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- PDB-7jx0: NVS-PI3-4 bound to the PI3Kg catalytic subunit p110 gamma -

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Basic information

Entry
Database: PDB / ID: 7jx0
TitleNVS-PI3-4 bound to the PI3Kg catalytic subunit p110 gamma
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / PI3K / inhibitor / phosphoinositides / p110 / PIK3CG / TRANSFERASE / TRANSFERASE-TRANSFERASE Inhibitor complex
Function / homology
Function and homology information


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 / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis ...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 / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / 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 / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / mast cell degranulation / 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-mediated signaling / phosphatidylinositol phosphate biosynthetic process / regulation of angiogenesis / phosphorylation / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / ephrin receptor binding / neutrophil chemotaxis / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of endothelial cell migration / T cell activation / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / kinase activity / phospholipase C-activating G protein-coupled receptor signaling pathway / 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 / inflammatory response / immune response / G protein-coupled receptor signaling pathway / 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- 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-VLV / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.15 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 26, 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)111,1302
Polymers110,7271
Non-polymers4031
Water00
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)143.620, 67.560, 106.830
Angle α, β, γ (deg.)90.000, 95.410, 90.000
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 / 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-VLV / N~3~-{[5-(4-acetylphenyl)-4-methyl-1,3-thiazol-2-yl]carbamoyl}-N-tert-butyl-beta-alaninamide


Mass: 402.510 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H26N4O3S / Feature type: SUBJECT OF INVESTIGATION
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: 2.33 Å3/Da / Density % sol: 47.21 %
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: 100 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, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 3.15→44.736 Å / Num. obs: 17573 / % possible obs: 98.08 % / Redundancy: 3 % / CC1/2: 0.994 / Rmerge(I) obs: 0.119 / Net I/σ(I): 7.92
Reflection shellResolution: 3.15→3.26 Å / Rmerge(I) obs: 1.118 / Mean I/σ(I) obs: 0.84 / Num. unique obs: 1761 / CC1/2: 0.425 / % possible all: 99.04

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.16_3549refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5jha

5jha


Resolution: 3.15→44.736 Å / SU ML: 0.53 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 29.93 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2722 846 5.01 %
Rwork0.2288 16681 -
obs0.2309 17560 98.13 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 242.31 Å2 / Biso mean: 108.3027 Å2 / Biso min: 43.23 Å2
Refinement stepCycle: final / Resolution: 3.15→44.736 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6506 0 54 0 6560
Biso mean--127.86 --
Num. residues----801
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
3.1501-3.34740.38461470.3438278499
3.3474-3.60570.351460.2867278399
3.6057-3.96840.30081470.2473277698
3.9684-4.54210.25961440.2094274898
4.5421-5.72070.24391470.212278798
5.7207-44.7360.24791480.2075280397
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)
15.0764-1.4091-0.46031.74431.06033.6426-0.05510.7736-1.5646-0.423-0.00420.25210.3090.07680.07430.90460.0024-0.05920.6319-0.15941.038631.6338-29.574417.6549
25.792-0.18931.35183.1772-1.4513.0798-0.0277-1.9218-0.91651.0333-0.07030.55430.6066-0.62840.09721.0523-0.06410.22461.44140.39721.15966.6878-22.838340.1401
34.4689-0.5211-1.31641.9970.00643.4167-0.25860.0386-0.62450.2040.2740.88340.0481-0.93010.07690.84430.0268-0.03810.82930.16660.884621.3044-24.418629.2866
42.57820.1893-2.02214.625-1.91095.7798-0.00330.5060.2524-0.4449-0.2361-0.29040.34810.23520.19060.78030.03750.09471.0584-0.07990.732666.5046-12.924811.2889
54.9882-0.2965-0.84074.8403-1.55144.56390.29241.1469-0.2866-0.6521-0.39730.04920.3040.08810.09910.81970.05730.06761.0301-0.12440.644657.2734-18.069514.3545
61.7417-0.69140.71372.2533-1.59653.1331-0.6104-0.5598-0.13330.22210.1808-0.27580.26280.840.45150.78380.0001-0.0260.98530.01750.789658.8023-19.266542.0154
75.6852-2.36113.68383.9784-0.143.12820.1596-0.7007-0.84880.6170.15530.20680.1664-0.1965-0.30380.67970.0021-0.01340.4470.07260.68843.2686-24.999733.4555
86.6891-2.07591.48082.0401-0.33772.50840.46071.357-0.0856-0.2-0.44560.3853-0.2254-0.34520.00040.75630.077-0.06990.93070.00960.560221.3742-10.575213.5718
93.556-1.88393.14965.4317-0.4064.5574-0.5021-0.62680.7490.87350.43240.3978-0.7225-0.43090.07760.8150.12790.09380.6263-0.07740.807122.60122.819932.8982
103.90030.92412.5532.96991.36711.9339-0.4334-0.71750.58140.596-0.01790.3371-0.5809-0.630.34631.19720.22340.08380.6889-0.08470.655830.65762.930739.3835
114.5193-0.94720.42544.8531-2.29352.9333-0.5854-0.98021.61460.654-0.07780.0558-1.427-0.28910.59761.1808-0.045-0.33090.8495-0.2581.287939.4067.708739.3055
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 145 through 208 )A145 - 208
2X-RAY DIFFRACTION2chain 'A' and (resid 209 through 286 )A209 - 286
3X-RAY DIFFRACTION3chain 'A' and (resid 287 through 361 )A287 - 361
4X-RAY DIFFRACTION4chain 'A' and (resid 362 through 415 )A362 - 415
5X-RAY DIFFRACTION5chain 'A' and (resid 416 through 514 )A416 - 514
6X-RAY DIFFRACTION6chain 'A' and (resid 515 through 600 )A515 - 600
7X-RAY DIFFRACTION7chain 'A' and (resid 601 through 688 )A601 - 688
8X-RAY DIFFRACTION8chain 'A' and (resid 689 through 837 )A689 - 837
9X-RAY DIFFRACTION9chain 'A' and (resid 838 through 955 )A838 - 955
10X-RAY DIFFRACTION10chain 'A' and (resid 956 through 1038 )A956 - 1038
11X-RAY DIFFRACTION11chain 'A' and (resid 1039 through 1088 )A0

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