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- PDB-3qk0: Crystal structure of PI3K-gamma in complex with benzothiazole 82 -

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Basic information

Entry
Database: PDB / ID: 3qk0
TitleCrystal structure of PI3K-gamma in complex with benzothiazole 82
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / p110 / transferase / kinase / inhibitor / ATP-binding / p84 / p101 / 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 / 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 ...secretory granule localization / negative regulation of triglyceride catabolic process / 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 / phosphatidylinositol phosphate biosynthetic process / phosphatidylinositol-mediated signaling / regulation of cell adhesion mediated by integrin / Synthesis of PIPs at the plasma membrane / regulation of angiogenesis / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / T cell activation / ephrin receptor binding / positive regulation of endothelial cell migration / neutrophil chemotaxis / 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 / inflammatory response / immune 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-QK0 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsWhittington, D.A. / Tang, J. / Yakowec, P.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Discovery and Optimization of a Series of Benzothiazole Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors.
Authors: D'Angelo, N.D. / Kim, T.S. / Andrews, K. / Booker, S.K. / Caenepeel, S. / Chen, K. / D'Amico, D. / Freeman, D. / Jiang, J. / Liu, L. / McCarter, J.D. / San Miguel, T. / Mullady, E.L. / ...Authors: D'Angelo, N.D. / Kim, T.S. / Andrews, K. / Booker, S.K. / Caenepeel, S. / Chen, K. / D'Amico, D. / Freeman, D. / Jiang, J. / Liu, L. / McCarter, J.D. / San Miguel, T. / Mullady, E.L. / Schrag, M. / Subramanian, R. / Tang, J. / Wahl, R.C. / Wang, L. / Whittington, D.A. / Wu, T. / Xi, N. / Xu, Y. / Yakowec, P. / Yang, K. / Zalameda, L.P. / Zhang, N. / Hughes, P. / Norman, M.H.
History
DepositionJan 31, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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)110,5895
Polymers109,8241
Non-polymers7654
Water1267
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)144.525, 67.835, 107.096
Angle α, β, γ (deg.)90.00, 95.34, 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 subunit gamma / PI3K-gamma / PtdIns-3-kinase subunit gamma / Phosphatidylinositol-4 / 5- ...PI3-kinase subunit gamma / PI3K-gamma / PtdIns-3-kinase subunit gamma / Phosphatidylinositol-4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / PtdIns-3-kinase subunit p110-gamma / p120-PI3K


Mass: 109824.055 Da / Num. of mol.: 1 / Fragment: catalytic domain (UNP Residues 144-1102)
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
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-QK0 / N-[6-(6-chloro-5-{[(4-fluorophenyl)sulfonyl]amino}pyridin-3-yl)-1,3-benzothiazol-2-yl]acetamide


Mass: 476.932 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H14ClFN4O3S2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 7 / 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: 2.38 Å3/Da / Density % sol: 48.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 21% PEG 3350, 240 mM ammonium sulfate, 2 mM dithiothreitol, 100 mM Tris, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Sep 10, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.85→30 Å / Num. all: 24355 / Num. obs: 24209 / % possible obs: 99.4 % / Observed criterion σ(I): -3 / Redundancy: 3.4 % / Biso Wilson estimate: 96.2 Å2 / Rmerge(I) obs: 0.058 / Χ2: 1.183 / Net I/σ(I): 18.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2% possible all
2.85-2.9530.5742.1923381.52296.9
2.95-3.073.30.45923951.51499.2
3.07-3.213.40.33324041.46599.9
3.21-3.383.40.21824141.4499.9
3.38-3.593.50.14124041.43499.8
3.59-3.873.50.08824201.28399.9
3.87-4.253.50.05724470.987100
4.25-4.873.50.04124470.7899.9
4.87-6.123.50.03624510.66199.9
6.12-303.40.02824890.88199.1

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
DENZOdata reduction
EPMRphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1E8Y

1e8y


Resolution: 2.85→30 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.908 / WRfactor Rfree: 0.2957 / WRfactor Rwork: 0.2409 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7752 / SU B: 44.307 / SU ML: 0.387 / SU R Cruickshank DPI: 0.3697 / SU Rfree: 0.4484 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.438 / Stereochemistry target values: Engh & Huber / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2771 1432 5.9 %RANDOM
Rwork0.2258 ---
obs0.2289 24207 99.44 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 168.56 Å2 / Biso mean: 90.0258 Å2 / Biso min: 42.03 Å2
Baniso -1Baniso -2Baniso -3
1--1.83 Å20 Å20.88 Å2
2--2.5 Å20 Å2
3----0.51 Å2
Refinement stepCycle: LAST / Resolution: 2.85→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6638 0 46 7 6691
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0226824
X-RAY DIFFRACTIONr_angle_refined_deg1.0541.9669237
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3295811
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.89424.272316
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.582151235
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.0121540
X-RAY DIFFRACTIONr_chiral_restr0.0720.21040
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025059
X-RAY DIFFRACTIONr_nbd_refined0.1990.23135
X-RAY DIFFRACTIONr_nbtor_refined0.30.24664
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1350.2195
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2230.234
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1650.21
X-RAY DIFFRACTIONr_mcbond_it0.3691.54198
X-RAY DIFFRACTIONr_mcangle_it0.66726632
X-RAY DIFFRACTIONr_scbond_it0.65632983
X-RAY DIFFRACTIONr_scangle_it1.0844.52605
LS refinement shellResolution: 2.85→2.923 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.42 91 -
Rwork0.362 1589 -
all-1680 -
obs--96.28 %
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)
15.3072-0.56310.38760.9924-0.58562.76480.1103-0.0926-1.2413-0.0130.27770.57310.2522-0.514-0.388-0.2431-0.0601-0.0035-0.31990.2080.188421.6977-13.783728.465
24.9895-1.8368-0.30495.19222.3188.02390.4684-0.6224-0.93340.09650.37040.841-0.0662-1.4917-0.8388-0.4439-0.05260.09550.06950.48020.319412.0723-11.885731.9709
32.72961.1068-1.40133.6894-1.6144.98830.02370.26640.1252-0.06190.12060.0429-0.10180.8051-0.1443-0.2118-0.02830.03850.3804-0.113-0.237566.7294-4.267414.3749
44.2511-1.9272-0.17633.8602-1.86913.81880.00310.7379-0.02870.0456-0.0071-0.061-0.11430.61940.004-0.1591-0.00770.01090.3138-0.1681-0.196756.617-6.069312.3122
53.6498-0.52862.12780.243-0.17982.52260.1074-0.0694-0.50160.07970.11790.1762-0.01830.1076-0.2253-0.02640.01410.0341-0.13560.01390.019946.1521-10.019534.4142
63.8326-1.17331.57821.7544-0.54742.62240.07770.5096-0.10130.07620.11040.2428-0.4417-0.1874-0.1881-0.07060.11160.0656-0.02570.0925-0.044720.16765.078217.462
74.9392-1.36822.11452.2002-0.34261.584-0.8924-0.39510.84390.54560.2898-0.1874-0.6608-0.15180.60250.39870.2058-0.0963-0.2124-0.1031-0.047529.73519.738537.1361
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A147 - 248
2X-RAY DIFFRACTION2A269 - 320
3X-RAY DIFFRACTION3A357 - 436
4X-RAY DIFFRACTION4A457 - 522
5X-RAY DIFFRACTION5A545 - 725
6X-RAY DIFFRACTION6A726 - 885
7X-RAY DIFFRACTION7A886 - 1092

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