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- PDB-5jhb: Structure of Phosphoinositide 3-kinase gamma (PI3K) bound to the ... -

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Basic information

Entry
Database: PDB / ID: 5jhb
TitleStructure of Phosphoinositide 3-kinase gamma (PI3K) bound to the potent inhibitor PIKin3
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / Inhibitor / Lipid kinase / PI3K
Function / homology
Function and homology information


negative regulation of cardiac muscle contraction / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / secretory granule localization / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / T cell chemotaxis / negative regulation of fibroblast apoptotic process ...negative regulation of cardiac muscle contraction / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / secretory granule localization / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / regulation of calcium ion transmembrane transport / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Co-stimulation by ICOS / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / dendritic cell chemotaxis / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / mast cell degranulation / hepatocyte apoptotic process / phosphatidylinositol-mediated signaling / regulation of cell adhesion mediated by integrin / phosphatidylinositol phosphate biosynthetic process / positive regulation of MAP kinase activity / Synthesis of PIPs at the plasma membrane / positive regulation of Rac protein signal transduction / CD28 dependent PI3K/Akt signaling / regulation of angiogenesis / T cell proliferation / GPVI-mediated activation cascade / ephrin receptor binding / neutrophil chemotaxis / positive regulation of endothelial cell migration / T cell activation / cellular response to cAMP / positive regulation of cytokine production / phosphatidylinositol 3-kinase/protein kinase B signal transduction / platelet aggregation / endocytosis / Constitutive Signaling by Aberrant PI3K in Cancer / G beta:gamma signalling through PI3Kgamma / cell migration / PIP3 activates AKT signaling / positive regulation of cytosolic calcium ion concentration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / angiogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / adaptive immune response / non-specific serine/threonine protein kinase / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein kinase activity / immune response / G protein-coupled receptor signaling pathway / inflammatory response / innate immune response / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / identical protein binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / PI3-kinase family, Ras-binding domain ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / Phosphatidylinositol 3-kinase, accessory domain (PIK) / 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 / C2 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-6K5 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsBurke, J.E. / Inglis, A.J. / Williams, R.L.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)U105184308 United Kingdom
CitationJournal: Nat Commun / Year: 2017
Title: Deconvolution of Buparlisib's mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention.
Authors: Bohnacker, T. / Prota, A.E. / Beaufils, F. / Burke, J.E. / Melone, A. / Inglis, A.J. / Rageot, D. / Sele, A.M. / Cmiljanovic, V. / Cmiljanovic, N. / Bargsten, K. / Aher, A. / Akhmanova, A. / ...Authors: Bohnacker, T. / Prota, A.E. / Beaufils, F. / Burke, J.E. / Melone, A. / Inglis, A.J. / Rageot, D. / Sele, A.M. / Cmiljanovic, V. / Cmiljanovic, N. / Bargsten, K. / Aher, A. / Akhmanova, A. / Diaz, J.F. / Fabbro, D. / Zvelebil, M. / Williams, R.L. / Steinmetz, M.O. / Wymann, M.P.
History
DepositionApr 20, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Mar 15, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2017Group: Database references
Revision 1.2Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 10, 2024Group: 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)110,4543
Polymers109,8981
Non-polymers5562
Water57632
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-13 kcal/mol
Surface area37080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)142.530, 67.600, 106.550
Angle α, β, γ (deg.)90.000, 96.230, 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: 109898.203 Da / Num. of mol.: 1 / Mutation: Fragment 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, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-6K5 / [1-{4-[6-amino-4-(trifluoromethyl)pyridin-3-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-yl}-3-(chloromethyl)azetidin-3-yl]methanol


Mass: 459.853 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21ClF3N7O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / 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: 2.32 Å3/Da / Density % sol: 47.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 17% PEG 4000, 250 mM (NH4)2SO4 and 100mM Tris pH-7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 2, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.48→62.08 Å / Num. obs: 35274 / % possible obs: 98.1 % / Redundancy: 3.2 % / Biso Wilson estimate: 70.25 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.036 / Rpim(I) all: 0.024 / Rrim(I) all: 0.043 / Net I/σ(I): 17.5 / Num. measured all: 113523
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.48-2.543.30.553199.5
11.09-62.082.90.025194.9

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Processing

Software
NameVersionClassification
Aimless0.1.29data scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3sd5

3sd5


Resolution: 2.48→62.08 Å / SU ML: 0.39 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 34.28
RfactorNum. reflection% reflection
Rfree0.2771 1766 5.01 %
Rwork0.2307 --
obs0.2332 35260 98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 268.28 Å2 / Biso mean: 102.0387 Å2 / Biso min: 32.74 Å2
Refinement stepCycle: final / Resolution: 2.48→62.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6584 0 57 32 6673
Biso mean--90.28 67.78 -
Num. residues----811
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0036761
X-RAY DIFFRACTIONf_angle_d0.5789143
X-RAY DIFFRACTIONf_chiral_restr0.0221026
X-RAY DIFFRACTIONf_plane_restr0.0031149
X-RAY DIFFRACTIONf_dihedral_angle_d11.592514
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.48-2.54710.37881370.34562582271999
2.5471-2.6220.36551310.330226042735100
2.622-2.70670.40211270.31682593272099
2.7067-2.80340.39941380.31132627276599
2.8034-2.91560.40481300.319725792709100
2.9156-3.04830.371390.291426182757100
3.0483-3.2090.38921320.29362599273199
3.209-3.41010.32641410.27622617275899
3.4101-3.67340.28981240.26572502262695
3.6734-4.0430.28111310.23012488261995
4.043-4.62780.25571440.18862554269896
4.6278-5.82990.26551350.20412535267096
5.8299-62.10170.20311570.18332596275396
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)
11.3491-0.98411.31151.1174-0.42081.9895-0.09810.4521-1.06040.07410.32410.41980.10410.6150.50140.4247-0.07340.05390.7136-0.33940.735734.0559-29.866923.1113
20.6719-0.55890.46370.5373-0.33960.27720.04650.3397-0.78170.20080.28890.2774-0.03380.49850.080.41080.0273-0.00360.5575-0.12110.391148.8999-28.896633.7312
30.5456-0.19990.15150.2274-0.10780.49960.11871.2752-0.71710.01020.23050.4328-0.3395-0.15780.11590.46390.0935-0.04560.7403-0.0920.551320.5597-18.187813.0262
41.3105-0.16890.32240.3012-0.08150.1144-1.00730.56760.41470.75250.0773-0.0089-0.43480.002-0.66940.98220.327-0.1827-0.0796-0.02160.370724.466-4.024834.9457
50.0365-0.0005-0.07950.0376-0.02880.2507-0.2844-0.15690.63710.0768-0.24920.1469-0.3814-0.1201-0.30861.5348-0.0057-0.39720.4887-0.20021.141337.76471.149538.0261
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 144 through 484 )A144 - 484
2X-RAY DIFFRACTION2chain 'A' and (resid 485 through 688 )A485 - 688
3X-RAY DIFFRACTION3chain 'A' and (resid 689 through 837 )A689 - 837
4X-RAY DIFFRACTION4chain 'A' and (resid 838 through 1038 )A838 - 1038
5X-RAY DIFFRACTION5chain 'A' and (resid 1039 through 1091 )A0

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