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- PDB-4fhj: Crystal Structure of PI3K-gamma in Complex with Imidazopyridine 2 -

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Basic information

Entry
Database: PDB / ID: 4fhj
TitleCrystal Structure of PI3K-gamma in Complex with Imidazopyridine 2
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTransferase/Inhibitor / inhibitor / p110 / kinase / transferase / ATP-binding / p84 / p101 / Transferase-Inhibitor complex
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 / phosphatidylinositol 3-kinase complex, class IB / negative regulation of fibroblast apoptotic process / sphingosine-1-phosphate receptor signaling pathway / dendritic cell chemotaxis / 1-phosphatidylinositol-4-phosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / 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) / positive regulation of Rac protein signal transduction / hepatocyte apoptotic process / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / regulation of cell adhesion mediated by integrin / Synthesis of PIPs at the plasma membrane / 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 / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / C2 domain ...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 / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / C2 domain / 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-0TZ / 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
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 1.0Jul 18, 2012Provider: repository / Type: Initial release
Revision 1.1Aug 29, 2012Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Sep 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)110,5166
Polymers109,8241
Non-polymers6925
Water95553
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)143.442, 67.300, 106.039
Angle α, β, γ (deg.)90.000, 95.670, 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 / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-0TZ / 3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-amine


Mass: 307.313 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H13N9
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 53 / 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: 46.96 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: 19.6% PEG 3350, 0.1M Tris, 0.1M ammonium sulfate, 10 mM DTT, pH 7.8, 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: Sep 8, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 31165 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Rmerge(I) obs: 0.071 / Χ2: 1.036 / Net I/σ(I): 11.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.6-2.693.40.57630470.925198.1
2.69-2.83.70.46530990.9361100
2.8-2.933.70.33131270.9871100
2.93-3.083.70.22430601.0211100
3.08-3.283.70.15931171.081100
3.28-3.533.70.10231151.0931100
3.53-3.883.70.07731061.1361100
3.88-4.453.70.06731351.197199.9
4.45-5.63.60.05531470.9921100
5.6-503.60.0332120.98199.8

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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
Resolution: 2.6→44.58 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.921 / Occupancy max: 1 / Occupancy min: 1 / SU B: 25.952 / SU ML: 0.264 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.784 / ESU R Free: 0.316 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.2533 1553 5 %RANDOM
Rwork0.2107 ---
obs0.2128 31102 99.46 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 154.15 Å2 / Biso mean: 72.2468 Å2 / Biso min: 31.82 Å2
Baniso -1Baniso -2Baniso -3
1--2.16 Å20 Å20.42 Å2
2--5.41 Å20 Å2
3----3.17 Å2
Refinement stepCycle: LAST / Resolution: 2.6→44.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6460 0 43 53 6556
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.026638
X-RAY DIFFRACTIONr_angle_refined_deg0.9391.9629016
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.545807
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.62824.415299
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.582151110
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2371533
X-RAY DIFFRACTIONr_chiral_restr0.0620.21036
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0214958
LS refinement shellResolution: 2.6→2.666 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.297 100 -
Rwork0.3 2005 -
all-2105 -
obs--96.12 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
15.51880.67790.20391.50450.33344.0170.12680.0228-1.22890.0606-0.13870.47740.3606-0.73310.0120.1468-0.044-0.02850.1438-0.05610.554621.0141-14.599926.9508
25.7697-1.5922-0.85633.23932.50067.3460.2108-0.1386-0.66570.1877-0.14780.54140.1057-1.1398-0.06310.0825-0.09110.09520.3322-0.03160.490111.399-12.486831.019
35.37720.44020.9943.9819-2.31197.3021-0.08531.06020.24520.0215-0.1537-0.2677-0.47811.45710.2390.0804-0.08460.00471.0529-0.07560.073766.0792-2.929413.9517
45.9749-0.2270.14322.2526-2.18626.63280.12721.0854-0.023-0.2296-0.1703-0.1758-0.16580.99870.04320.1232-0.01940.05230.7479-0.1740.09655.8245-5.347411.6744
54.5238-0.77911.97840.7209-0.19213.31280.0418-0.1275-0.51580.10180.0520.080.10620.2541-0.09390.1848-0.0060.01610.0717-0.0220.165145.2312-9.863133.5799
64.5294-0.78490.67723.1354-0.06331.81160.10390.64350.0097-0.2106-0.09630.5102-0.355-0.3674-0.00760.21860.0920.00470.2679-0.05410.166619.53315.325517.3926
73.3663-1.55750.76713.5102-0.37892.469-0.3354-0.5170.68650.72330.0089-0.1094-0.4704-0.11580.32650.5341-0.0044-0.03050.1769-0.22750.309228.112719.06237.3004
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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