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- PDB-7jwe: Gedatolisib bound to the PI3Kg catalytic subunit p110 gamma -

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Basic information

Entry
Database: PDB / ID: 7jwe
TitleGedatolisib bound to the PI3Kg catalytic subunit p110 gamma
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / PIK3CG / mTOR / phosphoinositide / PIP3 / PI3K / p110 / SIGNALING PROTEIN
Function / homology
Function and homology information


secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / regulation of calcium ion transmembrane transport / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis ...secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / regulation of calcium ion transmembrane transport / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / dendritic cell chemotaxis / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / hepatocyte apoptotic process / positive regulation of Rac protein signal transduction / regulation of cell adhesion mediated by integrin / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / ephrin receptor binding / T cell activation / neutrophil chemotaxis / positive regulation of endothelial cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / Signaling by CSF1 (M-CSF) in myeloid cells / kinase activity / positive regulation of cytosolic calcium ion concentration / angiogenesis / 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 / inflammatory response / G protein-coupled receptor signaling pathway / phosphorylation / protein serine kinase activity / innate immune response / protein serine/threonine kinase activity / ATP binding / membrane / identical protein binding / 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. / Phosphoinositide 3-kinase C2 / Phosphoinositide 3-kinase, region postulated to contain C2 domain ...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. / 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) / 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
Gedatolisib / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsBurke, J.E. / Rathinaswamy, M.K. / Harris, N.J.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR) Canada
CitationJournal: Elife / Year: 2021
Title: Disease related mutations in PI3K gamma disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors.
Authors: Rathinaswamy, M.K. / Gaieb, Z. / Fleming, K.D. / Borsari, C. / Harris, N.J. / Moeller, B.J. / Wymann, M.P. / Amaro, R.E. / Burke, J.E.
History
DepositionAug 25, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 17, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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 gamma isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)111,3432
Polymers110,7271
Non-polymers6161
Water1629
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)143.500, 67.620, 106.330
Angle α, β, γ (deg.)90.000, 95.430, 90.000
Int Tables number5
Space group name H-MC121
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

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


Mass: 110727.102 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-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-VL1 / Gedatolisib / N-{4-[4,6-bis(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-N'-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}urea / Gedatolisib


Mass: 615.726 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H41N9O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 9 / 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: 2.32 Å3/Da / Density % sol: 46.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 100 mM Tris pH 7.5, 250 mM (NH4)2SO4 and 20-22% PEG 4000

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Data collection

DiffractionMean temperature: 77 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Aug 24, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.55→44.59 Å / Num. obs: 33183 / % possible obs: 99.41 % / Redundancy: 3.3 % / Biso Wilson estimate: 73.57 Å2 / CC1/2: 0.999 / CC star: 0.999 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.0394 / Rrim(I) all: 0.07285 / Net I/σ(I): 11.91
Reflection shellResolution: 2.55→2.641 Å / Redundancy: 3.4 % / Rmerge(I) obs: 1.349 / Mean I/σ(I) obs: 0.87 / Num. unique obs: 3303 / CC1/2: 0.385 / CC star: 0.746 / Rpim(I) all: 0.8561 / Rrim(I) all: 1.602 / % possible all: 99.4

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5jha

5jha


Resolution: 2.55→44.59 Å / SU ML: 0.48 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 31.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2529 1658 5 %
Rwork0.209 31515 -
obs0.2112 33173 99.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 187.2 Å2 / Biso mean: 88.8962 Å2 / Biso min: 46.99 Å2
Refinement stepCycle: final / Resolution: 2.55→44.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6612 0 86 9 6707
Biso mean--88.78 65.51 -
Num. residues----815
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.55-2.620.45171390.39332630276999
2.62-2.710.36511350.341725952730100
2.71-2.810.34251380.287726082746100
2.81-2.920.32121370.27592599273699
2.92-3.050.31741380.26826332771100
3.05-3.210.33321370.251926042741100
3.21-3.410.26851380.23032612275099
3.41-3.680.27521380.209826142752100
3.68-4.050.25081370.18992622275999
4.05-4.630.18131400.16382646278699
4.63-5.830.21711390.19232641278099
5.83-44.590.24241420.19212711285399
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)
13.94250.0624-0.38081.1091-0.53572.48290.01340.0538-0.51020.01210.18030.33460.0822-0.09740.00020.72540.0148-0.0290.5026-0.00020.786432.4592-28.020624.3913
23.7849-0.76580.98151.1744-0.05462.24180.0643-0.0219-0.40930.00570.0447-0.03390.10810.46090.00010.68080.00370.02460.5779-0.02540.683551.4597-25.963630.1933
33.8573-1.17840.982.765-0.20251.6434-0.19480.08660.38350.15250.10610.3206-0.4023-0.3722-0.00030.72590.06050.03210.6090.0540.684723.6856-7.680425.2945
40.5965-0.15790.02550.5043-0.46530.4023-0.4247-0.25141.0390.4429-0.1156-0.8175-0.54670.2435-0.00071.36180.0335-0.24750.9002-0.15171.261138.99212.7237.9537
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 145 through 422 )A145 - 422
2X-RAY DIFFRACTION2chain 'A' and (resid 423 through 688 )A423 - 688
3X-RAY DIFFRACTION3chain 'A' and (resid 689 through 1037 )A689 - 1037
4X-RAY DIFFRACTION4chain 'A' and (resid 1038 through 1090 )A0

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