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- PDB-2chw: A pharmacological map of the PI3-K family defines a role for p110... -

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Basic information

Entry
Database: PDB / ID: 2chw
TitleA pharmacological map of the PI3-K family defines a role for p110 alpha in signaling: The structure of complex of phosphoinositide 3- kinase gamma with inhibitor PIK-39
ComponentsPHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM
KeywordsTRANSFERASE/INHIBITOR / COMPLEX TRANSFERASE-INHIBITOR / PHOSPHOINOSITIDE / KINASE / LIPID / INHIBITOR / 3-KINASE / SIGNALING / QUINAZOLINONE / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


negative regulation of cardiac muscle contraction / 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 / T cell chemotaxis / negative regulation of fibroblast apoptotic process ...negative regulation of cardiac muscle contraction / 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 / 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 / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / hepatocyte apoptotic process / phosphatidylinositol-mediated signaling / regulation of cell adhesion mediated by integrin / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / positive regulation of MAP kinase activity / 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / 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 / cytosol / cytoplasm
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 / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / C2 domain / 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 / C2 domain superfamily / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / 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-039 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsKnight, Z.A. / Gonzalez, B. / Feldman, M.E. / Zunder, E.R. / Goldenberg, D.D. / Williams, O. / Loewith, R. / Stokoe, D. / Balla, A. / Toth, B. ...Knight, Z.A. / Gonzalez, B. / Feldman, M.E. / Zunder, E.R. / Goldenberg, D.D. / Williams, O. / Loewith, R. / Stokoe, D. / Balla, A. / Toth, B. / Balla, T. / Weiss, W.A. / Williams, R.L. / Shokat, K.M.
CitationJournal: Cell(Cambridge,Mass.) / Year: 2006
Title: A Pharmacological Map of the Pi3-K Family Defines a Role for P110Alpha in Signaling
Authors: Knight, Z.A. / Gonzalez, B. / Feldman, M.E. / Zunder, E.R. / Goldenberg, D.D. / Williams, O. / Loewith, R. / Stokoe, D. / Balla, A. / Toth, B. / Balla, T. / Weiss, W.A. / Williams, R.L. / Shokat, K.M.
History
DepositionMar 16, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 22, 2006Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 16, 2019Group: Data collection / Experimental preparation / Other / Category: exptl_crystal_grow / pdbx_database_status
Item: _exptl_crystal_grow.method / _pdbx_database_status.status_code_sf
Revision 1.4Dec 13, 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
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)111,2072
Polymers110,7561
Non-polymers4511
Water1448
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)143.804, 67.523, 106.311
Angle α, β, γ (deg.)90.00, 95.45, 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 / PHOSPHOINOSITIDE 3-KINASE / PI3-KINASE P110 SUBUNIT GAMMA / PTDINS-3-KINASE P110 / PI3K / PI3KGAMMA


Mass: 110756.164 Da / Num. of mol.: 1
Fragment: HUMAN PI-3K GAMMA 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 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-039 / 2-((9H-PURIN-6-YLTHIO)METHYL)-5-CHLORO-3-(2-METHOXYPHENYL)QUINAZOLIN-4(3H)-ONE / PIK-39


Mass: 450.901 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H15ClN6O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / 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: 2.4 Å3/Da / Density % sol: 40 %
Crystal growMethod: vapor diffusion / pH: 7.5
Details: VAPOUR DIFFUSION 1 MICROLITER PROTEIN PLUS 1 MICROLITER RESERVOIR RESERVOIR: 17% PEG 4000, 250 MM AMMONIUM SULFATE AND 100 MM TRIS PH 7.5 PROTEIN: 4 MG/ML IN 0.5 MM AMMONIUM SULFATE, 20 MM ...Details: VAPOUR DIFFUSION 1 MICROLITER PROTEIN PLUS 1 MICROLITER RESERVOIR RESERVOIR: 17% PEG 4000, 250 MM AMMONIUM SULFATE AND 100 MM TRIS PH 7.5 PROTEIN: 4 MG/ML IN 0.5 MM AMMONIUM SULFATE, 20 MM TRIS PH 7.2, 1% ETHYLENE GLYCOL, 0.02% CHAPS AND 5 MM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.9793
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: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.6→62.14 Å / Num. obs: 31445 / % possible obs: 99.9 % / Observed criterion σ(I): -3.7 / Redundancy: 3.68 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 17.72
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 2.15 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
MOSFLMdata reduction
SCALAdata scaling
TRUNCATEdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1E8Z

1e8z


Resolution: 2.6→62.14 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.889 / SU B: 34.088 / SU ML: 0.355 / Cross valid method: THROUGHOUT / ESU R: 0.983 / ESU R Free: 0.376 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.299 1295 4.1 %RANDOM
Rwork0.237 ---
obs0.24 30150 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 62.69 Å2
Baniso -1Baniso -2Baniso -3
1--1.28 Å20 Å2-0.52 Å2
2--1.87 Å20 Å2
3----0.68 Å2
Refinement stepCycle: LAST / Resolution: 2.6→62.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6807 0 31 8 6846
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0226988
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4191.9659455
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7245832
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.48524.233326
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.775151268
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6251542
X-RAY DIFFRACTIONr_chiral_restr0.0960.21059
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.025205
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2420.23371
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3110.24770
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1720.2235
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2120.227
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1880.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5621.54288
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.98426799
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.28633076
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.0154.52656
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: 2.6→2.67 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.406 94
Rwork0.341 2191

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