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- PDB-5ngb: X-Ray Diffraction Crystal Structure of the murine PI3K p110delta ... -

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Basic information

Entry
Database: PDB / ID: 5ngb
TitleX-Ray Diffraction Crystal Structure of the murine PI3K p110delta in complex with a pan inhibitor
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / PI3K p110
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 / cytoplasm / cytosol
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-8WH / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform / phosphatidylinositol-4,5-bisphosphate 3-kinase
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsBerndt, A. / Williams, R.L.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MC_U105184308 United Kingdom
CitationJournal: ChemMedChem / Year: 2017
Title: Identification of a Potent Phosphoinositide 3-Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs.
Authors: Pirali, T. / Ciraolo, E. / Aprile, S. / Massarotti, A. / Berndt, A. / Griglio, A. / Serafini, M. / Mercalli, V. / Landoni, C. / Campa, C.C. / Margaria, J.P. / Silva, R.L. / Grosa, G. / ...Authors: Pirali, T. / Ciraolo, E. / Aprile, S. / Massarotti, A. / Berndt, A. / Griglio, A. / Serafini, M. / Mercalli, V. / Landoni, C. / Campa, C.C. / Margaria, J.P. / Silva, R.L. / Grosa, G. / Sorba, G. / Williams, R. / Hirsch, E. / Tron, G.C.
History
DepositionMar 17, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 13, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Feb 20, 2019Group: Advisory / Data collection / Derived calculations
Category: pdbx_data_processing_status / pdbx_validate_close_contact ...pdbx_data_processing_status / pdbx_validate_close_contact / struct_conn / struct_conn_type
Revision 1.3Jan 17, 2024Group: 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)124,7452
Polymers124,3131
Non-polymers4311
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area36430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.437, 143.586, 220.193
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 / Putative uncharacterized protein


Mass: 124313.070 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: RESIDUES 106-1044 / Source: (gene. exp.) Mus musculus (house mouse) / Gene: Pik3cd / Plasmid: PFASTBAC HTA / Production host: Spodoptera frugiperda (fall armyworm) / Variant (production host): Sf21 / References: UniProt: Q3UDT3, UniProt: O35904*PLUS
#2: Chemical ChemComp-8WH / 3-[[4-(2-morpholin-4-yl-4-oxidanylidene-3~{H}-quinolin-8-yl)-1,2,3-triazol-1-yl]methyl]benzoic acid


Mass: 431.444 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21N5O4

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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

Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 6.8
Details: 26% (V/V) GLYCEROL, 13% (W/V) PEG 4K, 3 MM NANO3, 3 MM NA2HPO4, 3 MM (NH4)2SO4, 100 MM IMIDAZOLE PH 6.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9763 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 16, 2012
RadiationMonochromator: SILICON CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.9→45.63 Å / Num. obs: 22926 / % possible obs: 99.8 % / Redundancy: 10 % / Biso Wilson estimate: 40 Å2 / Rmerge(I) obs: 0.251 / Rpim(I) all: 0.085 / Rrim(I) all: 0.266 / Rsym value: 0.252 / Net I/σ(I): 11.9
Reflection shellResolution: 2.9→3.06 Å / Redundancy: 9.6 % / Rmerge(I) obs: 1.104 / Mean I/σ(I) obs: 2.9 / Num. unique all: 3242 / Rpim(I) all: 0.377 / Rrim(I) all: 1.168 / % possible all: 98.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSMarch 15 2012data reduction
SCALA3.3.20data scaling
PHASER2.5.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2WXH

2wxh


Resolution: 2.9→45.63 Å / Cor.coef. Fo:Fc: 0.888 / Cor.coef. Fo:Fc free: 0.831 / SU B: 21.734 / SU ML: 0.402 / Cross valid method: THROUGHOUT / ESU R Free: 0.472 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29011 1170 5.1 %RANDOM
Rwork0.24213 ---
obs0.24456 21718 99.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 50.567 Å2
Baniso -1Baniso -2Baniso -3
1-2.67 Å20 Å2-0 Å2
2--0.02 Å20 Å2
3----2.69 Å2
Refinement stepCycle: 1 / Resolution: 2.9→45.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6593 0 32 0 6625
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0196770
X-RAY DIFFRACTIONr_bond_other_d0.0030.026323
X-RAY DIFFRACTIONr_angle_refined_deg1.4921.979135
X-RAY DIFFRACTIONr_angle_other_deg1.0933.00114660
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6625804
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.67723.905315
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.737151224
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.7271542
X-RAY DIFFRACTIONr_chiral_restr0.0740.21005
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.027362
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021398
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.2735.0213252
X-RAY DIFFRACTIONr_mcbond_other3.2735.023251
X-RAY DIFFRACTIONr_mcangle_it5.4277.5094044
X-RAY DIFFRACTIONr_mcangle_other5.4277.5114045
X-RAY DIFFRACTIONr_scbond_it2.8725.2933517
X-RAY DIFFRACTIONr_scbond_other2.8715.2923518
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.9187.8385092
X-RAY DIFFRACTIONr_long_range_B_refined10.83493.46428219
X-RAY DIFFRACTIONr_long_range_B_other10.83493.46228220
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.893→2.968 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.446 68 -
Rwork0.326 1524 -
obs--97.55 %

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