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- PDB-3p2b: Crystal Structure of PI3K gamma with 3-(2-morpholino-6-(pyridin-3... -

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Basic information

Entry
Database: PDB / ID: 3p2b
TitleCrystal Structure of PI3K gamma with 3-(2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenol
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PI3-kinase p110 subunit gamma / Transferase / Lipid Kinase / ATP Binding / 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 / 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 / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / phosphorylation / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / neutrophil chemotaxis / ephrin receptor binding / 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- and 4-kinases signature 2. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / 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-P2B / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.2 Å
AuthorsKnapp, M.S. / Elling, R.A. / Ornelas, E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Identification and structure-activity relationship of 2-morpholino 6-(3-hydroxyphenyl) pyrimidines, a class of potent and selective PI3 kinase inhibitors.
Authors: Pecchi, S. / Renhowe, P.A. / Taylor, C. / Kaufman, S. / Merritt, H. / Wiesmann, M. / Shoemaker, K.R. / Knapp, M.S. / Ornelas, E. / Hendrickson, T.F. / Fantl, W. / Voliva, C.F.
History
DepositionOct 1, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 17, 2011Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)111,1062
Polymers110,7561
Non-polymers3491
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)141.120, 66.780, 105.970
Angle α, β, γ (deg.)90.000, 96.950, 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 / PtdIns-3-kinase subunit gamma / PI3-kinase subunit gamma / PI3K-gamma / Phosphatidylinositol-4 / 5- ...PtdIns-3-kinase subunit gamma / PI3-kinase subunit gamma / PI3K-gamma / Phosphatidylinositol-4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / PtdIns-3-kinase subunit p110-gamma / p120-PI3K


Mass: 110756.164 Da / Num. of mol.: 1 / Fragment: UNP residues 144-1102 / Mutation: Q459R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG, PK3CG / Plasmid: pVL1393 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Tn5
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-P2B / 3-[2-morpholin-4-yl-6-(pyridin-3-ylamino)pyrimidin-4-yl]phenol


Mass: 349.386 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / 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: 2.24 Å3/Da / Density % sol: 45.03 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 16-19% PEG 4000, 0.2M Sodium Acetate, 0.1M Sodium Citrate, 0.1M TRIS pH 8.5 [Protein] ~6mg/mL in 20mM Tris pH 7.2, 50mM AmmSO4, 1% Betaine, 1% Ethylene Glycol, 0.02% CHAPS, 5mM DTT Drop: 1uL ...Details: 16-19% PEG 4000, 0.2M Sodium Acetate, 0.1M Sodium Citrate, 0.1M TRIS pH 8.5 [Protein] ~6mg/mL in 20mM Tris pH 7.2, 50mM AmmSO4, 1% Betaine, 1% Ethylene Glycol, 0.02% CHAPS, 5mM DTT Drop: 1uL + 1uL, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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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: Nov 25, 2009
RadiationMonochromator: double-crystal, Si(111) liquid N2 cooled / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.05→105.191 Å / Num. all: 18727 / Num. obs: 17914 / % possible obs: 99.2 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.2 % / Rsym value: 0.081 / Net I/σ(I): 10.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
3.05-3.213.20.5241.5881727350.52499.9
3.21-3.413.20.3232.4833025670.32399.7
3.41-3.653.20.1854.1782324240.18599.6
3.65-3.943.20.1166.4730822770.11699.8
3.94-4.313.20.07410662520720.07499.4
4.31-4.823.20.05811.9602818900.05899.3
4.82-5.573.20.0679.5532516810.06799.1
5.57-6.8230.0768.3419213760.07697.9
6.82-9.643.10.03514.4338410880.03597
9.64-70.0423.20.03118.319616170.03197.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 34.91 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.05 Å70.04 Å
Translation3.05 Å70.04 Å

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.15data scaling
PHASER2.1.4phasing
PHENIX1.6.1_357refinement
PDB_EXTRACT3.1data extraction
BOSdata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.2→70.04 Å / Occupancy max: 1 / Occupancy min: 0.43 / SU ML: 0.43 / σ(F): 1.35 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.263 834 5.14 %RANDOM
Rwork0.1823 ---
obs0.1866 16226 98.9 %-
all-16226 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 61.479 Å2 / ksol: 0.323 e/Å3
Displacement parametersBiso max: 470.34 Å2 / Biso mean: 81.712 Å2 / Biso min: 12.03 Å2
Baniso -1Baniso -2Baniso -3
1-0.9927 Å20 Å23.7736 Å2
2---6.7497 Å20 Å2
3---5.757 Å2
Refinement stepCycle: LAST / Resolution: 3.2→70.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6383 0 26 17 6426
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0026552
X-RAY DIFFRACTIONf_angle_d0.4918890
X-RAY DIFFRACTIONf_chiral_restr0.0351023
X-RAY DIFFRACTIONf_plane_restr0.0021126
X-RAY DIFFRACTIONf_dihedral_angle_d10.3622368
LS refinement shellResolution: 3.2→3.4004 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.3051 128 -
Rwork0.2158 2576 -
all-2704 -
obs-2731 100 %
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)
12.8011-0.8646-0.58320.49810.4231.61140.01220.326-0.515-0.0356-0.07540.18040.0421-0.030.07360.10030.13170.02650.0825-0.08780.112536.3764-11.938320.5005
22.43691.74751.47971.25331.06110.8984-0.4327-2.6358-0.17360.3150.47520.15230.18461.12320.03010.37980.12140.41722.998-0.38030.651560.0207-11.444957.9862
33.7789-1.43310.01660.56820.14272.34-0.0101-0.6979-0.2507-0.00460.05770.07870.10970.432-0.02290.130.0049-0.02070.29340.12080.14243.3723-11.693333.2544
42.8728-0.0801-0.99530.93630.07960.95550.24791.6841-0.46240.382-0.29490.0858-0.5696-0.97520.06410.29290.3277-0.07550.9394-0.06190.167217.5894-0.77997.006
54.5123-2.47990.25363.4760.31862.25410.4062-0.05280.41830.2885-0.53960.4146-0.6506-0.48360.11160.06350.2325-0.0050.17010.06420.097618.392310.718327.1877
63.3131-1.49360.09722.48841.03623.38270.2474-0.60821.12460.2474-0.1966-0.6633-0.68740.0711-0.06710.4409-0.0329-0.01890.2446-0.09370.450731.141815.081938.9431
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 143:522)A143 - 522
2X-RAY DIFFRACTION2(chain A and resid 525:548)A525 - 548
3X-RAY DIFFRACTION3(chain A and resid 549:721)A549 - 721
4X-RAY DIFFRACTION4(chain A and resid 722:783)A722 - 783
5X-RAY DIFFRACTION5(chain A and resid 784:952)A784 - 952
6X-RAY DIFFRACTION6(chain A and resid 953:1087)A953 - 1087

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