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- PDB-3ene: Complex of PI3K gamma with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 3ene
TitleComplex of PI3K gamma with an inhibitor
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / lipid kinase / phosphoinositide / inhibitor / 3-kinase / signaling / pyrazolopyrimidine / PIK-208 / S2 / Kinase
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-NPZ / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsApsel, B. / Blair, J.A. / Gonzalez, B.Z. / Nazif, T.M. / Feldman, M.E. / Williams, R.L. / Shokat, K.M. / Knight, Z.A.
CitationJournal: Nat.Chem.Biol. / Year: 2008
Title: Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases
Authors: Apsel, B. / Blair, J.A. / Gonzalez, B. / Nazif, T.M. / Feldman, M.E. / Aizenstein, B. / Hoffman, R. / Williams, R.L. / Shokat, K.M. / Knight, Z.A.
History
DepositionSep 25, 2008Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 14, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Nov 1, 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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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)110,0712
Polymers109,7961
Non-polymers2751
Water68538
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.302, 68.244, 106.069
Angle α, β, γ (deg.)90.000, 95.190, 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 / PI3-kinase p110 subunit gamma / PtdIns-3-kinase subunit p110 / PI3Kgamma / PI3K / p120-PI3K


Mass: 109796.062 Da / Num. of mol.: 1 / Fragment: UNP residues 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Plasmid: pvl1393 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-NPZ / 1-methyl-3-naphthalen-2-yl-1H-pyrazolo[3,4-d]pyrimidin-4-amine


Mass: 275.308 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13N5
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 38 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE SEQUENCE OF CDC42 IS BASED ON REFERENCE 1 AND 3 IN THE DATABASE, PK3CG_HUMAN.

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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: 2.37 Å3/Da / Density % sol: 48.07 %
Crystal growTemperature: 288 K / Method: vapor diffusion / pH: 7.5
Details: 17% PEG 4000, 0.25M ammonium sulphate, 0.1M Tris pH 7.5, VAPOR DIFFUSION, temperature 288K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9793 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jan 5, 2005 / Details: Torroidal Mirror
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.4→62.14 Å / Num. all: 40149 / Num. obs: 40149 / % possible obs: 99.3 % / Redundancy: 3.7 % / Biso Wilson estimate: 51.2 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 6.8
Reflection shellResolution: 2.4→2.53 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.36 / Mean I/σ(I) obs: 2 / Rsym value: 0.36 / % possible all: 99.3

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALACCP4_3.2.5data scaling
REFMAC5.1.24refinement
PDB_EXTRACT3.006data extraction
ADSCQuantumdata collection
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1e8z

1e8z


Resolution: 2.4→57.07 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.901 / Occupancy max: 1 / Occupancy min: 1 / SU B: 9.817 / SU ML: 0.227 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.441 / ESU R Free: 0.285 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.276 1636 4.1 %RANDOM
Rwork0.227 ---
obs0.229 40148 99.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 58.67 Å2 / Biso mean: 26.414 Å2 / Biso min: 15.14 Å2
Baniso -1Baniso -2Baniso -3
1--0.59 Å20 Å21.44 Å2
2--2.86 Å20 Å2
3----2.01 Å2
Refinement stepCycle: LAST / Resolution: 2.4→57.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6845 0 21 38 6904
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0217018
X-RAY DIFFRACTIONr_bond_other_d0.0040.026421
X-RAY DIFFRACTIONr_angle_refined_deg1.5011.9559495
X-RAY DIFFRACTIONr_angle_other_deg0.892314961
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0235835
X-RAY DIFFRACTIONr_chiral_restr0.0860.21063
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.027631
X-RAY DIFFRACTIONr_gen_planes_other0.0060.021407
X-RAY DIFFRACTIONr_nbd_refined0.2110.21595
X-RAY DIFFRACTIONr_nbd_other0.2240.27327
X-RAY DIFFRACTIONr_nbtor_other0.0890.24307
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1970.2122
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.280.26
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2190.227
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0980.21
X-RAY DIFFRACTIONr_mcbond_it0.5121.54207
X-RAY DIFFRACTIONr_mcangle_it0.93926825
X-RAY DIFFRACTIONr_scbond_it1.58232811
X-RAY DIFFRACTIONr_scangle_it2.5864.52670
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.343 114
Rwork0.291 2838
all-2952
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)
13.7408-0.6099-0.6032.21220.14083.401-0.0167-0.6154-0.42690.26780.135-0.3150.21570.1789-0.11830.036-0.0239-0.07310.04470.04520.166533.884-15.81334.285
23.32831.49590.56743.4136-1.36866.3862-0.04010.2919-0.3438-0.4775-0.1104-0.8701-0.03051.2510.15050.174-0.03990.2020.4261-0.1770.590558.762-10.88614.158
35.03120.07140.73721.83241.28276.85330.0261-0.48930.07390.0564-0.1060.3403-0.3675-1.02880.07990.08450.05030.06220.43460.09040.07565.177-6.69938.061
47.81480.67261.09040.3151-0.20793.621-0.01260.3936-0.214-0.1760.1105-0.08030.0062-0.2578-0.09790.1762-0.0582-0.03980.07-0.03870.086713.972-11.01111.456
55.02680.27471.88052.9849-0.66793.82990.0561-1.02420.16920.4650.0154-0.3574-0.3620.1539-0.07140.2602-0.1401-0.00510.2668-0.10980.243246.8615.4735.778
62.94851.33750.58033.67520.30842.5056-0.11030.15860.6525-0.31220.09540.1499-0.49240.04150.01490.3644-0.04390.05320.00890.01960.196837.56618.78116.97
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A144 - 193
2X-RAY DIFFRACTION1A313 - 320
3X-RAY DIFFRACTION1A655 - 735
4X-RAY DIFFRACTION2A194 - 312
5X-RAY DIFFRACTION3A357 - 548
6X-RAY DIFFRACTION4A554 - 650
7X-RAY DIFFRACTION5A736 - 884
8X-RAY DIFFRACTION6A885 - 1092

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