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- PDB-2v4l: complex of human phosphoinositide 3-kinase catalytic subunit gamm... -

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Basic information

Entry
Database: PDB / ID: 2v4l
Titlecomplex of human phosphoinositide 3-kinase catalytic subunit gamma (p110 gamma) with PIK-284
ComponentsPHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM
KeywordsTRANSFERASE / LIPID KINASE / PHOSPHOINOSITIDE / PYRAZOLOPYRIMIDINE / S1 / KINASE / PIK-284 / 3-KINASE / INHIBITOR / SIGNALING
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 / phosphatidylinositol-mediated signaling / hepatocyte apoptotic process / 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-ABJ / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsApsel, B. / Gonzalez, B. / Blair, J.A. / 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: PDBE / Processing site: PDBE
Revision 1.0Oct 14, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Apr 17, 2013Group: Database references / Derived calculations / Non-polymer description
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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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)111,0252
Polymers110,7561
Non-polymers2691
Water90150
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.353, 68.440, 106.619
Angle α, β, γ (deg.)90.00, 95.33, 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 / P120-PI3K / PI3K / ...PI3-KINASE P110 SUBUNIT GAMMA / PTDINS-3-KINASE SUBUNIT P110 / PI3KGAMMA / P120-PI3K / PI3K / PHOSPHOINOSITIDE 3-KINASE GAMMA


Mass: 110756.164 Da / Num. of mol.: 1 / Fragment: CATALYTIC SUBUNIT, RESIDUES 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PVL1393 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-ABJ / 3-[4-AMINO-1-(1-METHYLETHYL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN-3-YL]PHENOL


Mass: 269.302 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H15N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer details3-(4-AMINO-1-ISOPROPYL-1H-PYRAZOLO[3, 4-D]PYRIMIDIN-3-YL)PHENOL (284): THIS IS COMPOUND S1 IN THE ...3-(4-AMINO-1-ISOPROPYL-1H-PYRAZOLO[3, 4-D]PYRIMIDIN-3-YL)PHENOL (284): THIS IS COMPOUND S1 IN THE NAT CHEM BIOL PUBLICATION APSEL ET AL
Sequence detailsRESIDUES 144-1102

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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: 2.49 Å3/Da / Density % sol: 50 % / Description: NONE
Crystal growpH: 7.5
Details: RESERVOIR: 16-17% PEG 4000, 250 MM (NH4)2SO4 AND 100MM TRIS PH 7.5 PROTEIN: 4 MG/ML IN A BUFFER CONTAINING 0.5 MM (NH4)2SO4, 20 MM TRIS PH 7.2, 1% ETHYLENE GLYCOL, 0.02% CHAPS AND 5 MM DTT ...Details: RESERVOIR: 16-17% PEG 4000, 250 MM (NH4)2SO4 AND 100MM TRIS PH 7.5 PROTEIN: 4 MG/ML IN A BUFFER CONTAINING 0.5 MM (NH4)2SO4, 20 MM TRIS PH 7.2, 1% ETHYLENE GLYCOL, 0.02% CHAPS AND 5 MM DTT DROPS WERE 1MICROLITER PROTEIN PLUS 1 MICROLITER RESERVOIR

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.934
DetectorType: ADSC CCD / 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: 0.934 Å / Relative weight: 1
ReflectionResolution: 2.5→54.4 Å / Num. obs: 33672 / % possible obs: 99.7 % / Observed criterion σ(I): -3.7 / Redundancy: 3.7 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 10
Reflection shellResolution: 2.5→2.64 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 1.7 / % possible all: 97.4

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2CHX

2chx


Resolution: 2.5→54.39 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.88 / SU B: 11.231 / SU ML: 0.257 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.681 / ESU R Free: 0.344 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.296 1440 4.1 %RANDOM
Rwork0.248 ---
obs0.25 33672 97.2 %-
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 mean: 21.03 Å2
Baniso -1Baniso -2Baniso -3
1--1.33 Å20 Å21.06 Å2
2--2.93 Å20 Å2
3----1.4 Å2
Refinement stepCycle: LAST / Resolution: 2.5→54.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6850 0 20 50 6920
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0217020
X-RAY DIFFRACTIONr_bond_other_d0.0020.026413
X-RAY DIFFRACTIONr_angle_refined_deg1.4571.9559497
X-RAY DIFFRACTIONr_angle_other_deg0.867314946
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1575836
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0830.21064
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.027635
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021400
X-RAY DIFFRACTIONr_nbd_refined0.220.21630
X-RAY DIFFRACTIONr_nbd_other0.2260.27543
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0880.24334
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1980.2141
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.4260.28
X-RAY DIFFRACTIONr_symmetry_vdw_other0.3030.223
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4890.22
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5121.54211
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.93426830
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.44732809
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.3494.52667
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.56 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.401 105
Rwork0.265 2475
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)
13.1332-0.2514-0.28291.8150.26953.06160.0066-0.5054-0.44750.3270.0834-0.32840.2520.1945-0.08990.0963-0.0722-0.06720.05850.02620.179233.6997-15.741234.2413
23.26761.97620.01022.2962-0.15423.84520.03870.3208-0.2343-0.2993-0.0804-0.78730.0260.97450.04170.2761-0.04420.16890.5359-0.15860.613358.5036-10.707614.0466
33.3141-0.21660.42091.39470.33925.39070.0222-0.33780.15390.1241-0.08290.3725-0.3121-0.66260.06070.19810.01570.07710.41470.06880.1614.9885-6.686138.186
46.40031.01161.29720.2659-0.21983.4073-0.02360.3057-0.2824-0.23780.1491-0.03270.0506-0.2298-0.12560.1779-0.0759-0.01880.0944-0.05310.083813.8464-10.967911.6046
53.83640.18551.64162.6692-0.45613.60240.0392-0.78130.08390.460.0392-0.3892-0.31630.1272-0.07840.2908-0.15380.01550.2623-0.11080.275846.53525.637335.9046
63.19620.97370.3263.2878-0.13441.9693-0.0670.09990.7636-0.2110.07950.1058-0.55490.0813-0.01240.4286-0.09640.07180.1458-0.01750.233837.385718.914216.871
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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