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- PDB-6oco: HUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 6 -

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Basic information

Entry
Database: PDB / ID: 6oco
TitleHUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 6
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Keywordstransferase/transferase inhibitor / PI3KDELTA KINASE / TRANSFERASE / transferase-transferase inhibitor complex
Function / homology
Function and homology information


B cell chemotaxis / RHOC GTPase cycle / PI3K events in ERBB4 signaling / Interleukin-7 signaling / GAB1 signalosome / PI3K events in ERBB2 signaling / MET activates PI3K/AKT signaling / CDC42 GTPase cycle / RHOD GTPase cycle / RHOJ GTPase cycle ...B cell chemotaxis / RHOC GTPase cycle / PI3K events in ERBB4 signaling / Interleukin-7 signaling / GAB1 signalosome / PI3K events in ERBB2 signaling / MET activates PI3K/AKT signaling / CDC42 GTPase cycle / RHOD GTPase cycle / RHOJ GTPase cycle / RAC3 GTPase cycle / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / FLT3 Signaling / RND2 GTPase cycle / RND1 GTPase cycle / IRS-mediated signalling / GPVI-mediated activation cascade / Signaling by SCF-KIT / Downstream signal transduction / PI3K/AKT activation / Signaling by ALK / Role of phospholipids in phagocytosis / Tie2 Signaling / Role of LAT2/NTAL/LAB on calcium mobilization / Costimulation by the CD28 family / CD28 dependent PI3K/Akt signaling / RAC1 GTPase cycle / RAC2 GTPase cycle / Interleukin receptor SHC signaling / RND3 GTPase cycle / PI-3K cascade:FGFR1 / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR3 / PI-3K cascade:FGFR4 / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / PI3K Cascade / PIP3 activates AKT signaling / GP1b-IX-V activation signalling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Synthesis of PIPs at the plasma membrane / RHOA GTPase cycle / RHOF GTPase cycle / DAP12 signaling / RHOU GTPase cycle / RHOV GTPase cycle / mast cell differentiation / mast cell chemotaxis / Regulation of signaling by CBL / Downstream TCR signaling / natural killer cell differentiation / RHOG GTPase cycle / positive regulation of epithelial tube formation / RET signaling / natural killer cell chemotaxis / Interleukin-3, Interleukin-5 and GM-CSF signaling / neutrophil extravasation / VEGFA-VEGFR2 Pathway / positive regulation of neutrophil apoptotic process / respiratory burst involved in defense response / phosphatidylinositol 3-kinase regulator activity / phosphatidylinositol 3-kinase activator activity / 1-phosphatidylinositol-3-kinase regulator activity / T cell chemotaxis / positive regulation of endoplasmic reticulum unfolded protein response / ErbB-3 class receptor binding / natural killer cell activation / transmembrane receptor protein tyrosine kinase adaptor activity / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / enzyme-substrate adaptor activity / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / Extra-nuclear estrogen signaling / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / G alpha (q) signalling events / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / intracellular glucose homeostasis / B cell activation / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / RET signaling / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / T cell differentiation / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / phosphorylation / insulin-like growth factor receptor binding / positive regulation of endothelial cell proliferation / neutrophil chemotaxis / response to endoplasmic reticulum stress / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of endothelial cell migration
Similarity search - Function
PI3Kdelta, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain ...PI3Kdelta, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / 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 / Rho GTPase activation protein / 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 / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-M5V / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform / Phosphatidylinositol 3-kinase regulatory subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Bos taurus (cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.58 Å
AuthorsLesburg, C.A. / Augustin, M.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Discovery and optimization of heteroaryl piperazines as potent and selective PI3K delta inhibitors.
Authors: Zhou, H. / McGowan, M.A. / Lipford, K. / Christopher, M. / Fradera, X. / Witter, D. / Lesburg, C.A. / Li, C. / Methot, J.L. / Lampe, J. / Achab, A. / Shaffer, L. / Goldenblatt, P. / Shah, S. ...Authors: Zhou, H. / McGowan, M.A. / Lipford, K. / Christopher, M. / Fradera, X. / Witter, D. / Lesburg, C.A. / Li, C. / Methot, J.L. / Lampe, J. / Achab, A. / Shaffer, L. / Goldenblatt, P. / Shah, S. / Bass, A. / Schroeder, G. / Chen, D. / Zeng, H. / Augustin, M.A. / Katz, J.D.
History
DepositionMar 25, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.year
Revision 1.2Mar 13, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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 delta isoform
B: Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,5703
Polymers137,1812
Non-polymers3891
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4310 Å2
ΔGint-15 kcal/mol
Surface area54180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.017, 108.981, 142.394
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 116187.164 Da / Num. of mol.: 1 / Fragment: PI3-KINASE P110 DELTA AND P85 FRAGMENT
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CD / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O00329, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Protein Phosphatidylinositol 3-kinase regulatory subunit alpha / PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit ...PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha / PtdIns-3-kinase regulatory subunit p85-alpha


Mass: 20993.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: PIK3R1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P23727
#3: Chemical ChemComp-M5V / 4-[(1S,4S)-5-(3-chlorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-(pyridin-3-yl)pyrimidine-5-carbonitrile


Mass: 388.853 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H17ClN6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / 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: 2.65 Å3/Da / Density % sol: 53.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 16.60 % PEG6000 0.10 M KCl 0.10 M MES pH=6.00

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00003 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 30, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 2.58→86.54 Å / Num. obs: 45261 / % possible obs: 99.9 % / Redundancy: 8.2 % / CC1/2: 0.998 / Rmerge(I) obs: 0.064 / Rrim(I) all: 0.068 / Χ2: 0.991 / Net I/σ(I): 18.9
Reflection shellResolution: 2.58→2.83 Å / Redundancy: 8.2 % / Rmerge(I) obs: 0.541 / Mean I/σ(I) obs: 4.28 / Num. unique obs: 201 / CC1/2: 0.992 / Rrim(I) all: 0.578 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
XSCALEdata scaling
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: NONE

Resolution: 2.58→86.54 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.913 / SU B: 14.574 / SU ML: 0.314 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.746 / ESU R Free: 0.356
RfactorNum. reflection% reflectionSelection details
Rfree0.296 874 2 %RANDOM
Rwork0.2589 ---
obs0.2596 41902 94.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 135.29 Å2 / Biso mean: 61.731 Å2 / Biso min: 23.58 Å2
Baniso -1Baniso -2Baniso -3
1-0.38 Å20 Å20 Å2
2--0.81 Å20 Å2
3----1.19 Å2
Refinement stepCycle: final / Resolution: 2.58→86.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8987 0 28 14 9029
Biso mean--74.8 58.51 -
Num. residues----1100
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0228813
X-RAY DIFFRACTIONr_bond_other_d0.0010.026253
X-RAY DIFFRACTIONr_angle_refined_deg1.0221.96511922
X-RAY DIFFRACTIONr_angle_other_deg0.926314952
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2151090
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.58824.07398
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.563151513
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.3941555
X-RAY DIFFRACTIONr_chiral_restr0.0560.21323
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0219782
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021791
LS refinement shellResolution: 2.58→2.647 Å
RfactorNum. reflection% reflection
Rfree0.418 69 -
Rwork0.369 3090 -
obs--95.99 %

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