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- PDB-4aof: Selective small molecule inhibitor discovered by chemoproteomic a... -

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Basic information

Entry
Database: PDB / ID: 4aof
TitleSelective small molecule inhibitor discovered by chemoproteomic assay platform reveals regulation of Th17 cell differentiation by PI3Kgamma
ComponentsPHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM
KeywordsTRANSFERASE
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-7L0 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsBergamini, G. / Bell, K. / Shimamura, S. / Werner, T. / Cansfield, A. / Muller, K. / Perrin, J. / Rau, C. / Ellard, K. / Hopf, C. ...Bergamini, G. / Bell, K. / Shimamura, S. / Werner, T. / Cansfield, A. / Muller, K. / Perrin, J. / Rau, C. / Ellard, K. / Hopf, C. / Doce, C. / Leggate, D. / Mangano, R. / Mathieson, T. / OMahony, A. / Plavec, I. / Rharbaoui, F. / Reinhard, F. / Savitski, M.M. / Ramsden, N. / Hirsch, E. / Drewes, G. / Rausch, O. / Bantscheff, M. / Neubauer, G.
CitationJournal: Nat.Chem.Biol. / Year: 2012
Title: A Selective Inhibitor Reveals Pi3Kgamma Dependence of T(H)17 Cell Differentiation.
Authors: Bergamini, G. / Bell, K. / Shimamura, S. / Werner, T. / Cansfield, A. / Muller, K. / Perrin, J. / Rau, C. / Ellard, K. / Hopf, C. / Doce, C. / Leggate, D. / Mangano, R. / Mathieson, T. / ...Authors: Bergamini, G. / Bell, K. / Shimamura, S. / Werner, T. / Cansfield, A. / Muller, K. / Perrin, J. / Rau, C. / Ellard, K. / Hopf, C. / Doce, C. / Leggate, D. / Mangano, R. / Mathieson, T. / O'Mahony, A. / Plavec, I. / Rharbaoui, F. / Reinhard, F. / Savitski, M.M. / Ramsden, N. / Hirsch, E. / Drewes, G. / Rausch, O. / Bantscheff, M. / Neubauer, G.
History
DepositionMar 26, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 9, 2012Provider: repository / Type: Initial release
Revision 1.1May 30, 2012Group: Other
Revision 1.2Jul 11, 2012Group: Other
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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)110,2302
Polymers109,8981
Non-polymers3311
Water52229
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.771, 68.047, 109.873
Angle α, β, γ (deg.)90.00, 94.61, 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 / 2.7.1.153 / ...PI3-KINASE SUBUNIT GAMMA / PI3K-GAMMA / PI3KGAMMA / PTDINS-3-KINASE SUBUNIT GAMMA / 2.7.1.153 / 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: 109898.203 Da / Num. of mol.: 1 / Fragment: P110 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-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-7L0 / N-[6-(5-methylsulfonylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]ethanamide


Mass: 331.350 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H13N5O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 29 / 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: 2.52 Å3/Da / Density % sol: 51.22 % / Description: NONE
Crystal growpH: 7.6
Details: 19% PEG 3350, 0.2 M AMMONIUM SULFATE, 0.1 M TRIS-HCL PH 7.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 0.933
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Jul 12, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 3.3→71.07 Å / Num. obs: 15062 / % possible obs: 94.2 % / Observed criterion σ(I): 2 / Redundancy: 3 % / Rmerge(I) obs: 0.19 / Net I/σ(I): 7.2
Reflection shellResolution: 3.3→3.48 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.9 / Mean I/σ(I) obs: 0.9 / % possible all: 94.7

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1E8Y

1e8y


Resolution: 3.3→109.76 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.825 / SU B: 93.804 / SU ML: 0.743 / Cross valid method: THROUGHOUT / ESU R Free: 0.818 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.34582 759 5 %RANDOM
Rwork0.23639 ---
obs0.24195 14294 93.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 65.29 Å2
Baniso -1Baniso -2Baniso -3
1--4.27 Å20 Å23.79 Å2
2---3.19 Å20 Å2
3---8.07 Å2
Refinement stepCycle: LAST / Resolution: 3.3→109.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6741 0 23 29 6793
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0226910
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2721.9629355
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5865829
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.44124.317322
X-RAY DIFFRACTIONr_dihedral_angle_3_deg22.056151245
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.741541
X-RAY DIFFRACTIONr_chiral_restr0.0870.21052
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025157
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2350.23705
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3090.24590
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1690.2306
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1820.228
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3020.21
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.3271.54278
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.50226759
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.66132983
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it0.9514.52596
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: 3.3→3.386 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.46 61 -
Rwork0.325 1026 -
obs--93.55 %

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