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- PDB-4fhk: Crystal Structure of PI3K-gamma in Complex with Imidazopyridazine 19e -

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Basic information

Entry
Database: PDB / ID: 4fhk
TitleCrystal Structure of PI3K-gamma in Complex with Imidazopyridazine 19e
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTransferase/Transferase Inhibitor / p110 / kinase / ATP-binding / p84 / p101 / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


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 / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis ...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 / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / 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-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / mast cell degranulation / 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-mediated signaling / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / phosphorylation / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / ephrin receptor binding / neutrophil chemotaxis / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of endothelial cell migration / T cell activation / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / kinase activity / phospholipase C-activating G protein-coupled receptor signaling pathway / 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 / inflammatory response / immune response / G protein-coupled receptor signaling pathway / 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-/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. / 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. / 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-0U0 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsShaffer, P.L. / Tang, J. / Yakowec, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors.
Authors: Peterson, E.A. / Boezio, A.A. / Andrews, P.S. / Boezio, C.M. / Bush, T.L. / Cheng, A.C. / Choquette, D. / Coats, J.R. / Colletti, A.E. / Copeland, K.W. / DuPont, M. / Graceffa, R. / ...Authors: Peterson, E.A. / Boezio, A.A. / Andrews, P.S. / Boezio, C.M. / Bush, T.L. / Cheng, A.C. / Choquette, D. / Coats, J.R. / Colletti, A.E. / Copeland, K.W. / DuPont, M. / Graceffa, R. / Grubinska, B. / Kim, J.L. / Lewis, R.T. / Liu, J. / Mullady, E.L. / Potashman, M.H. / Romero, K. / Shaffer, P.L. / Stanton, M.K. / Stellwagen, J.C. / Teffera, Y. / Yi, S. / Cai, T. / La, D.S.
History
DepositionJun 6, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 10, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.2Sep 13, 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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

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)110,5946
Polymers109,8241
Non-polymers7705
Water43224
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.544, 67.931, 106.487
Angle α, β, γ (deg.)90.000, 95.400, 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 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: 109824.055 Da / Num. of mol.: 1 / Fragment: catalytic domain (UNP residues 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-0U0 / 3-[2-methyl-6-(pyrazin-2-ylamino)pyrimidin-4-yl]-N-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-2-amine


Mass: 385.385 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H15N11
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / 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: 2.37 Å3/Da / Density % sol: 48.09 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 21% PEG 3350, 0.1M Tris, 0.2M ammonium sulfate, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 16, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 21084 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Rmerge(I) obs: 0.076 / Χ2: 1.04 / Net I/σ(I): 11.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
3-3.113.80.63821081.0611100
3.11-3.233.80.4320901.0141100
3.23-3.383.80.27620911.0341100
3.38-3.563.80.18820971.0861100
3.56-3.783.80.1220871.0551100
3.78-4.073.80.08420900.9981100
4.07-4.483.70.06821191.021100
4.48-5.133.70.06121061.048199.8
5.13-6.463.60.05521011.045199.7
6.46-503.60.03821951.038199.7

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMAC5.6.0117refinement
PDB_EXTRACT3.11data extraction
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB Entry 3QAQ

3qaq


Resolution: 3→40.96 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.908 / Occupancy max: 1 / Occupancy min: 1 / SU B: 41.541 / SU ML: 0.362 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.451 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.2597 1050 5 %RANDOM
Rwork0.222 ---
obs0.2238 21082 99.13 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 194 Å2 / Biso mean: 91.5559 Å2 / Biso min: 42.39 Å2
Baniso -1Baniso -2Baniso -3
1--2.68 Å20 Å2-0.2 Å2
2--5.88 Å20 Å2
3----3.24 Å2
Refinement stepCycle: LAST / Resolution: 3→40.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6460 0 49 24 6533
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.026645
X-RAY DIFFRACTIONr_angle_refined_deg0.841.9639025
X-RAY DIFFRACTIONr_dihedral_angle_1_deg3.9225807
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.4924.415299
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.539151110
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.3021533
X-RAY DIFFRACTIONr_chiral_restr0.0520.21036
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0214965
LS refinement shellResolution: 3→3.058 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.305 66 -
Rwork0.295 1274 -
all-1340 -
obs--89.69 %
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)
17.8307-0.3280.11481.2103-0.08465.13190.1933-0.1995-1.8101-0.07130.04560.5920.2033-0.6437-0.23890.2154-0.0581-0.06780.08970.07920.679221.5469-14.631927.3199
26.8695-1.8983-0.3273.24181.276611.39730.3413-0.5309-1.07080.02110.14620.41550.0989-1.4489-0.48750.0784-0.07490.08760.46280.24880.723311.9448-12.409631.3517
35.00051.0591-0.30946.2961-3.17839.3389-0.07161.40360.1586-0.41010.011-0.4195-0.23151.50460.06050.106-0.08020.06451.2927-0.13710.106266.6281-3.253314.0939
48.5005-1.49671.49924.6231-1.30616.12480.12091.743-0.2414-0.1939-0.0474-0.2766-0.4111.1805-0.07350.2243-0.00150.08271.0737-0.25240.124256.3299-5.649811.8177
57.3499-1.24853.93790.8688-0.64284.69490.1374-0.1692-0.94260.06830.14060.10870.04690.2031-0.2780.14920.00170.0510.05810.0220.245945.8487-9.864833.9307
66.2339-0.77141.56393.5624-1.03542.8569-0.07140.75110.0447-0.33340.18960.6573-0.5052-0.4314-0.11820.3010.1232-0.0040.2520.060.188720.0675.239817.4441
77.1946-1.77621.20884.25-0.60882.4204-0.8298-0.97091.57610.92150.2426-0.1548-0.7783-0.26490.58720.69280.1423-0.15630.165-0.27560.508128.792919.326537.2721
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A145 - 252
2X-RAY DIFFRACTION2A269 - 321
3X-RAY DIFFRACTION3A357 - 435
4X-RAY DIFFRACTION4A458 - 522
5X-RAY DIFFRACTION5A546 - 725
6X-RAY DIFFRACTION6A726 - 885
7X-RAY DIFFRACTION7A886 - 1092

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