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- PDB-7oil: mPI3Kd in complex with compound 58 -

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Basic information

Entry
Database: PDB / ID: 7oil
TitlemPI3Kd in complex with compound 58
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / mPI3kd / 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 activation / phosphatidylinositol-mediated signaling / B cell homeostasis / homeostasis of number of cells / defense response to fungus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of angiogenesis / chemotaxis / cell migration / kinase activity / adaptive immune response / cell surface receptor signaling pathway / cell differentiation / inflammatory response / phosphorylation / 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. / Phosphoinositide 3-kinase C2 ...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. / 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 / C2 domain superfamily / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-VEN / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.95 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 11, 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

Downloads & links

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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)125,4093
Polymers124,8351
Non-polymers5752
Water4,342241
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-9 kcal/mol
Surface area37680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)142.010, 64.750, 116.380
Angle α, β, γ (deg.)90.000, 103.390, 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 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-VEN / 2-[(1S)-1-cyclopropylethyl]-5-[4-methyl-2-[[6-(2-oxidanylidenepyrrolidin-1-yl)pyridin-2-yl]amino]-1,3-thiazol-5-yl]-7-methylsulfonyl-3H-isoindol-1-one / 141754136 / 2-[(1S)-1-cyclopropylethyl]-5-[4-methyl-2-[[6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]amino]-1,3-thiazol-5-yl]-7-methylsulfonyl-3H-isoindol-1-one


Mass: 551.680 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H29N5O4S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 241 / 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: 41 %
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-E / Wavelength: 1.542 Å
DetectorType: RIGAKU SATURN A200 / Detector: CCD / Date: Aug 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.542 Å / Relative weight: 1
ReflectionResolution: 1.95→31.13 Å / Num. obs: 75151 / % possible obs: 99.2 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.139 / Net I/σ(I): 6.2
Reflection shellResolution: 1.95→1.99 Å / Rmerge(I) obs: 1.319 / Num. unique obs: 4003

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Processing

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

Resolution: 1.95→31.127 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.9 / SU B: 8.291 / SU ML: 0.209 / Cross valid method: FREE R-VALUE / ESU R: 0.191 / ESU R Free: 0.18
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2893 3750 5.025 %
Rwork0.2389 70876 -
all0.241 --
obs-74626 99.251 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 40.119 Å2
Baniso -1Baniso -2Baniso -3
1-0.169 Å2-0 Å2-0.191 Å2
2--2.197 Å2-0 Å2
3----2.043 Å2
Refinement stepCycle: LAST / Resolution: 1.95→31.127 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6675 0 39 241 6955
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0136861
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176522
X-RAY DIFFRACTIONr_angle_refined_deg1.6651.6439265
X-RAY DIFFRACTIONr_angle_other_deg1.2781.57515024
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7915816
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.05222.417360
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.735151239
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4581541
X-RAY DIFFRACTIONr_chiral_restr0.080.2855
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.027598
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021574
X-RAY DIFFRACTIONr_nbd_refined0.2220.21489
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1860.26090
X-RAY DIFFRACTIONr_nbtor_refined0.1690.23221
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0810.23320
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2020.2242
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0950.25
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2650.211
X-RAY DIFFRACTIONr_nbd_other0.1920.247
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2460.24
X-RAY DIFFRACTIONr_mcbond_it3.7834.043297
X-RAY DIFFRACTIONr_mcbond_other3.7754.0393296
X-RAY DIFFRACTIONr_mcangle_it5.6026.0324102
X-RAY DIFFRACTIONr_mcangle_other5.6046.0334103
X-RAY DIFFRACTIONr_scbond_it4.0374.4353562
X-RAY DIFFRACTIONr_scbond_other4.0564.4613521
X-RAY DIFFRACTIONr_scangle_it6.3176.4955160
X-RAY DIFFRACTIONr_scangle_other6.3466.535104
X-RAY DIFFRACTIONr_lrange_it8.69546.0867687
X-RAY DIFFRACTIONr_lrange_other8.71546.2637599
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.95-20.3792660.37748680.37755180.3490.39493.0410.377
2-2.0550.3582580.36350390.36253790.5320.51998.47560.365
2.055-2.1140.3412400.34649440.34552100.550.53699.5010.345
2.114-2.1790.3322440.3248340.32150890.6220.6699.78390.314
2.179-2.250.322330.30646680.30649050.6760.71399.91840.295
2.25-2.3290.3292400.28745160.28947580.7690.78499.9580.271
2.329-2.4160.32270.25843600.26145930.8240.83399.86940.237
2.416-2.5140.3162490.25542140.25844660.8230.84599.93280.233
2.514-2.6250.322210.24439930.24842190.8410.8799.88150.218
2.625-2.7520.2971780.23138750.23440560.8550.88199.9260.206
2.752-2.90.2941890.23737080.23939000.8690.88999.92310.212
2.9-3.0740.2622180.21234370.21536560.8940.91899.97260.193
3.074-3.2840.31940.22132590.22634540.8810.91799.9710.206
3.284-3.5440.3121530.2430940.24332480.8750.91299.96920.228
3.544-3.8770.2811700.21127980.21529680.9080.9341000.204
3.877-4.3270.2141380.18825820.1927210.9380.94599.96320.183
4.327-4.980.2441000.17422780.17723790.9370.95299.9580.174
4.98-6.060.3081010.2219460.22520470.9350.9471000.221
6.06-8.4130.229850.2115300.21116170.9330.94199.87630.209
8.413-31.1270.274460.2189330.229830.9470.95199.59310.242

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