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- PDB-9gdi: HUMAN PI3KDELTA IN COMPLEX WITH ISOCUMARIN INHIBITOR 10 -

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Basic information

Entry
Database: PDB / ID: 9gdi
TitleHUMAN PI3KDELTA IN COMPLEX WITH ISOCUMARIN INHIBITOR 10
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 / 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 / CD28 dependent PI3K/Akt signaling / RAC1 GTPase cycle / RAC2 GTPase cycle / Interleukin receptor SHC signaling / RND3 GTPase cycle / Co-stimulation by ICOS / 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 chemotaxis / mast cell differentiation / Regulation of signaling by CBL / positive regulation of neutrophil apoptotic process / Downstream TCR signaling / RHOG GTPase cycle / natural killer cell differentiation / positive regulation of epithelial tube formation / natural killer cell chemotaxis / neutrophil extravasation / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / VEGFA-VEGFR2 Pathway / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol 3-kinase regulator activity / respiratory burst involved in defense response / phosphatidylinositol 3-kinase activator activity / phosphatidylinositol 3-kinase complex / T cell chemotaxis / ErbB-3 class receptor binding / transmembrane receptor protein tyrosine kinase adaptor activity / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Co-stimulation by ICOS / phosphatidylinositol 3-kinase complex, class IA / natural killer cell activation / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / Extra-nuclear estrogen signaling / 1-phosphatidylinositol-3-kinase activity / G alpha (q) signalling events / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / phosphatidylinositol-mediated signaling / intracellular glucose homeostasis / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / B cell activation / RET signaling / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / T cell differentiation / CD28 dependent PI3K/Akt signaling / Interleukin receptor SHC signaling / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase binding / T cell costimulation / insulin-like growth factor receptor binding / positive regulation of endothelial cell proliferation / neutrophil chemotaxis / 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. / Rho GTPase activation protein / 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 3/4-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
: / 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 (domestic cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.81 Å
AuthorsPala, D. / Bruno, P. / Capelli, A.M. / Biagetti, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of CHF-6523, an Inhaled Selective PI3K delta Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease.
Authors: Bruno, P. / Pala, D. / Micoli, A. / Corsi, M. / Accetta, A. / Carzaniga, L. / Ronchi, P. / Fiorelli, C. / Formica, M. / Pizzirani, D. / Mazzucato, R. / Guariento, S. / Bertolini, S. / ...Authors: Bruno, P. / Pala, D. / Micoli, A. / Corsi, M. / Accetta, A. / Carzaniga, L. / Ronchi, P. / Fiorelli, C. / Formica, M. / Pizzirani, D. / Mazzucato, R. / Guariento, S. / Bertolini, S. / Martucci, C. / Allen, A.D. / Mileo, V. / Capacchi, S. / Gallo, P.M. / Fioni, A. / Xanxo Fernandez, S. / Villetti, G. / Puccini, P. / Civelli, M. / Guala, M. / Retini, M. / Martinelli, P. / Visentini, F. / Pavoni, V. / Daldosso, M. / Fontana, S. / Biagetti, M. / Capelli, A.M.
History
DepositionAug 5, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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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)141,1754
Polymers140,6272
Non-polymers5482
Water724
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4530 Å2
ΔGint-21 kcal/mol
Surface area53080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.474, 108.618, 142.402
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 119633.023 Da / Num. of mol.: 1
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: 20993.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: PIK3R1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P23727
#3: Chemical ChemComp-A1IJ1 / 3-[(1S)-1-[4-azanyl-3-(3-fluoranyl-5-oxidanyl-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)isochromen-1-one


Mass: 512.535 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H25FN6O3
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.49 Å3/Da / Density % sol: 50.56 %
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: 0.99998 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 4, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99998 Å / Relative weight: 1
ReflectionResolution: 2.81→86.36 Å / Num. obs: 34545 / % possible obs: 99 % / Redundancy: 5.2 % / Rmerge(I) obs: 0.035 / Net I/σ(I): 25.25
Reflection shellResolution: 2.81→3.06 Å / Rmerge(I) obs: 0.451 / Num. unique obs: 7702

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.6.0117refinement
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.81→86.36 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.86 / SU B: 38.662 / SU ML: 0.355 / Cross valid method: THROUGHOUT / ESU R Free: 0.437 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29897 770 2.2 %RANDOM
Rwork0.24575 ---
obs0.24695 33775 99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 104.416 Å2
Baniso -1Baniso -2Baniso -3
1--0.13 Å20 Å20 Å2
2--0.05 Å20 Å2
3---0.08 Å2
Refinement stepCycle: LAST / Resolution: 2.81→86.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8904 0 39 4 8947
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.029129
X-RAY DIFFRACTIONr_bond_other_d0.0010.026362
X-RAY DIFFRACTIONr_angle_refined_deg1.0351.97312319
X-RAY DIFFRACTIONr_angle_other_deg0.936315469
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.20551082
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.49324.058446
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.293151692
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.2571566
X-RAY DIFFRACTIONr_chiral_restr0.0570.21346
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219973
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021864
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.81→2.883 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.33 54 -
Rwork0.351 2277 -
obs--99.49 %
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)
15.87852.7879-3.02125.5184-1.67626.4937-0.2993-0.26270.15790.19440.2218-0.1265-0.0538-0.1680.07740.7156-0.10610.03180.8294-0.02820.165843.21817.471-11.254
22.38250.5912-0.28224.96591.96145.5220.1094-0.12520.79860.16590.0107-0.1755-1.34160.1311-0.12021.10050.01340.06090.89460.09810.627122.33934.52917.364
31.8642-0.0969-0.66283.94130.36212.5648-0.33750.2849-0.4543-0.21950.13650.59410.698-0.39960.2011.1973-0.16940.04341.0209-0.10850.59575.887-8.5527.342
43.9405-0.5336-1.05282.54410.14572.8087-0.08390.121-0.6142-0.00790.11190.86810.2695-0.9078-0.02790.735-0.0064-0.01350.96810.1020.5186-0.69910.42117.522
54.2940.4936-2.16542.6116-0.64826.00030.0722-0.24690.07090.215-0.1655-0.8525-0.19741.14980.09320.7056-0.0277-0.0660.96290.11490.46735.95216.89323.18
64.01510.59530.75671.6819-0.23366.0860.1881-0.757-0.10960.8903-0.2265-0.1039-0.1470.24170.03841.0496-0.0355-0.0620.9050.10870.359621.72212.9745.862
73.73572.9096-6.37542.5882-5.456213.0905-0.2674-0.1235-0.3229-0.2532-0.1769-0.31160.3550.4050.44430.9991-0.04350.11110.9313-0.05410.450530.44-8.2916.786
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 - 1030
7X-RAY DIFFRACTION7B440 - 599

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