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- PDB-7ois: mPI3Kd in complex with compound 7 -

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Basic information

Entry
Database: PDB / ID: 7ois
TitlemPI3Kd in complex with compound 7
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / Inhibitor / complex
Function / homology
Function and homology information


Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of signaling by CBL / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / phosphatidylinositol 3-kinase complex ...Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of signaling by CBL / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / phosphatidylinositol 3-kinase complex / 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 / B cell homeostasis / B cell activation / phosphatidylinositol-mediated signaling / homeostasis of number of cells / defense response to fungus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of angiogenesis / chemotaxis / kinase activity / adaptive immune response / cell differentiation / cell surface receptor signaling pathway / inflammatory response / negative regulation of gene expression / innate immune response / positive regulation of gene expression / ATP binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PI3Kdelta, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding 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 ...PI3Kdelta, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding 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 / C2 domain superfamily / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-VEW / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsPetersen, J.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of AZD8154, a Dual PI3K gamma delta Inhibitor for the Treatment of Asthma.
Authors: Perry, M.W.D. / Bjorhall, K. / Bold, P. / Brulls, M. / Borjesson, U. / Carlsson, J. / Chang, H.A. / Chen, Y. / Eriksson, A. / Fihn, B.M. / Fransson, R. / Fredlund, L. / Ge, H. / Huang, H. / ...Authors: Perry, M.W.D. / Bjorhall, K. / Bold, P. / Brulls, M. / Borjesson, U. / Carlsson, J. / Chang, H.A. / Chen, Y. / Eriksson, A. / Fihn, B.M. / Fransson, R. / Fredlund, L. / Ge, H. / Huang, H. / Karabelas, K. / Lamm Bergstrom, E. / Lever, S. / Lindmark, H. / Mogemark, M. / Nikitidis, A. / Palmgren, A.P. / Pemberton, N. / Petersen, J. / Rodrigo Blomqvist, M. / Smith, R.W. / Thomas, M.J. / Ullah, V. / Tyrchan, C. / Wennberg, T. / Westin Eriksson, A. / Yang, W. / Zhao, S. / Oster, L.
History
DepositionMay 12, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 14, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 29, 2021Group: Advisory / Database references / Structure summary
Category: database_2 / entity ...database_2 / entity / entity_name_com / pdbx_unobs_or_zero_occ_atoms / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _entity.pdbx_ec / _struct_ref.db_code / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_db_accession
Revision 1.2May 1, 2024Group: Data collection / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
AAA: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)125,4463
Polymers124,8351
Non-polymers6122
Water27,5991532
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area100 Å2
ΔGint-7 kcal/mol
Surface area37540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.900, 64.960, 116.140
Angle α, β, γ (deg.)90.000, 103.590, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11AAA-1946-

HOH

21AAA-1981-

HOH

31AAA-2583-

HOH

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Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform / PI3-kinase subunit delta / PI3K-delta / PI3Kdelta / PtdIns-3-kinase subunit delta / ...PI3-kinase subunit delta / PI3K-delta / PI3Kdelta / PtdIns-3-kinase subunit delta / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit delta / PtdIns-3-kinase subunit p110-delta / p110delta


Mass: 124834.523 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Pik3cd
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: O35904, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-VEW / N-[5-[2-[(1S)-1-cyclopropylethyl]-7-[(3-methylsulfonylphenyl)sulfamoyl]-1-oxidanylidene-3H-isoindol-5-yl]-4-methyl-1,3-thiazol-2-yl]ethanamide


Mass: 588.719 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H28N4O6S3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1532 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.08 Å3/Da / Density % sol: 40.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: ethylene glycol per PEG 8000, carboxylic acids mix, buffer system 2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-D / Wavelength: 1.542 Å
DetectorType: RIGAKU SATURN A200 / Detector: CCD / Date: Dec 1, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.542 Å / Relative weight: 1
ReflectionResolution: 2.3→31.21 Å / Num. obs: 45929 / % possible obs: 99.9 % / Redundancy: 2.5 % / Rmerge(I) obs: 0.153 / Net I/σ(I): 7.6
Reflection shellResolution: 2.3→2.38 Å / Rmerge(I) obs: 0.345 / Num. unique obs: 4484

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
iMOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Internal Model

Resolution: 2.3→31.024 Å / Cor.coef. Fo:Fc: 0.911 / Cor.coef. Fo:Fc free: 0.818 / WRfactor Rfree: 0.318 / WRfactor Rwork: 0.223 / SU B: 12.065 / SU ML: 0.303 / Average fsc free: 0.7008 / Average fsc work: 0.7482 / Cross valid method: FREE R-VALUE / ESU R: 0.43 / ESU R Free: 0.312
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.3062 2316 5.043 %
Rwork0.2085 43610 -
all0.213 --
obs-45926 99.859 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL PLUS MASK
Displacement parametersBiso mean: 43.984 Å2
Baniso -1Baniso -2Baniso -3
1-0.805 Å2-0 Å2-0.442 Å2
2--1.797 Å2-0 Å2
3----2.139 Å2
Refinement stepCycle: LAST / Resolution: 2.3→31.024 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6675 0 40 1532 8247
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0136861
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176522
X-RAY DIFFRACTIONr_angle_refined_deg1.3561.6449266
X-RAY DIFFRACTIONr_angle_other_deg1.131.57515024
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4215816
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.19322.417360
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.396151239
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9231541
X-RAY DIFFRACTIONr_chiral_restr0.0580.2855
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.027597
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021574
X-RAY DIFFRACTIONr_nbd_refined0.2320.22522
X-RAY DIFFRACTIONr_symmetry_nbd_other0.20.27337
X-RAY DIFFRACTIONr_nbtor_refined0.1590.23217
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0760.23311
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.3690.21497
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0710.26
X-RAY DIFFRACTIONr_metal_ion_refined0.4520.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2140.229
X-RAY DIFFRACTIONr_nbd_other0.1850.274
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.3160.236
X-RAY DIFFRACTIONr_mcbond_it2.8154.4253297
X-RAY DIFFRACTIONr_mcbond_other2.8154.4243296
X-RAY DIFFRACTIONr_mcangle_it4.316.6134102
X-RAY DIFFRACTIONr_mcangle_other4.316.6154103
X-RAY DIFFRACTIONr_scbond_it2.6244.6583562
X-RAY DIFFRACTIONr_scbond_other2.6234.6773521
X-RAY DIFFRACTIONr_scangle_it4.1516.8855161
X-RAY DIFFRACTIONr_scangle_other4.1566.9125104
X-RAY DIFFRACTIONr_lrange_it16.07658.7969967
X-RAY DIFFRACTIONr_lrange_other15.18857.6489091
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.3590.3481690.223197X-RAY DIFFRACTION99.9703
2.359-2.4240.3071550.23113X-RAY DIFFRACTION99.9694
2.424-2.4930.3561700.2322997X-RAY DIFFRACTION99.9684
2.493-2.570.3331470.1882955X-RAY DIFFRACTION99.9678
2.57-2.6530.3221700.1832813X-RAY DIFFRACTION100
2.653-2.7460.3111530.1912765X-RAY DIFFRACTION99.9657
2.746-2.8490.3691540.2672656X-RAY DIFFRACTION99.9644
2.849-2.9640.3461480.2072565X-RAY DIFFRACTION99.9632
2.964-3.0940.3551010.1772522X-RAY DIFFRACTION100
3.094-3.2440.2651140.1582372X-RAY DIFFRACTION99.9598
3.244-3.4170.2661120.1662232X-RAY DIFFRACTION99.9574
3.417-3.6220.2941200.1782125X-RAY DIFFRACTION100
3.622-3.8680.294960.1762019X-RAY DIFFRACTION99.8584
3.868-4.1730.2971040.1691862X-RAY DIFFRACTION99.9492
4.173-4.5630.2751060.2151721X-RAY DIFFRACTION99.8361
4.563-5.0880.257750.2521570X-RAY DIFFRACTION99.9392
5.088-5.8490.272680.2951398X-RAY DIFFRACTION99.9318
5.849-7.1020.364560.3191224X-RAY DIFFRACTION99.7662
7.102-9.7930.274590.272926X-RAY DIFFRACTION99.7974
9.793-31.0240.281390.284578X-RAY DIFFRACTION98.72

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