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- PDB-3dpd: Achieving multi-isoform PI3K inhibition in a series of substitute... -

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Basic information

Entry
Database: PDB / ID: 3dpd
TitleAchieving multi-isoform PI3K inhibition in a series of substituted 3,4-Dihydro-2H-benzo[1,4]oxazines
ComponentsPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
KeywordsTRANSFERASE / PHOSPHOINOSITIDE 3-KINASE GAMMA / SECONDARY MESSENGER GENERATION / PI3K / PI 3K / Kinase
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-/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. / 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 / 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-41A / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsCeska, T.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Achieving multi-isoform PI3K inhibition in a series of substituted 3,4-dihydro-2H-benzo[1,4]oxazines
Authors: Perry, B. / Alexander, R. / Bennett, G. / Buckley, G. / Ceska, T. / Crabbe, T. / Dale, V. / Gowers, L. / Horsley, H. / James, L. / Jenkins, K. / Crepy, K. / Kulisa, C. / Lightfoot, H. / ...Authors: Perry, B. / Alexander, R. / Bennett, G. / Buckley, G. / Ceska, T. / Crabbe, T. / Dale, V. / Gowers, L. / Horsley, H. / James, L. / Jenkins, K. / Crepy, K. / Kulisa, C. / Lightfoot, H. / Lock, C. / Mack, S. / Morgan, T. / Nicolas, A.-L. / Pitt, W. / Sabin, V. / Wright, S.
History
DepositionJul 8, 2008Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Aug 26, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)111,0232
Polymers110,7561
Non-polymers2661
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)142.230, 67.770, 105.870
Angle α, β, γ (deg.)90.000, 95.960, 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 / PI3-kinase p110 subunit gamma / PtdIns-3-kinase subunit p110 / PI3Kgamma / PI3K / p120-PI3K


Mass: 110756.164 Da / Num. of mol.: 1 / Fragment: residues 144-1102
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Plasmid: PVL1393 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-41A / 5,5-dimethyl-2-morpholin-4-yl-5,6-dihydro-1,3-benzothiazol-7(4H)-one


Mass: 266.359 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H18N2O2S
Sequence detailsTHE SEQUENCE IS BASED ON REFERENCE 1 OR 3 IN THE DATABASE, P48736.

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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: 2.29 Å3/Da / Density % sol: 46.31 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 7.25
Details: 19% PEG 4000, 0.25M (NH4)2SO4, 0.1M TRIS PH 7.2 , pH 7.25 , VAPOR DIFFUSION, HANGING DROP, temperature 290K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX14.2 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jul 3, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.85→105.409 Å / Num. all: 68314 / Num. obs: 22970 / % possible obs: 97.4 % / Redundancy: 3 % / Rmerge(I) obs: 0.091 / Rsym value: 0.091 / Net I/σ(I): 5.4
Reflection shellResolution: 2.85→3 Å / Redundancy: 3 % / Rmerge(I) obs: 0.509 / Mean I/σ(I) obs: 1.4 / Num. measured all: 10050 / Num. unique all: 3377 / Rsym value: 0.509 / % possible all: 98.5

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Processing

Software
NameVersionClassificationNB
SCALA3.2.25data processing
CNSrefinement
PDB_EXTRACT3.006data extraction
ADSCQuantumdata collection
MOSFLMdata reduction
SCALAdata scaling
CNSphasing
CNX2002refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1e8y

1e8y


Resolution: 2.85→30 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.757 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.318 2262 9.6 %Random
Rwork0.242 ---
obs-22943 96.9 %-
Displacement parametersBiso max: 127.3 Å2 / Biso mean: 62.175 Å2 / Biso min: 2.15 Å2
Baniso -1Baniso -2Baniso -3
1-5.33 Å20 Å2-6.657 Å2
2---13.663 Å20 Å2
3---8.333 Å2
Refinement stepCycle: LAST / Resolution: 2.85→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6861 0 18 0 6879
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.083
X-RAY DIFFRACTIONc_mcbond_it2.4581.5
X-RAY DIFFRACTIONc_scbond_it3.5162
X-RAY DIFFRACTIONc_mcangle_it3.9772
X-RAY DIFFRACTIONc_scangle_it5.0372.5
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2a41.parama41.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top

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