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- PDB-3apd: Crystal structure of human PI3K-gamma in complex with CH5108134 -

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Basic information

Entry
Database: PDB / ID: 3apd
TitleCrystal structure of human PI3K-gamma in complex with CH5108134
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTransferase/Transferase inhibitor / phosphoinositide 3-kinase gamma / Kinase / Transferase / 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- 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-MMY / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsNakamura, M. / Fukami, T.A. / Miyazaki, T. / Yoshida, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799
Authors: Ohwada, J. / Ebiike, H. / Kawada, H. / Tsukazaki, M. / Nakamura, M. / Miyazaki, T. / Morikami, K. / Yoshinari, K. / Yoshida, M. / Kondoh, O. / Kuramoto, S. / Ogawa, K. / Aoki, Y. / Shimma, N.
History
DepositionOct 14, 2010Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 13, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 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

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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)111,0164
Polymers110,4481
Non-polymers5693
Water27015
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.950, 67.460, 106.280
Angle α, β, γ (deg.)90.000, 95.680, 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 / PtdIns-3-kinase subunit gamma / Phosphatidylinositol-4 / 5- ...PI3-kinase subunit gamma / PI3K-gamma / PtdIns-3-kinase subunit gamma / Phosphatidylinositol-4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / PtdIns-3-kinase subunit p110-gamma / p120-PI3K


Mass: 110447.805 Da / Num. of mol.: 1 / Fragment: residues 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Plasmid: pFastBac1 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-MMY / 5-(2-Morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-ylamine


Mass: 376.415 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H20N8O
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 15 / 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: 2.3 Å3/Da / Density % sol: 46.3 % / Mosaicity: 0.172 °
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.2
Details: 20% PEG3350, 0.2M (NH4)2SO4, 0.1M Tris-HCl, streak seeding, pH 7.2, vapor diffusion, hanging drop, temperature 293K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 25, 2006 / Details: mirrors
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.548→60.953 Å / Num. all: 33084 / Num. obs: 33084 / % possible obs: 99.7 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.046 / Rsym value: 0.046 / Net I/σ(I): 17.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) allNum. measured allNum. unique all% possible all
2.55-2.613.760.681.139107241999.41
2.61-2.693.760.531.468947237799.94
2.69-2.763.770.41.938613228699.69
2.76-2.853.760.312.488431224299.66
2.85-2.943.770.243.248326220999.86
2.94-3.053.760.184.377839208699.95
3.05-3.163.740.145.67600203199.75
3.16-3.293.750.17.6173231952100
3.29-3.443.730.0710.367113190799.87
3.44-3.63.710.0513.796610178099.86
3.6-3.83.670.0416.556267170699.94
3.8-4.033.570.0320.515723160299.97
4.03-4.313.530.0322.175376152499.46
4.31-4.653.560.0323.015074142799.36
4.65-5.13.610.0323.434677129599.56
5.1-5.73.560.0322.294258119599.65
5.7-6.583.660.0324.493879105999.9
6.58-8.063.690.0229.79326688699.94
8.06-11.393.610.0231.44258271699.63
11.39-60.953.250.0228.61125038597.37

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
REFMACrefmac_5.5.0109refinement
PDB_EXTRACT3.1data extraction
ADSCQuantumdata collection
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1E8Y

1e8y


Resolution: 2.55→60.95 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.886 / WRfactor Rfree: 0.3047 / WRfactor Rwork: 0.2442 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7277 / SU B: 14.822 / SU ML: 0.327 / SU R Cruickshank DPI: 0.7486 / SU Rfree: 0.3762 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.376 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3162 1675 5.1 %RANDOM
Rwork0.2498 ---
obs0.2532 33084 100 %-
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 max: 105.28 Å2 / Biso mean: 59.4382 Å2 / Biso min: 10.11 Å2
Baniso -1Baniso -2Baniso -3
1--0.88 Å20 Å21.2 Å2
2--2.6 Å20 Å2
3----1.49 Å2
Refinement stepCycle: LAST / Resolution: 2.55→60.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6562 0 38 15 6615
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0226743
X-RAY DIFFRACTIONr_bond_other_d0.0010.024449
X-RAY DIFFRACTIONr_angle_refined_deg1.081.969163
X-RAY DIFFRACTIONr_angle_other_deg0.8013.00110837
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.215830
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.63824.262298
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.247151113
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.4511535
X-RAY DIFFRACTIONr_chiral_restr0.060.21048
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0217452
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021349
X-RAY DIFFRACTIONr_mcbond_it1.7424182
X-RAY DIFFRACTIONr_mcbond_other0.35521681
X-RAY DIFFRACTIONr_mcangle_it3.07436729
X-RAY DIFFRACTIONr_scbond_it4.19142561
X-RAY DIFFRACTIONr_scangle_it6.18162434
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection allNum. reflection obs
2.548-2.6140.4931070.385230824152415
2.614-2.6860.5051220.366225223742374
2.686-2.7630.3671180.35216422822282
2.763-2.8480.412990.33213722362236
2.848-2.9410.3751150.302209122062206
2.941-3.0440.3731020.282198220842084
3.044-3.1590.3921170.288191720342034
3.159-3.2880.392860.287186119471947
3.288-3.4330.341920.256180718991899
3.433-3.60.296750.244170117761776
3.6-3.7940.2891150.237159217071707
3.794-4.0230.302830.238151916021602
4.023-4.30.285780.233144815261526
4.3-4.6420.261720.207134614181418
4.642-5.0830.291570.213124713041304
5.083-5.6780.334710.25112912001200
5.678-6.5470.312540.254100210561056
6.547-7.9950.306530.215848901901
7.995-11.210.231390.168667706706
11.21-60.9530.272200.289391411411

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