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- PDB-4anu: Complexes of PI3Kgamma with isoform selective inhibitors. -

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Entry
Database: PDB / ID: 4anu
TitleComplexes of PI3Kgamma with isoform selective inhibitors.
ComponentsPHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM
KeywordsTRANSFERASE
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-EM7 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.81 Å
AuthorsFoster, P.G. / Lougheed, J.C.
CitationJournal: J.Med.Chem. / Year: 2012
Title: The Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase Gamma Inhibitors
Authors: Leahy, J.W. / Buhr, C.A. / Johnson, H.W.B. / Kim, B.G. / Baik, T. / Cannoy, J. / Forsyth, T.P. / Jeong, J.W. / Lee, M.S. / Ma, S. / Noson, K. / Wang, L. / Williams, M. / Nuss, J.M. / Brooks, ...Authors: Leahy, J.W. / Buhr, C.A. / Johnson, H.W.B. / Kim, B.G. / Baik, T. / Cannoy, J. / Forsyth, T.P. / Jeong, J.W. / Lee, M.S. / Ma, S. / Noson, K. / Wang, L. / Williams, M. / Nuss, J.M. / Brooks, E. / Heald, N. / Holst, C. / Jaeger, C. / Lam, S. / Lougheed, J.C. / Nguyen, L. / Plonowski, A. / Stout, T. / Foster, P.G. / Wu, X. / Yakes, M.F. / Yu, R. / Zhang, W. / Lamb, P. / Raeber, O.
History
DepositionMar 22, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 9, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 27, 2012Group: Other

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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)112,4913
Polymers112,0991
Non-polymers3922
Water46826
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)145.252, 68.529, 106.856
Angle α, β, γ (deg.)90.00, 95.29, 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 SUBUNIT GAMMA / PI3K-GAMMA / PI3KGAMMA / PTDINS-3-KINASE SUBUNIT GAMMA / ...PI3-KINASE SUBUNIT GAMMA / PI3K-GAMMA / PI3KGAMMA / PTDINS-3-KINASE SUBUNIT GAMMA / PHOSPHATIDYLINOSITOL-4\ / 5-BISPHOSPHATE 3-KINASE 110 KDA CATALYTIC SUBUNIT GAMMA / PTDINS-3-KINASE SUBUNIT P110-GAMMA / P110GAMMA / PHOSPHOINOSITIDE-3-KINASE CATALYTIC GAMMA POLYPEPTIDE / SERINE/THREONINE PROTEIN KINASE PIK3CG / P120-PI3K


Mass: 112098.672 Da / Num. of mol.: 1 / Fragment: CATALYTIC SUBUNIT GAMMA, RESIDUES 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P48736, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-EM7 / 3-AMINO-N-METHYL-6-[3-(1H-TETRAZOL-5-YL)PHENYL]PYRAZINE-2-CARBOXAMIDE


Mass: 296.287 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H12N8O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 26 / 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: 49 % / Description: NONE
Crystal growpH: 7.2 / Details: pH 7.2

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Data collection

DiffractionMean temperature: 155 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97946
DetectorType: MARRESEARCH SX-165 / Detector: CCD / Date: Oct 8, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.81→28.7 Å / Num. obs: 24447 / % possible obs: 94.9 % / Observed criterion σ(I): -3 / Redundancy: 3.8 % / Rmerge(I) obs: 0.11 / Net I/σ(I): 9.5
Reflection shellResolution: 2.81→3.05 Å / Redundancy: 3.9 % / Rmerge(I) obs: 1.01 / Mean I/σ(I) obs: 1.6 / % possible all: 98.1

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: IN-HOUSE PI3KG STRUCTURE

Resolution: 2.81→28.7 Å / Cor.coef. Fo:Fc: 0.901 / Cor.coef. Fo:Fc free: 0.828 / SU B: 20.475 / SU ML: 0.406 / Cross valid method: THROUGHOUT / ESU R Free: 0.538 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.33815 1242 5.1 %RANDOM
Rwork0.25371 ---
obs0.25807 22934 93.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 62.576 Å2
Baniso -1Baniso -2Baniso -3
1-0.23 Å20 Å20.11 Å2
2---0.02 Å20 Å2
3----0.2 Å2
Refinement stepCycle: LAST / Resolution: 2.81→28.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6757 0 27 26 6810
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0226929
X-RAY DIFFRACTIONr_bond_other_d0.0010.024752
X-RAY DIFFRACTIONr_angle_refined_deg1.5561.9629373
X-RAY DIFFRACTIONr_angle_other_deg1.01311585
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.9045826
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.59124.329328
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.775151260
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2781542
X-RAY DIFFRACTIONr_chiral_restr0.0940.21048
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.027549
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021380
X-RAY DIFFRACTIONr_nbd_refined0.2460.22010
X-RAY DIFFRACTIONr_nbd_other0.2060.25171
X-RAY DIFFRACTIONr_nbtor_refined0.1940.23349
X-RAY DIFFRACTIONr_nbtor_other0.0910.23631
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1650.2227
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0170.22
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1450.25
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1710.218
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6291.54335
X-RAY DIFFRACTIONr_mcbond_other0.0821.51667
X-RAY DIFFRACTIONr_mcangle_it1.08926743
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.09433032
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.7414.52630
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: 2.81→2.882 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.501 71 -
Rwork0.347 1753 -
obs--97.28 %

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