.0408-3.2010.28971420.22082788X-RAY DIFFRACTION100
3.201-3.40150.26831220.19772794X-RAY DIFFRACTION100
3.4015-3.6640.26461550.17612731X-RAY DIFFRACTION100
3.664-4.03240.23591410.16662799X-RAY DIFFRACTION100
4.0324-4.61520.21371450.14482749X-RAY DIFFRACTION100
4.6152-5.81210.22981530.16522804X-RAY DIFFRACTION100
5.8121-41.22020.2571480.21672841X-RAY DIFFRACTION99
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)
10.29520.1469-0.06830.2798-0.010.27560.02380.7787-0.3380.13230.3649-0.03560.17080.16870.01740.30420.1756-0.09030.4374-0.19520.338537.374-19.055612.4256
20.5227-0.15040.11730.2163-0.38320.38280.2573-0.1933-0.4910.26010.14080.71970.1681-0.46720.08270.31110.10730.2760.52870.30010.739911.6909-9.875737.6998
30.2776-0.03870.00830.18040.17320.22390.15560.3097-0.1293-0.3101-0.0961-0.09960.06080.68650.00460.28980.20720.1080.7529-0.01470.207164.7916-6.514414.9306
40.03610.0674-0.02830.04810.05210.0589-0.27190.6535-0.17850.15870.07690.07770.43160.151100.51840.17250.14210.6542-0.01410.285756.1167-7.792415.0782
50.989-0.3356-0.08810.45020.19981.32180.20480.1283-0.1439-0.04250.02440.09780.0980.36210.30770.20120.0997-0.0490.16470.04990.142147.3474-9.355535.3328
60.2889-0.03260.01790.1408-0.0480.0933-0.02780.5191-0.1605-0.02020.09360.2631-0.151-0.1694-0.03130.32160.2132-0.07120.54440.13270.386917.65055.1312.5157
7-0.002-0.00930.00950.0283-0.01130.00990.04790.1073-0.00220.0998-0.03740.0611-0.02390.0308-0.00550.34190.3193-0.0220.37060.10980.337727.51765.624918.9157
80.1388-0.00840.08380.04560.00650.04710.13080.20430.01890.57510.13970.3726-0.11280.00880.02250.49830.2490.07740.23350.21670.251230.61576.165135.1456
90.47240.33440.07460.83660.46390.05010.4347-0.25040.35540.8287-0.11150.1934-1.0830.85450.15920.51180.46550.2566-0.4280.16340.296931.13920.14137.1484
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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