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- PDB-6aud: PI3K-gamma K802T in complex with Cpd 8 10-((1-(tert-butyl)piperid... -

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Basic information

Entry
Database: PDB / ID: 6aud
TitlePI3K-gamma K802T in complex with Cpd 8 10-((1-(tert-butyl)piperidin-4-yl)sulfinyl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE INHBITOR / p110 delta / SBDD / TRANSFERASE-TRANSFERASE INHBITOR 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-/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 3/4-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-BWY / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.015 Å
AuthorsMurray, J.M. / Ultsch, M.
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Design of Selective Benzoxazepin PI3K delta Inhibitors Through Control of Dihedral Angles.
Authors: Safina, B.S. / Elliott, R.L. / Forrest, A.K. / Heald, R.A. / Murray, J.M. / Nonomiya, J. / Pang, J. / Salphati, L. / Seward, E.M. / Staben, S.T. / Ultsch, M. / Wei, B. / Yang, W. / Sutherlin, D.P.
History
DepositionAug 31, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 15, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 4, 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

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)111,1822
Polymers110,6991
Non-polymers4831
Water5,224290
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)139.051, 66.065, 102.492
Angle α, β, γ (deg.)90.00, 98.06, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1557-

HOH

21A-1589-

HOH

DetailsMonomer as determined bygel filtration

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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: 110699.023 Da / Num. of mol.: 1 / Fragment: p110 gamma, residues 144-1102 / Mutation: K802T
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-BWY / 10-[(S)-(1-tert-butylpiperidin-4-yl)sulfinyl]-2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine


Mass: 482.641 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H34N6O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 290 / 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: 2.41 Å3/Da / Density % sol: 48.89 % / Mosaicity: 1.255 °
Crystal growTemperature: 289 K / Method: vapor diffusion / pH: 8.5 / Details: PEG 3350, 0.2M NH4SO4, 0.1M Tris-HCl 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 0.999 Å
DetectorType: MACSCIENCE / Detector: CCD / Date: Aug 21, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 60464 / % possible obs: 99.9 % / Redundancy: 3.6 % / Biso Wilson estimate: 33.06 Å2 / Rmerge(I) obs: 0.063 / Χ2: 1.028 / Net I/σ(I): 11.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2-2.073.50.55559931.0161100
2.07-2.153.50.40460061.0421100
2.15-2.253.50.31360301.0491100
2.25-2.373.50.22360401.0411100
2.37-2.523.50.1760211.0251100
2.52-2.713.60.12260351.0331100
2.71-2.993.70.08560351.0231100
2.99-3.423.70.0660661.02199.9
3.42-4.313.70.04860761.014199.9
4.31-503.70.03661621.019199.3

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Processing

Software
NameVersionClassification
PHENIX(1.12-2829_final)refinement
DENZOdata reduction
SCALEPACKdata scaling
PDB_EXTRACT3.22data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3r7r

3r7r


Resolution: 2.015→28.119 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.36 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2331 3017 4.99 %
Rwork0.2027 --
obs0.2043 60446 99.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.015→28.119 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6796 0 34 290 7120
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0026983
X-RAY DIFFRACTIONf_angle_d0.5939454
X-RAY DIFFRACTIONf_dihedral_angle_d16.2184199
X-RAY DIFFRACTIONf_chiral_restr0.0421062
X-RAY DIFFRACTIONf_plane_restr0.0041196
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0149-2.04630.3091110.28042102X-RAY DIFFRACTION82
2.0463-2.07990.3191310.26672664X-RAY DIFFRACTION100
2.0799-2.11570.26371390.25982584X-RAY DIFFRACTION100
2.1157-2.15420.26441400.25152602X-RAY DIFFRACTION100
2.1542-2.19560.29921290.24712665X-RAY DIFFRACTION100
2.1956-2.24040.26711350.25012581X-RAY DIFFRACTION100
2.2404-2.28910.30571370.23812645X-RAY DIFFRACTION100
2.2891-2.34230.28131390.22322621X-RAY DIFFRACTION100
2.3423-2.40090.27851230.22662653X-RAY DIFFRACTION100
2.4009-2.46570.28791430.23162589X-RAY DIFFRACTION100
2.4657-2.53820.25921420.22932641X-RAY DIFFRACTION100
2.5382-2.62010.29151280.22912625X-RAY DIFFRACTION100
2.6201-2.71370.28371240.22782645X-RAY DIFFRACTION100
2.7137-2.82220.27991520.22942595X-RAY DIFFRACTION100
2.8222-2.95060.22621410.22612640X-RAY DIFFRACTION100
2.9506-3.10590.26221510.22592642X-RAY DIFFRACTION100
3.1059-3.30020.24391250.2122644X-RAY DIFFRACTION100
3.3002-3.55460.23461490.19672609X-RAY DIFFRACTION100
3.5546-3.91150.21051360.17612676X-RAY DIFFRACTION100
3.9115-4.47550.18491600.1662628X-RAY DIFFRACTION100
4.4755-5.63120.19991420.16742648X-RAY DIFFRACTION100
5.6312-28.12140.19451400.17962730X-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)
10.5933-0.46190.1790.76510.22850.46920.09940.5107-0.3895-0.2409-0.0140.03210.42070.12790.00160.43320.038-0.04120.3918-0.0170.373833.6206-38.27757.721
22.16070.09820.6151.953-0.55082.17790.1327-0.4345-0.03450.20550.04010.3534-0.0779-0.76030.01390.3197-0.03310.08030.52440.11120.45276.0114-33.097332.4045
33.13760.24620.01620.7172-0.28982.58990.0534-0.26330.1010.0722-0.05650.0639-0.06970.3311-0.00010.22310.025-0.00770.2808-0.03970.21860.2157-22.87312.1194
41.5590.4464-0.15830.41330.47370.90860.0028-0.1897-0.0306-0.2121-0.05360.24260.27060.1116-0.01390.35420.03970.04870.34230.02060.288652.8618-25.594610.2434
52.238-0.21341.55250.1613-0.14481.47750.0134-0.3163-0.10450.07150.01-0.04820.03950.001500.27030.03570.00040.28540.03050.281441.8489-30.709931.5402
61.5016-1.37440.61862.0334-0.81621.4914-0.02570.18570.1006-0.24870.04130.056-0.2002-0.09390.00040.34790.0067-0.02990.30880.03280.332314.0051-14.4448.8709
70.7556-0.0080.48690.78830.39580.4514-0.08760.0763-0.23210.3863-0.06080.18670.06620.0052-00.35780.05630.04080.2670.01960.292724.8379-15.933932.5812
80.1295-0.06940.16720.21890.01840.2125-0.05030.12810.2697-0.35960.1298-0.29650.00720.454600.31750.05080.02320.25360.01950.316522.9547-14.598316.2317
92.0161-0.91430.32582.1889-0.60192.0447-0.0416-0.16680.30780.230.0441-0.2112-0.34310.074-0.0020.34370.0143-0.00460.264-0.02450.274824.6445-1.953535.3057
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 144:190)
2X-RAY DIFFRACTION2(chain A and resid 191:321)
3X-RAY DIFFRACTION3(chain A and resid 350:488)
4X-RAY DIFFRACTION4(chain A and resid 495:533)
5X-RAY DIFFRACTION5(chain A and resid 544:725)
6X-RAY DIFFRACTION6(chain A and resid 726:836)
7X-RAY DIFFRACTION7(chain A and resid 837:866)
8X-RAY DIFFRACTION8(chain A and resid 867:881)
9X-RAY DIFFRACTION9(chain A and resid 882:1090)

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