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- PDB-6dgt: Selective PI3K beta inhibitor bound to PI3K delta -

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Basic information

Entry
Database: PDB / ID: 6dgt
TitleSelective PI3K beta inhibitor bound to PI3K delta
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PI3K delta / p110 / inhibitor / 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 / 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-GFJ / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.601 Å
AuthorsSomoza, J. / Villasenor, A. / McGrath, M.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3-Kinase (PI3K) beta Inhibitor.
Authors: Chandrasekhar, J. / Dick, R. / Van Veldhuizen, J. / Koditek, D. / Lepist, E.I. / McGrath, M.E. / Patel, L. / Phillips, G. / Sedillo, K. / Somoza, J.R. / Therrien, J. / Till, N.A. / Treiberg, ...Authors: Chandrasekhar, J. / Dick, R. / Van Veldhuizen, J. / Koditek, D. / Lepist, E.I. / McGrath, M.E. / Patel, L. / Phillips, G. / Sedillo, K. / Somoza, J.R. / Therrien, J. / Till, N.A. / Treiberg, J. / Villasenor, A.G. / Zherebina, Y. / Perreault, S.
History
DepositionMay 18, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 1, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 22, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)108,1112
Polymers107,6381
Non-polymers4721
Water77543
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)63.517, 143.502, 221.256
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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: 107638.477 Da / Num. of mol.: 1 / Fragment: residues 106-1043
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Pik3cd / Production host: Escherichia coli (E. coli)
References: UniProt: O35904, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Chemical ChemComp-GFJ / 4-[1-(5,8-difluoroquinolin-4-yl)-2-methyl-4-(4H-1,2,4-triazol-3-yl)-1H-benzimidazol-6-yl]-3-fluoropyridin-2-amine


Mass: 472.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H15F3N8
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 43 / 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: 2.34 Å3/Da / Density % sol: 47.42 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 25% peg 300, 0.1M tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 14, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 152619 / % possible obs: 99.8 % / Redundancy: 4.8 % / Net I/σ(I): 15.467
Reflection shellResolution: 2.6→2.64 Å

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155)refinement
HKL-2000data reduction
HKL-2000data scaling
EPMRphasing
RefinementResolution: 2.601→40.056 Å / SU ML: 0.46 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 35.44
RfactorNum. reflection% reflection
Rfree0.3183 1999 6.36 %
Rwork0.2314 --
obs0.237 31431 99.52 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.601→40.056 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6218 0 35 43 6296
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0196397
X-RAY DIFFRACTIONf_angle_d1.8948642
X-RAY DIFFRACTIONf_dihedral_angle_d16.7533832
X-RAY DIFFRACTIONf_chiral_restr0.084958
X-RAY DIFFRACTIONf_plane_restr0.0111090
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.601-2.66610.37641360.30842005X-RAY DIFFRACTION96
2.6661-2.73810.37891410.30272077X-RAY DIFFRACTION100
2.7381-2.81870.40481410.30312080X-RAY DIFFRACTION100
2.8187-2.90960.37521430.29132104X-RAY DIFFRACTION100
2.9096-3.01360.40951420.27762083X-RAY DIFFRACTION100
3.0136-3.13420.3851410.29192090X-RAY DIFFRACTION100
3.1342-3.27680.3691420.25542086X-RAY DIFFRACTION100
3.2768-3.44950.37761410.25172075X-RAY DIFFRACTION100
3.4495-3.66540.31451430.23292107X-RAY DIFFRACTION100
3.6654-3.94820.2641450.20772126X-RAY DIFFRACTION100
3.9482-4.34510.29281430.18982102X-RAY DIFFRACTION100
4.3451-4.97290.28181440.19592134X-RAY DIFFRACTION100
4.9729-6.26140.34381460.22692140X-RAY DIFFRACTION100
6.2614-40.06040.26951510.21942223X-RAY DIFFRACTION99

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