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- PDB-6c1s: Phosphoinositide 3-Kinase gamma bound to an pyrrolopyridinone Inh... -

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Basic information

Entry
Database: PDB / ID: 6c1s
TitlePhosphoinositide 3-Kinase gamma bound to an pyrrolopyridinone Inhibitor
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTransferase/Transferase Inhibitor / kinase / inhibitor / Transferase-Transferase Inhibitor complex
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 / 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 ...secretory granule localization / negative regulation of triglyceride catabolic process / 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 / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / hepatocyte apoptotic process / positive regulation of Rac protein signal transduction / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / regulation of cell adhesion mediated by integrin / Synthesis of PIPs at the plasma membrane / regulation of angiogenesis / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / T cell activation / ephrin receptor binding / positive regulation of endothelial cell migration / neutrophil chemotaxis / 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 / inflammatory response / immune 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-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. ...PIK3 catalytic subunit gamma, adaptor-binding domain / PIK3 catalytic subunit gamma adaptor-binding domain / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / C2 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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / C2 domain superfamily / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Ubiquitin-like (UB roll) / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Roll / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-EFV / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.31 Å
AuthorsJacobs, M.D. / Griffin, J.P.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase gamma (PI3K gamma ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS).
Authors: Come, J.H. / Collier, P.N. / Henderson, J.A. / Pierce, A.C. / Davies, R.J. / Le Tiran, A. / O'Dowd, H. / Bandarage, U.K. / Cao, J. / Deininger, D. / Grey, R. / Krueger, E.B. / Lowe, D.B. / ...Authors: Come, J.H. / Collier, P.N. / Henderson, J.A. / Pierce, A.C. / Davies, R.J. / Le Tiran, A. / O'Dowd, H. / Bandarage, U.K. / Cao, J. / Deininger, D. / Grey, R. / Krueger, E.B. / Lowe, D.B. / Liang, J. / Liao, Y. / Messersmith, D. / Nanthakumar, S. / Sizensky, E. / Wang, J. / Xu, J. / Chin, E.Y. / Damagnez, V. / Doran, J.D. / Dworakowski, W. / Griffith, J.P. / Jacobs, M.D. / Khare-Pandit, S. / Mahajan, S. / Moody, C.S. / Aronov, A.M.
History
DepositionJan 5, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 27, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 11, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 4, 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 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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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)112,0296
Polymers111,2691
Non-polymers7615
Water2,720151
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)144.760, 67.550, 107.530
Angle α, β, γ (deg.)90.000, 95.530, 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: 111268.758 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) / Strain (production host): sf9
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-EFV / {4-[2-(5,6-dimethoxypyridin-3-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}acetonitrile


Mass: 376.369 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 18.015 Da / Num. of mol.: 151 / 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: 2.35 Å3/Da / Density % sol: 47.69 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 25% PEG3350, 200MM Lithium Sulfate, 10 MM DTT, 10 MM EDTA, 100 MM Tris

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 11, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.49→62.63 Å / Num. obs: 90461 / % possible obs: 54.2 % / Redundancy: 2.7 % / Biso Wilson estimate: 66.98 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.064 / Rrim(I) all: 0.116 / Net I/σ(I): 4.1 / Num. measured all: 243828 / Scaling rejects: 0
Reflection shellResolution: 1.49→1.58 Å / Redundancy: 1.6 % / Num. unique obs: 1683 / % possible all: 7

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Processing

Software
NameClassification
BUSTERrefinement
XDSdata reduction
autoPROCdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4wwo

4wwo


Resolution: 2.31→41.12 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.92 / SU R Cruickshank DPI: 0.538 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.505 / SU Rfree Blow DPI: 0.29 / SU Rfree Cruickshank DPI: 0.297
RfactorNum. reflection% reflectionSelection details
Rfree0.257 1650 4.93 %RANDOM
Rwork0.197 ---
obs0.199 33478 73.4 %-
Displacement parametersBiso max: 218.78 Å2 / Biso mean: 87.57 Å2 / Biso min: 35.61 Å2
Baniso -1Baniso -2Baniso -3
1-2.4156 Å20 Å23.7812 Å2
2--0.1107 Å20 Å2
3----2.5263 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: final / Resolution: 2.31→41.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6670 0 48 151 6869
Biso mean--91.79 68.36 -
Num. residues----826
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2412SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes177HARMONIC2
X-RAY DIFFRACTIONt_gen_planes962HARMONIC5
X-RAY DIFFRACTIONt_it6856HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion890SEMIHARMONIC5
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_contact7947SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6856HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg9280HARMONIC21.19
X-RAY DIFFRACTIONt_omega_torsion2.75
X-RAY DIFFRACTIONt_other_torsion23.08
LS refinement shellResolution: 2.31→2.38 Å / Rfactor Rfree error: 0 / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.344 15 9.32 %
Rwork0.2779 146 -
all0.2831 161 -
obs--4.09 %
Refinement TLS params.Method: refined / Origin x: 35.0899 Å / Origin y: 47.2102 Å / Origin z: 27.5997 Å
111213212223313233
T-0.1529 Å20.0225 Å20.1073 Å2--0.3382 Å20.0534 Å2---0.3034 Å2
L4.9102 °2-1.3542 °21.2436 °2-1.6218 °2-0.5084 °2--2.2611 °2
S0.0011 Å °0.1967 Å °-0.3622 Å °0.1166 Å °0.1653 Å °0.3355 Å °-0.392 Å °-0.0481 Å °-0.1663 Å °
Refinement TLS groupSelection details: { A|144 - A|1090 }

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