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- PDB-9gg9: HUMAN PI3KGAMMA IN COMPLEX WITH ISOCUMARIN INHIBITOR 11 -

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Basic information

Entry
Database: PDB / ID: 9gg9
TitleHUMAN PI3KGAMMA IN COMPLEX WITH ISOCUMARIN INHIBITOR 11
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / PI3KGAMMA KINASE / PI3KGAMMA KINASE INHIBITOR
Function / homology
Function and homology information


negative regulation of cardiac muscle contraction / negative regulation of triglyceride catabolic process / secretory granule localization / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / T cell chemotaxis / negative regulation of fibroblast apoptotic process ...negative regulation of cardiac muscle contraction / negative regulation of triglyceride catabolic process / secretory granule localization / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / regulation of calcium ion transmembrane transport / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Co-stimulation by ICOS / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / dendritic cell chemotaxis / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / hepatocyte apoptotic process / phosphatidylinositol-mediated signaling / regulation of cell adhesion mediated by integrin / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / positive regulation of MAP kinase activity / positive regulation of Rac protein signal transduction / CD28 dependent PI3K/Akt signaling / regulation of angiogenesis / T cell proliferation / GPVI-mediated activation cascade / ephrin receptor binding / neutrophil chemotaxis / positive regulation of endothelial cell migration / T cell activation / cellular response to cAMP / positive regulation of cytokine production / phosphatidylinositol 3-kinase/protein kinase B signal transduction / platelet aggregation / endocytosis / Constitutive Signaling by Aberrant PI3K in Cancer / G beta:gamma signalling through PI3Kgamma / cell migration / PIP3 activates AKT signaling / positive regulation of cytosolic calcium ion concentration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / angiogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / adaptive immune response / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / protein kinase activity / immune response / G protein-coupled receptor signaling pathway / inflammatory response / innate immune response / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / identical protein binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-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 ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-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 3/4-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
: / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 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 13, 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 gamma isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,7844
Polymers112,0991
Non-polymers6863
Water18010
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area390 Å2
ΔGint-29 kcal/mol
Surface area37770 Å2
Unit cell
Length a, b, c (Å)144.651, 68.816, 106.754
Angle α, β, γ (deg.)90.00, 95.36, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform / PI3-kinase subunit gamma / PI3K-gamma / PI3Kgamma / PtdIns-3-kinase subunit gamma / ...PI3-kinase subunit gamma / PI3K-gamma / PI3Kgamma / PtdIns-3-kinase subunit gamma / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma / PtdIns-3-kinase subunit p110-gamma / p110gamma / Phosphoinositide-3-kinase catalytic gamma polypeptide / Serine/threonine protein kinase PIK3CG / p120-PI3K


Mass: 112098.672 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P48736, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, phosphatidylinositol-4-phosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A1IKW / 3-[(1~{S})-1-[4-azanyl-3-(3-fluoranyl-5-oxidanyl-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-4-phenyl-isochromen-1-one


Mass: 493.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H20FN5O3
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 2.36 Å3/Da / Density % sol: 47.87 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: PEG4000, (NH4)2SO4, TRIS

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99988 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 19, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99988 Å / Relative weight: 1
ReflectionResolution: 3→106.29 Å / Num. obs: 20358 / % possible obs: 96 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.049 / Net I/σ(I): 19.45
Reflection shellResolution: 3→3.25 Å / Rmerge(I) obs: 0.447 / Num. unique obs: 4340

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.6.0117refinement
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→106.29 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.888 / SU B: 52.464 / SU ML: 0.442 / Cross valid method: THROUGHOUT / ESU R Free: 0.499 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28529 600 2.9 %RANDOM
Rwork0.21299 ---
obs0.21511 19758 96.03 %-
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: 86.589 Å2
Baniso -1Baniso -2Baniso -3
1--0.05 Å20 Å2-0.04 Å2
2---0.04 Å20 Å2
3---0.09 Å2
Refinement stepCycle: LAST / Resolution: 3→106.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6777 0 47 10 6834
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.026533
X-RAY DIFFRACTIONr_bond_other_d0.0010.024501
X-RAY DIFFRACTIONr_angle_refined_deg1.0971.9588899
X-RAY DIFFRACTIONr_angle_other_deg0.981310711
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8245824
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.81423.925265
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.115151013
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.0151532
X-RAY DIFFRACTIONr_chiral_restr0.0580.21032
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0217284
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021345
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: 3→3.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.364 45 -
Rwork0.296 1423 -
obs--96.58 %
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)
14.087-0.04511.48451.0259-0.01062.85940.1810.0408-0.4777-0.02170.0037-0.10660.26220.0483-0.18460.3324-0.08620.13480.1303-0.01250.2612-41.859-13-29.306
24.66842.6180.33954.2213-2.159110.0426-0.13710.9791-0.2413-0.99370.3231-0.50.23260.4802-0.18610.687-0.17070.30040.977-0.06820.8897-8.366-8.571-39.879
36.0738-0.8780.26191.94790.77785.93150.0587-0.37910.11780.2107-0.05470.3055-0.2338-0.6838-0.00410.3469-0.02180.16690.50790.09150.234-62.466-6.334-13.808
43.23140.57781.03922.504-0.1082.86380.0526-0.21690.52580.0441-0.0085-0.1501-0.61310.1836-0.04410.5673-0.13430.21160.3843-0.08530.4041-26.0413.794-28.119
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A144 - 252
2X-RAY DIFFRACTION1A351 - 374
3X-RAY DIFFRACTION1A545 - 725
4X-RAY DIFFRACTION2A267 - 323
5X-RAY DIFFRACTION3A378 - 522
6X-RAY DIFFRACTION4A726 - 1092

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