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- PDB-7r2b: PI3Kdelta in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 7r2b
TitlePI3Kdelta in complex with an inhibitor
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsHYDROLASE / kinase / complex / inhibitor
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 / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / phosphatidylinositol 3-kinase complex ...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 / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / 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 / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / B cell activation / phosphatidylinositol-mediated signaling / B cell homeostasis / homeostasis of number of cells / defense response to fungus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of angiogenesis / chemotaxis / cell migration / kinase activity / adaptive immune response / cell surface receptor signaling pathway / cell differentiation / 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 / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-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. / Phosphoinositide 3-kinase C2 ...PI3Kdelta, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-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. / 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 / C2 domain superfamily / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-H5I / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsGutmann, S. / Rummel, G. / Shrestha, B.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Not funded Switzerland
CitationJournal: J.Med.Chem. / Year: 2022
Title: Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor.
Authors: Fairhurst, R.A. / Furet, P. / Imbach-Weese, P. / Stauffer, F. / Rueeger, H. / McCarthy, C. / Ripoche, S. / Oswald, S. / Arnaud, B. / Jary, A. / Maira, M. / Schnell, C. / Guthy, D.A. / ...Authors: Fairhurst, R.A. / Furet, P. / Imbach-Weese, P. / Stauffer, F. / Rueeger, H. / McCarthy, C. / Ripoche, S. / Oswald, S. / Arnaud, B. / Jary, A. / Maira, M. / Schnell, C. / Guthy, D.A. / Wartmann, M. / Kiffe, M. / Desrayaud, S. / Blasco, F. / Widmer, T. / Seiler, F. / Gutmann, S. / Knapp, M. / Caravatti, G.
History
DepositionFeb 4, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 18, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 6, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)108,2492
Polymers107,8241
Non-polymers4251
Water2,270126
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area34490 Å2
Unit cell
Length a, b, c (Å)142.29, 64.056, 117.185
Angle α, β, γ (deg.)90, 103.19, 90
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 / PI3-kinase subunit delta / PI3K-delta / PI3Kdelta / PtdIns-3-kinase subunit delta / ...PI3-kinase subunit delta / PI3K-delta / PI3Kdelta / PtdIns-3-kinase subunit delta / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit delta / PtdIns-3-kinase subunit p110-delta / p110delta


Mass: 107823.664 Da / Num. of mol.: 1 / Fragment: P110 SUBUNIT, UNP RESIDUES 106-1044
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 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-H5I / (4~{S})-3-[6-[2-azanyl-4-(trifluoromethyl)pyrimidin-5-yl]-2-morpholin-4-yl-pyrimidin-4-yl]-4-methyl-1,3-oxazolidin-2-one


Mass: 425.365 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H18F3N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 126 / Source method: isolated from a natural source / Formula: H2O
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: 2.41 Å3/Da / Density % sol: 48.99 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop
Details: 4 mM NaNO4,36mM AS,.9mM Na2HPO4,13.1% glycerol, 9.1% PEG4000, 0.1M imidazole pH6.9

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 6, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.515→114.095 Å / Num. obs: 35003 / % possible obs: 99.3 % / Redundancy: 3.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.069 / Rpim(I) all: 0.045 / Net I/σ(I): 10.6
Reflection shellResolution: 2.515→2.558 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.615 / Mean I/σ(I) obs: 3.3 / Num. unique obs: 1742 / CC1/2: 0.745 / Rpim(I) all: 0.401

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (3-FEB-2022)refinement
autoPROC1.1.7 (20-OCT-2021)data reduction
autoPROC1.1.7 (20-OCT-2021)data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5IS5

5is5


Resolution: 2.7→58.14 Å / Cor.coef. Fo:Fc: 0.913 / Cor.coef. Fo:Fc free: 0.907 / SU R Cruickshank DPI: 0.697 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.664 / SU Rfree Blow DPI: 0.322 / SU Rfree Cruickshank DPI: 0.329
RfactorNum. reflection% reflectionSelection details
Rfree0.2659 1420 -RANDOM
Rwork0.2224 ---
obs0.2247 28306 99.2 %-
Displacement parametersBiso mean: 70.83 Å2
Baniso -1Baniso -2Baniso -3
1-1.3417 Å20 Å2-3.1238 Å2
2---10.0902 Å20 Å2
3---8.7485 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: LAST / Resolution: 2.7→58.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5815 0 30 126 5971
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0085972HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.938114HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1912SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1035HARMONIC5
X-RAY DIFFRACTIONt_it5972HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion805SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4670SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.7
X-RAY DIFFRACTIONt_other_torsion17.85
LS refinement shellResolution: 2.7→2.72 Å
RfactorNum. reflection% reflection
Rfree0.2447 29 -
Rwork0.2308 --
obs0.2316 567 100 %
Refinement TLS params.Origin x: 18.5075 Å / Origin y: -15.4869 Å / Origin z: -28.2877 Å
111213212223313233
T-0.1135 Å2-0.1486 Å2-0.0218 Å2--0.0462 Å20.0065 Å2---0.0828 Å2
L0.7783 °20.1087 °2-0.2866 °2-0.9287 °2-0.1053 °2--3.2146 °2
S-0.087 Å °-0.0578 Å °-0.2892 Å °-0.0578 Å °0.011 Å °0.7821 Å °-0.2892 Å °0.7821 Å °0.0759 Å °
Refinement TLS groupSelection details: { A|* }

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