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- PDB-7jiu: HUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 2F -

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Basic information

Entry
Database: PDB / ID: 7jiu
TitleHUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 2F
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PI3KALPHA KINASE / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / IRS-mediated signalling / cellular response to hydrostatic pressure / autosome genomic imprinting / PI3K events in ERBB4 signaling / Activated NTRK2 signals through PI3K ...response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / IRS-mediated signalling / cellular response to hydrostatic pressure / autosome genomic imprinting / PI3K events in ERBB4 signaling / Activated NTRK2 signals through PI3K / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / vasculature development / regulation of cellular respiration / Signaling by cytosolic FGFR1 fusion mutants / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / Nephrin family interactions / anoikis / Signaling by LTK in cancer / Costimulation by the CD28 family / Signaling by LTK / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / relaxation of cardiac muscle / MET activates PI3K/AKT signaling / PI3K/AKT activation / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / negative regulation of macroautophagy / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / protein kinase activator activity / PI-3K cascade:FGFR4 / response to dexamethasone / PI-3K cascade:FGFR1 / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / CD28 dependent PI3K/Akt signaling / PI3K events in ERBB2 signaling / negative regulation of anoikis / PI3K Cascade / RET signaling / intercalated disc / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / regulation of multicellular organism growth / endothelial cell migration / positive regulation of TOR signaling / RAC2 GTPase cycle / GAB1 signalosome / Role of LAT2/NTAL/LAB on calcium mobilization / Role of phospholipids in phagocytosis / Interleukin receptor SHC signaling / adipose tissue development / positive regulation of lamellipodium assembly / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / phagocytosis / Signaling by FGFR4 in disease / phosphorylation / cardiac muscle contraction / Signaling by FLT3 ITD and TKD mutants / energy homeostasis / Signaling by FGFR2 in disease / Signaling by FGFR3 in disease / GPVI-mediated activation cascade / Tie2 Signaling / FLT3 Signaling / T cell costimulation / response to muscle stretch / Signaling by FLT3 fusion proteins / RAC1 GTPase cycle / Signaling by FGFR1 in disease / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Downstream signal transduction / liver development / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / response to activity / Regulation of signaling by CBL / cellular response to glucose stimulus / positive regulation of smooth muscle cell proliferation / Constitutive Signaling by EGFRvIII / regulation of protein phosphorylation / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / platelet activation / VEGFA-VEGFR2 Pathway
Similarity search - Function
PI3Kalpha, 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 ...PI3Kalpha, 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-VBS / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.12 Å
AuthorsLesburg, C.A. / Augustin, M.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Optimization of Versatile Oxindoles as Selective PI3K delta Inhibitors.
Authors: Methot, J.L. / Achab, A. / Christopher, M. / Zhou, H. / McGowan, M.A. / Trotter, B.W. / Fradera, X. / Lesburg, C.A. / Goldenblatt, P. / Hill, A. / Chen, D. / Otte, K.M. / Augustin, M. / Shah, S. / Katz, J.D.
History
DepositionJul 23, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 30, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 6, 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
Revision 1.2Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)110,5602
Polymers110,0841
Non-polymers4761
Water5,206289
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area40750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.457, 135.132, 142.045
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 alpha isoform / PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha / p110alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 110084.195 Da / Num. of mol.: 1 / Fragment: TRUNCATED PI3-KINASE ALPHA, residues 107-1052 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P42336, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-VBS / (3S)-3-benzyl-5-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]-3-methyl-1,3-dihydro-2H-indol-2-one


Mass: 475.544 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H25N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 289 / 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: 2.64 Å3/Da / Density % sol: 53.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: NOT AVAILABLE

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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: Sep 14, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 2.12→97.91 Å / Num. obs: 64620 / % possible obs: 99.8 % / Redundancy: 8.1 % / Biso Wilson estimate: 45.986 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.071 / Rsym value: 0.067 / Χ2: 0.998 / Net I/σ(I): 19.4
Reflection shellResolution: 2.12→2.37 Å / Redundancy: 8.4 % / Mean I/σ(I) obs: 3.99 / Num. unique obs: 18062 / CC1/2: 0.999 / Rrim(I) all: 0.614 / Rsym value: 0.577 / % possible all: 99.5

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0049refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PREVIOUSLY DETERMINED STRUCTURE

Resolution: 2.12→97.91 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.928 / SU B: 5.469 / SU ML: 0.142 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.215 / ESU R Free: 0.181 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2459 1612 2.5 %RANDOM
Rwork0.2118 ---
obs0.2127 63008 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 135.31 Å2 / Biso mean: 46.35 Å2 / Biso min: 18.84 Å2
Baniso -1Baniso -2Baniso -3
1-1.06 Å20 Å2-0 Å2
2--0.66 Å2-0 Å2
3----1.72 Å2
Refinement stepCycle: final / Resolution: 2.12→97.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7365 0 36 293 7694
Biso mean--67.48 45.74 -
Num. residues----900
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0197340
X-RAY DIFFRACTIONr_bond_other_d0.0010.026886
X-RAY DIFFRACTIONr_angle_refined_deg1.2691.9629973
X-RAY DIFFRACTIONr_angle_other_deg2.587315753
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2025901
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.9324.401334
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.56151229
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.681538
X-RAY DIFFRACTIONr_chiral_restr0.0750.21107
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0218326
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021703
LS refinement shellResolution: 2.121→2.176 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.349 107 -
Rwork0.281 4621 -
all-4728 -
obs--99.77 %

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