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- PDB-4xe0: Idelalisib bound to the p110 subunit of PI3K delta -

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Basic information

Entry
Database: PDB / ID: 4xe0
TitleIdelalisib bound to the p110 subunit of PI3K delta
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTransferase/transferase inhibitor / Zydelig / PI3K / kinase / Transferase-transferase inhibitor complex
Function / homology
Function and homology information


Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of signaling by CBL / positive regulation of cell migration by vascular endothelial growth factor signaling pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling ...Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of signaling by CBL / positive regulation of cell migration by vascular endothelial growth factor signaling pathway / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / positive regulation of epithelial tube formation / positive regulation of neutrophil apoptotic process / phosphatidylinositol 3-kinase complex / 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 / B cell activation / B cell homeostasis / homeostasis of number of cells / defense response to fungus / positive regulation of endothelial cell proliferation / positive regulation of endothelial cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of angiogenesis / chemotaxis / kinase activity / adaptive immune response / cell differentiation / cell surface receptor signaling pathway / positive regulation of cell migration / inflammatory response / phosphorylation / negative regulation of gene expression / innate immune response / positive regulation of gene expression / ATP binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PI3Kdelta, catalytic 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / C2 domain / Phosphatidylinositol 3-kinase, adaptor-binding domain ...PI3Kdelta, catalytic 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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-40L / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.434 Å
AuthorsSomoza, J.R. / Villasenor, A.
CitationJournal: J.Biol.Chem. / Year: 2015
Title: Structural, Biochemical, and Biophysical Characterization of Idelalisib Binding to Phosphoinositide 3-Kinase delta.
Authors: Somoza, J.R. / Koditek, D. / Villasenor, A.G. / Novikov, N. / Wong, M.H. / Liclican, A. / Xing, W. / Lagpacan, L. / Wang, R. / Schultz, B.E. / Papalia, G.A. / Samuel, D. / Lad, L. / McGrath, M.E.
History
DepositionDec 20, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 4, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 11, 2015Group: Database references
Revision 1.2Apr 8, 2015Group: Database references
Revision 1.3Aug 9, 2017Group: Database references / Derived calculations / Source and taxonomy
Category: citation / entity_src_gen / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Sep 27, 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

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Assembly

Deposited unit
A: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,1822
Polymers107,7671
Non-polymers4151
Water4,035224
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area860 Å2
ΔGint-4 kcal/mol
Surface area36390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)142.049, 64.590, 115.960
Angle α, β, γ (deg.)90.000, 103.090, 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 delta isoform / PtdIns-3-kinase subunit delta / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit delta / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit delta / p110delta


Mass: 107766.609 Da / Num. of mol.: 1 / Fragment: UNP residues 106-1043
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Pik3cd / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O35904, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-40L / 5-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]quinazolin-4(3H)-one / Idelalisib


Mass: 415.423 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18FN7O / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 224 / 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: 2.4 Å3/Da / Density % sol: 48.84 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: Crystals for seeding were obtained by vapor diffusion, followed by preparation of diffraction quality crystals.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.977 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 17, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977 Å / Relative weight: 1
ReflectionRedundancy: 3.6 % / Number: 136588 / Rmerge(I) obs: 0.085 / D res high: 2.43 Å / D res low: 69.18 Å / Num. obs: 38471 / % possible obs: 99.5 / Rejects: 28
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsRedundancy
2.432.5310.4333.4
9.1169.1810.0653.5
ReflectionResolution: 2.43→69.18 Å / Num. obs: 38471 / % possible obs: 99.5 % / Redundancy: 3.6 % / Biso Wilson estimate: 35.96 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.053 / Net I/σ(I): 9.7 / Num. measured all: 136588 / Scaling rejects: 28
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2.43-2.533.40.4332.71380740090.7660.27398.9
9.11-69.183.50.06520.327927970.9930.0499.9

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation7.63 Å69.18 Å
Translation7.63 Å69.18 Å

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
Aimless0.3.6data scaling
PHASER2.5.6phasing
PHENIXrefinement
PDB_EXTRACT3.15data extraction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2WXF

2wxf


Resolution: 2.434→69.179 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.64 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2888 2000 5.2 %Random selection
Rwork0.2131 36469 --
obs0.2171 38469 99.36 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.07 Å2 / Biso mean: 40.9772 Å2 / Biso min: 15.3 Å2
Refinement stepCycle: final / Resolution: 2.434→69.179 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6566 0 31 224 6821
Biso mean--24.32 40.19 -
Num. residues----815
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0096750
X-RAY DIFFRACTIONf_angle_d1.2029111
X-RAY DIFFRACTIONf_chiral_restr0.0441005
X-RAY DIFFRACTIONf_plane_restr0.0061151
X-RAY DIFFRACTIONf_dihedral_angle_d14.8062500
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.434-2.49490.3431410.23982576271798
2.4949-2.56230.2871420.22992586272899
2.5623-2.63770.30471400.23952559269999
2.6377-2.72290.28621440.220526152759100
2.7229-2.82020.32381420.22282584272699
2.8202-2.93310.33621430.219426172760100
2.9331-3.06660.26521410.22432569271099
3.0666-3.22830.30271440.22112613275799
3.2283-3.43060.34011400.217925832723100
3.4306-3.69540.25181440.21226162760100
3.6954-4.06730.27771430.19562597274099
4.0673-4.65570.27061440.19542617276199
4.6557-5.86520.29391430.20452631277499
5.8652-69.20690.27141490.21932706285599

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