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- PDB-6tns: PI3K delta in complex with 2methoxyN[2methoxy5(7{[(2R)4(oxetan3 y... -

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Basic information

Entry
Database: PDB / ID: 6tns
TitlePI3K delta in complex with 2methoxyN[2methoxy5(7{[(2R)4(oxetan3 yl)morpholin2yl]methoxy}1,3dihydro2 benzofuran5yl)pyridin3yl]ethane1 sulfonamide
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / PI3 Kinase Structure based design
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 / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol 3-kinase / phosphatidylinositol 3-kinase complex, class IA / 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 / 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 phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / 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-NQ5 / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.4 Å
AuthorsConvery, M.A. / Rowland, P. / Henley, Z.A. / Barton, N. / Down, K.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Optimization of Orally Bioavailable PI3K delta Inhibitors and Identification of Vps34 as a Key Selectivity Target.
Authors: Henley, Z.A. / Amour, A. / Barton, N. / Bantscheff, M. / Bergamini, G. / Bertrand, S.M. / Convery, M. / Down, K. / Dumpelfeld, B. / Edwards, C.D. / Grandi, P. / Gore, P.M. / Keeling, S. / ...Authors: Henley, Z.A. / Amour, A. / Barton, N. / Bantscheff, M. / Bergamini, G. / Bertrand, S.M. / Convery, M. / Down, K. / Dumpelfeld, B. / Edwards, C.D. / Grandi, P. / Gore, P.M. / Keeling, S. / Livia, S. / Mallett, D. / Maxwell, A. / Price, M. / Rau, C. / Reinhard, F.B.M. / Rowedder, J. / Rowland, P. / Taylor, J.A. / Thomas, D.A. / Hessel, E.M. / Hamblin, J.N.
History
DepositionDec 10, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 1, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation.year / _citation_author.name
Revision 1.2Feb 5, 2020Group: 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 1.3Mar 4, 2020Group: Data collection / Category: diffrn_source
Item: _diffrn_source.pdbx_synchrotron_beamline / _diffrn_source.type
Revision 1.4Sep 29, 2021Group: Database references / Refinement description / Source and taxonomy
Category: database_2 / entity_src_gen / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name / _software.name

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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)108,3592
Polymers107,8241
Non-polymers5361
Water5,062281
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area39070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.749, 64.582, 116.105
Angle α, β, γ (deg.)90.000, 103.100, 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: 107823.664 Da / Num. of mol.: 1
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-NQ5 / 2-methoxy-~{N}-[2-methoxy-5-[7-[[(2~{R})-4-(oxetan-3-yl)morpholin-2-yl]methoxy]-1,3-dihydro-2-benzofuran-5-yl]pyridin-3-yl]ethanesulfonamide


Mass: 535.610 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H33N3O8S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 281 / 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: 2.4 Å3/Da / Density % sol: 48.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: Morpheus condition: 0.1 M buffer system 1 pH 6.5, 0.1 M carboxylic acids, 30% ethylene glycol/PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Aug 30, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 2.4→69.03 Å / Num. obs: 38357 / % possible obs: 95.1 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.054 / Net I/σ(I): 11.9
Reflection shellResolution: 2.4→2.441 Å / Redundancy: 3 % / Rmerge(I) obs: 0.515 / Mean I/σ(I) obs: 2 / Num. unique obs: 1989 / % possible all: 99.3

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
autoPROCdata reduction
autoPROCdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.4→27.15 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.904 / SU R Cruickshank DPI: 0.402 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.402 / SU Rfree Blow DPI: 0.255 / SU Rfree Cruickshank DPI: 0.258
RfactorNum. reflection% reflectionSelection details
Rfree0.244 1838 4.8 %RANDOM
Rwork0.187 ---
obs0.19 38307 95.1 %-
Displacement parametersBiso max: 161.5 Å2 / Biso mean: 63 Å2 / Biso min: 24.54 Å2
Baniso -1Baniso -2Baniso -3
1-3.1645 Å20 Å23.7719 Å2
2---2.1322 Å20 Å2
3----1.0323 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: final / Resolution: 2.4→27.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6941 0 37 281 7259
Biso mean--44.65 56.97 -
Num. residues----863
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2546SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes176HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1031HARMONIC5
X-RAY DIFFRACTIONt_it7133HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion886SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8223SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7133HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg9633HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion2.8
X-RAY DIFFRACTIONt_other_torsion17.41
LS refinement shellResolution: 2.4→2.47 Å / Rfactor Rfree error: 0 / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.238 155 5.03 %
Rwork0.2047 2928 -
all0.2064 3083 -
obs--99.14 %
Refinement TLS params.Method: refined / Origin x: -20.1661 Å / Origin y: -14.6091 Å / Origin z: 28.8039 Å
111213212223313233
T-0.1782 Å20.0686 Å20.0113 Å2--0.1379 Å2-0.0115 Å2---0.2122 Å2
L0.8127 °2-0.0141 °2-0.1066 °2-0.5456 °20.2169 °2--1.7882 °2
S-0.0596 Å °0.0943 Å °0.1169 Å °0.0537 Å °-0.0183 Å °0.0183 Å °-0.051 Å °-0.4337 Å °0.0779 Å °
Refinement TLS groupSelection details: { A|* }

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