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- PDB-6fh5: PI3Kg IN COMPLEX WITH Compound 7 -

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Basic information

Entry
Database: PDB / ID: 6fh5
TitlePI3Kg IN COMPLEX WITH Compound 7
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / Kinase / 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-DD8 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.84 Å
AuthorsPetersen, J. / Barlaam, B.
CitationJournal: To Be Published
Title: Discovery and Optimisation of a Novel Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent and Selective Ataxia Telangiectasia Mutated (ATM) inhibitors
Authors: Barlaam, B. / Cadogan, E. / Cambell, A. / Colclough, N. / Dishington, A. / Durant, S. / Goldberg, K. / Hassall, L.A. / Hughes, G.D. / MacFaul, P.A. / McGuire, T.M. / Pass, M. / Patel, A. / ...Authors: Barlaam, B. / Cadogan, E. / Cambell, A. / Colclough, N. / Dishington, A. / Durant, S. / Goldberg, K. / Hassall, L.A. / Hughes, G.D. / MacFaul, P.A. / McGuire, T.M. / Pass, M. / Patel, A. / Pearson, S. / Petersen, J. / Pike, K.G. / Robb, G. / Stratton, N. / Xin, N. / Zhai, B.
History
DepositionJan 12, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 30, 2019Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: 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

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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)111,0882
Polymers110,7271
Non-polymers3601
Water28816
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area34820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)139.590, 67.066, 104.897
Angle α, β, γ (deg.)90.00, 97.28, 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 / 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 (butterflies/moths)
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-DD8 / 3-methyl-1-(oxan-4-yl)-8-pyridin-3-yl-imidazo[4,5-c]quinolin-2-one


Mass: 360.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / Source method: isolated from a natural source / Formula: H2O

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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: 2.62 Å3/Da / Density % sol: 53.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 20 Percent PEG3350, 175 mM AmSO4, 10 mM DTT and 100 mM Hepes pH 7.4 to 7.9

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.972 Å
DetectorType: DECTRIS PILATUS3 R CdTe 300K-W / Detector: PIXEL / Date: Aug 31, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.972 Å / Relative weight: 1
ReflectionResolution: 2.84→61.33 Å / Num. obs: 22591 / % possible obs: 98.1 % / Redundancy: 3.3 % / Biso Wilson estimate: 97.77 Å2 / Rmerge(I) obs: 0.087 / Net I/σ(I): 10.7
Reflection shellResolution: 2.84→2.99 Å / Redundancy: 3.5 % / Rmerge(I) obs: 1.013 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 3285 / % possible all: 97.9

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Processing

Software
NameVersionClassification
BUSTER2.11.6 PACIOREKrefinement
MOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Internal Model

Resolution: 2.84→53.51 Å / Cor.coef. Fo:Fc: 0.8922 / Cor.coef. Fo:Fc free: 0.8506 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.439
RfactorNum. reflection% reflectionSelection details
Rfree0.2957 1156 5.13 %RANDOM
Rwork0.2352 ---
obs0.2383 22518 98.02 %-
Displacement parametersBiso mean: 81.16 Å2
Baniso -1Baniso -2Baniso -3
1-20.0283 Å20 Å2-8.3854 Å2
2--6.1652 Å20 Å2
3----26.1935 Å2
Refine analyzeLuzzati coordinate error obs: 0.473 Å
Refinement stepCycle: LAST / Resolution: 2.84→53.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6535 0 27 16 6578
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0096703HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.089066HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2364SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes174HARMONIC2
X-RAY DIFFRACTIONt_gen_planes937HARMONIC5
X-RAY DIFFRACTIONt_it6703HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.27
X-RAY DIFFRACTIONt_other_torsion22.57
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion865SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7628SEMIHARMONIC4
LS refinement shellResolution: 2.84→2.98 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.3114 152 5.08 %
Rwork0.2631 2843 -
all0.2655 2995 -
obs--97.87 %

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