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- PDB-8bcy: HUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 13 -

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Basic information

Entry
Database: PDB / ID: 8bcy
TitleHUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 13
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / PI3KDELTA KINASE / PI3KDELTA KINASE INHIBITOR
Function / homology
Function and homology information


B cell chemotaxis / Signaling by ALK / MET activates PI3K/AKT signaling / RHOC GTPase cycle / CDC42 GTPase cycle / RAC1 GTPase cycle / RAC2 GTPase cycle / RHOD GTPase cycle / RHOJ GTPase cycle / RAC3 GTPase cycle ...B cell chemotaxis / Signaling by ALK / MET activates PI3K/AKT signaling / RHOC GTPase cycle / CDC42 GTPase cycle / RAC1 GTPase cycle / RAC2 GTPase cycle / RHOD GTPase cycle / RHOJ GTPase cycle / RAC3 GTPase cycle / FLT3 Signaling / RND3 GTPase cycle / RND2 GTPase cycle / RND1 GTPase cycle / PI3K events in ERBB4 signaling / Interleukin-7 signaling / GAB1 signalosome / PI3K events in ERBB2 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / IRS-mediated signalling / GPVI-mediated activation cascade / Signaling by SCF-KIT / Downstream signal transduction / PI3K/AKT activation / 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 / RAF/MAP kinase cascade / Interleukin receptor SHC signaling / 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 / 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 / VEGFA-VEGFR2 Pathway / neutrophil extravasation / positive regulation of neutrophil apoptotic process / phosphatidylinositol 3-kinase regulator activity / respiratory burst involved in defense response / phosphatidylinositol 3-kinase activator activity / 1-phosphatidylinositol-3-kinase regulator activity / T cell chemotaxis / natural killer cell activation / ErbB-3 class receptor binding / transmembrane receptor protein tyrosine kinase adaptor activity / positive regulation of endoplasmic reticulum unfolded protein response / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / Extra-nuclear estrogen signaling / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / 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) / B cell activation / intracellular glucose homeostasis / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / T cell differentiation / RET signaling / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / positive regulation of endothelial cell proliferation / T cell activation / response to endoplasmic reticulum stress / positive regulation of endothelial cell migration / B cell differentiation / neutrophil chemotaxis / phosphatidylinositol 3-kinase/protein kinase B signal transduction
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. / 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) / Rho GTPase activation protein / 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 / 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-I3H / 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 / MOLECULAR REPLACEMENT / Resolution: 2.43 Å
AuthorsPala, D. / Mazzucato, R. / Capelli, A.M. / Rancati, F. / Biagetti, M.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Application of an "inhalation by design" approach to the identification and in-vitro evaluation of novel purine based PI3K delta inhibitors.
Authors: Mazzucato, R. / Roberti, M. / Capelli, A.M. / Rancati, F. / Biagetti, M. / Fiorelli, C. / Bruno, P. / Ronchi, P. / Bertolini, S. / Corsi, M. / Pala, D.
History
DepositionOct 17, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 10, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)137,9243
Polymers137,4802
Non-polymers4441
Water54030
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4270 Å2
ΔGint-14 kcal/mol
Surface area51840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.603, 108.809, 142.623
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 / 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: 116600.633 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 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Protein Phosphatidylinositol 3-kinase regulatory subunit alpha / PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory ...PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha / PI3-kinase subunit p85-alpha / PtdIns-3-kinase regulatory subunit p85-alpha


Mass: 20879.555 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-I3H / 9-[2-(3,4-dichlorophenyl)ethyl]-2-(3-hydroxyphenyl)-8-oxidanylidene-7~{H}-purine-6-carboxamide


Mass: 444.271 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H15Cl2N5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 30 / 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: 2.65 Å3/Da / Density % sol: 53.58 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 16% PEG6000, 0.10 M KCL, 0.10 M MES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00001 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 2.43→86.51 Å / Num. obs: 51307 / % possible obs: 95.3 % / Redundancy: 4.9 % / Rsym value: 0.074 / Net I/σ(I): 11.83
Reflection shellResolution: 2.43→2.68 Å / Redundancy: 4.8 % / Num. unique obs: 51307 / Rsym value: 0.444 / % possible all: 96.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.43→86.51 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.934 / SU B: 25.026 / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.415 / ESU R Free: 0.272 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2634 1049 2 %RANDOM
Rwork0.2235 ---
obs0.2243 50258 95.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 201.53 Å2 / Biso mean: 77.927 Å2 / Biso min: 38.5 Å2
Baniso -1Baniso -2Baniso -3
1-3.08 Å20 Å2-0 Å2
2---1.5 Å20 Å2
3----1.58 Å2
Refinement stepCycle: final / Resolution: 2.43→86.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8878 0 30 30 8938
Biso mean--68.27 59.31 -
Num. residues----1087
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0198825
X-RAY DIFFRACTIONr_bond_other_d0.0010.028398
X-RAY DIFFRACTIONr_angle_refined_deg1.2511.96811944
X-RAY DIFFRACTIONr_angle_other_deg2.58319224
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.35851079
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.85124.01404
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.139151537
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2711557
X-RAY DIFFRACTIONr_chiral_restr0.0690.21334
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0219932
X-RAY DIFFRACTIONr_gen_planes_other0.0040.022047
LS refinement shellResolution: 2.43→2.493 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.343 72 -
Rwork0.3 3684 -
all-3756 -
obs--95.94 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.32831.4565-1.8873.9831-0.97333.892-0.0587-0.19820.17870.20970.0367-0.11510.0282-0.05920.02210.0903-0.041-0.00230.3367-0.01950.020143.38117.272-11.384
21.32640.56490.00734.0392.12083.25570.0891-0.06220.47920.01760.0943-0.1648-0.52750.0634-0.18330.23110.03180.06980.39870.06070.24322.81534.62417.756
31.42310.2367-0.34132.87050.25011.3893-0.16170.2108-0.3495-0.1888-0.02180.36060.4357-0.24420.18350.4216-0.10120.03090.5637-0.09910.1525.735-8.3456.942
43.1774-0.0095-0.56621.63730.37381.4969-0.11070.103-0.29250.02490.03450.52590.1929-0.43040.07630.149-0.01930.00350.42180.04670.2031-0.23910.62917.558
52.98230.4488-1.1651.84940.0233.8267-0.0111-0.1261-0.10210.1370.016-0.68580.03140.5582-0.0050.1434-0.0255-0.05040.42670.03470.260635.32616.10623.207
62.45190.51550.8991.5530.19393.68560.0725-0.3008-0.17570.4706-0.0692-0.17190.06770.1366-0.00340.323-0.0214-0.04590.3430.0390.040221.86912.69445.343
71.33631.0684-2.33051.0482-2.14184.877-0.1347-0.0666-0.1716-0.1322-0.0911-0.13790.23020.23690.22580.3341-0.02770.07680.4437-0.01260.131929.579-8.6227.526
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A17 - 108
2X-RAY DIFFRACTION2A109 - 278
3X-RAY DIFFRACTION3A279 - 474
4X-RAY DIFFRACTION4A475 - 675
5X-RAY DIFFRACTION5A676 - 830
6X-RAY DIFFRACTION6A831 - 1028
7X-RAY DIFFRACTION7B432 - 599

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