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- PDB-7oi4: mPI3Kd in complex with compound 12 -

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Basic information

Entry
Database: PDB / ID: 7oi4
TitlemPI3Kd in complex with compound 12
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / Inhibitor / complex / phosphor inositol 3 kinase
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 / positive regulation of cell migration by vascular endothelial growth factor signaling pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling ...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 / positive regulation of cell migration by vascular endothelial growth factor signaling pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / positive regulation of epithelial tube formation / positive regulation of neutrophil apoptotic process / 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-kinase complex, class IA / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / B cell activation / B cell homeostasis / homeostasis of number of cells / defense response to fungus / positive regulation of endothelial cell proliferation / positive regulation of endothelial cell migration / 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 / positive regulation of cell migration / 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-VEQ / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 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

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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)125,4022
Polymers124,8351
Non-polymers5681
Water6,575365
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area37360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.847, 65.161, 116.426
Angle α, β, γ (deg.)90.000, 103.752, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11AAA-1408-

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-VEQ / N-[5-[2-[(1S)-1-cyclopropylethyl]-7-[[4-[(dimethylamino)methyl]phenyl]sulfamoyl]-1-oxidanylidene-3H-isoindol-5-yl]-4-methyl-1,3-thiazol-2-yl]ethanamide


Mass: 567.723 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H33N5O4S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 365 / 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: 2.09 Å3/Da / Density % sol: 41.24 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
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: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9724 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Oct 10, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9724 Å / Relative weight: 1
ReflectionResolution: 1.8→113.09 Å / Num. obs: 93293 / % possible obs: 97.6 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.054 / Rrim(I) all: 0.064 / Net I/σ(I): 14.4
Reflection shellResolution: 1.8→1.83 Å / Rmerge(I) obs: 0.374 / Num. unique obs: 4573

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Processing

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

Resolution: 1.8→113.089 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.934 / SU B: 3.24 / SU ML: 0.101 / Cross valid method: FREE R-VALUE / ESU R: 0.144 / ESU R Free: 0.137
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2626 4789 5.133 %
Rwork0.2265 88504 -
all0.228 --
obs-93293 97.363 %
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: 40.747 Å2
Baniso -1Baniso -2Baniso -3
1-0.489 Å2-0 Å2-0.504 Å2
2--1.399 Å20 Å2
3----1.466 Å2
Refinement stepCycle: LAST / Resolution: 1.8→113.089 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6675 0 39 365 7079
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0136869
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176528
X-RAY DIFFRACTIONr_angle_refined_deg1.5981.6439278
X-RAY DIFFRACTIONr_angle_other_deg1.331.57515042
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4295820
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.13622.417360
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.86151241
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6481541
X-RAY DIFFRACTIONr_chiral_restr0.0830.2857
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.027611
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021576
X-RAY DIFFRACTIONr_nbd_refined0.2180.21506
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1830.26196
X-RAY DIFFRACTIONr_nbtor_refined0.170.23303
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0790.23228
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1690.2305
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1360.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.3460.212
X-RAY DIFFRACTIONr_nbd_other0.1890.244
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2080.28
X-RAY DIFFRACTIONr_mcbond_it3.734.0133301
X-RAY DIFFRACTIONr_mcbond_other3.7314.0123300
X-RAY DIFFRACTIONr_mcangle_it4.9515.9924108
X-RAY DIFFRACTIONr_mcangle_other4.9515.9944109
X-RAY DIFFRACTIONr_scbond_it4.414.523566
X-RAY DIFFRACTIONr_scbond_other4.4234.5433525
X-RAY DIFFRACTIONr_scangle_it6.5896.5985165
X-RAY DIFFRACTIONr_scangle_other6.6146.6285110
X-RAY DIFFRACTIONr_lrange_it9.07447.2227830
X-RAY DIFFRACTIONr_lrange_other9.09847.2257698
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
1.8-1.8470.3253290.27264830.27570690.8220.8496.36440.252
1.847-1.8970.2763350.26962710.2768290.8770.86496.73450.25
1.897-1.9520.3123530.26161640.26467300.8510.87396.83510.241
1.952-2.0120.293080.25459510.25664810.8710.88996.57460.238
2.012-2.0780.2943390.25557430.25762540.8670.89397.24980.24
2.078-2.1510.2942670.25656900.25861110.8820.88697.47990.242
2.151-2.2320.2782960.24154680.24359060.8880.90297.59570.231
2.232-2.3240.2793170.2452240.24256740.8880.90497.6560.233
2.324-2.4270.2493010.21449180.21653980.910.92296.6840.214
2.427-2.5450.3032520.2248310.22351870.8940.92397.9950.223
2.545-2.6830.2412310.2246520.22149750.9140.9298.15080.231
2.683-2.8450.2892230.24143650.24446810.8810.89698.01320.259
2.845-3.0420.2792160.2440680.24243810.8890.997.78590.265
3.042-3.2850.2732260.22937880.23141210.9010.92297.40350.255
3.285-3.5990.2922040.23935080.24237820.9050.92298.14910.268
3.599-4.0230.2311680.21132150.21234380.9390.94398.40020.246
4.023-4.6440.2341460.19328320.19530560.9360.94997.44760.247
4.644-5.6860.2191290.19923960.225660.9520.95198.40220.265
5.686-8.030.244860.22818980.22820250.9380.93897.97530.298
8.03-113.0890.23630.21910390.2211560.9530.95195.32870.307

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