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- PDB-7r26: PI3K delta in complex with SD5 -

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Basic information

Entry
Database: PDB / ID: 7r26
TitlePI3K delta in complex with SD5
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsHYDROLASE / kinase / inhibitor / complex
Function / homology
Function and homology information


Co-stimulation by ICOS / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / CD28 dependent PI3K/Akt signaling / 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 ...Co-stimulation by ICOS / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / CD28 dependent PI3K/Akt signaling / 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 / positive regulation of epithelial tube formation / positive regulation of neutrophil apoptotic process / phosphatidylinositol 3-kinase complex / 1-phosphatidylinositol-4-phosphate 3-kinase activity / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / vascular endothelial growth factor signaling pathway / phosphatidylinositol-mediated signaling / B cell homeostasis / B cell activation / 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 / chemotaxis / positive regulation of angiogenesis / cell migration / adaptive immune response / cell differentiation / cell surface receptor signaling pathway / positive regulation of cell migration / inflammatory response / negative regulation of gene expression / innate immune response / positive regulation of gene expression / ATP binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
PI3Kdelta, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / 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. ...PI3Kdelta, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Phosphatidylinositol 3-kinase, accessory domain (PIK) / 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 / C2 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 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-SD5 / 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: 2.3 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)108,2342
Polymers107,8241
Non-polymers4101
Water5,008278
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 area35700 Å2
Unit cell
Length a, b, c (Å)143.003, 64.53, 117.347
Angle α, β, γ (deg.)90, 103.32, 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-SD5 / 5-[2,6-di(morpholin-4-yl)pyrimidin-4-yl]-4-(trifluoromethyl)pyridin-2-amine


Mass: 410.394 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 278 / 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: 2.44 Å3/Da / Density % sol: 49.66 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop
Details: 31 mM NaNO4, 13 mM AS, 4 mM Na2HPO4, 20.9 % glycerol,8.55 % PEG4000, 0.1M imidazole pH6.8

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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: Nov 9, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.086→54.135 Å / Num. obs: 60437 / % possible obs: 97.1 % / Redundancy: 3.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.038 / Net I/σ(I): 17.1
Reflection shellResolution: 2.086→2.122 Å / Rmerge(I) obs: 0.622 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 3076 / CC1/2: 0.817

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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: 2.3→54.13 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.921 / SU R Cruickshank DPI: 0.274 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.274 / SU Rfree Blow DPI: 0.204 / SU Rfree Cruickshank DPI: 0.206
RfactorNum. reflection% reflectionSelection details
Rfree0.2408 2322 -RANDOM
Rwork0.2145 ---
obs0.2159 46365 99.6 %-
Displacement parametersBiso mean: 67.11 Å2
Baniso -1Baniso -2Baniso -3
1--1.7953 Å20 Å2-2.506 Å2
2---6.6281 Å20 Å2
3---8.4234 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: LAST / Resolution: 2.3→54.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6116 0 29 278 6423
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0086279HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.868510HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2074SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1074HARMONIC5
X-RAY DIFFRACTIONt_it6279HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion825SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4963SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.73
X-RAY DIFFRACTIONt_other_torsion16.73
LS refinement shellResolution: 2.3→2.32 Å
RfactorNum. reflection% reflection
Rfree0.2966 53 -
Rwork0.244 --
obs0.2471 928 99.89 %
Refinement TLS params.Origin x: -18.5184 Å / Origin y: 16.5401 Å / Origin z: 29.1327 Å
111213212223313233
T-0.073 Å20.1167 Å2-0.0176 Å2--0.1005 Å2-0.0093 Å2---0.1337 Å2
L0.8933 °2-0.0894 °2-0.3209 °2-0.9887 °20.0941 °2--3.1218 °2
S-0.0229 Å °0.0576 Å °-0.3449 Å °0.0576 Å °0.0011 Å °-0.6965 Å °-0.3449 Å °-0.6965 Å °0.0218 Å °
Refinement TLS groupSelection details: { A|* }

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