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- PDB-5l72: PI3 kinase delta in complex with N-[6-(5-methanesulfonamido-6-met... -

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Basic information

Entry
Database: PDB / ID: 5l72
TitlePI3 kinase delta in complex with N-[6-(5-methanesulfonamido-6-methoxypyridin-3-yl)-1,3-dihydro-2-benzofuran-4-yl]-2-(morpholin-4-yl)acetamide
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / PI3 kinase delta
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 homeostasis / B cell activation / phosphatidylinositol-mediated signaling / homeostasis of number of cells / defense response to fungus / 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 / inflammatory response / 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 / 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. / 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 / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / 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-6PF / 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: 3.06 Å
AuthorsRowland, P.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Evolution of a Novel, Orally Bioavailable Series of PI3K delta Inhibitors from an Inhaled Lead for the Treatment of Respiratory Disease.
Authors: Amour, A. / Barton, N. / Cooper, A.W. / Inglis, G. / Jamieson, C. / Luscombe, C.N. / Morrell, J. / Peace, S. / Perez, D. / Rowland, P. / Tame, C. / Uddin, S. / Vitulli, G. / Wellaway, N.
History
DepositionJun 1, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 27, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 24, 2016Group: Database references
Revision 1.2Sep 29, 2021Group: Database references / Structure summary
Category: database_2 / entity ...database_2 / entity / entity_name_com / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_ec / _struct_ref.db_code / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_db_accession
Revision 1.3Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)108,2842
Polymers107,8241
Non-polymers4611
Water4,828268
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area38610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.400, 64.360, 115.830
Angle α, β, γ (deg.)90.00, 102.88, 90.00
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
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-6PF / N-[6-(5-methanesulfonamido-6-methoxypyridin-3-yl)-1,3-dihydro-2-benzofuran-4-yl]-2-(morpholin-4-yl)acetamide


Mass: 460.503 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H24N4O6S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 268 / 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: 2.38 Å3/Da / Density % sol: 48.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Vapour diffusion using Morpheus screen with crystal seeding

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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 315 / Detector: CCD / Date: Apr 6, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 3.06→113 Å / Num. obs: 65937 / % possible obs: 97.4 % / Redundancy: 3.5 % / Biso Wilson estimate: 80.76 Å2 / CC1/2: 0.986 / Rmerge(I) obs: 0.139 / Net I/σ(I): 9.5
Reflection shellResolution: 3.06→3.07 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.563 / Mean I/σ(I) obs: 2.5 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 3.06→112.92 Å / Cor.coef. Fo:Fc: 0.9027 / Cor.coef. Fo:Fc free: 0.7992 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.522
RfactorNum. reflection% reflectionSelection details
Rfree0.2774 967 5.1 %RANDOM
Rwork0.1723 ---
obs0.1778 18943 97.39 %-
Displacement parametersBiso mean: 57.6 Å2
Baniso -1Baniso -2Baniso -3
1-8.8492 Å20 Å27.1351 Å2
2---5.4368 Å20 Å2
3----3.4123 Å2
Refine analyzeLuzzati coordinate error obs: 0.326 Å
Refinement stepCycle: 1 / Resolution: 3.06→112.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6925 0 32 268 7225
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.017110HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.139599HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2543SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes177HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1029HARMONIC5
X-RAY DIFFRACTIONt_it7110HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.54
X-RAY DIFFRACTIONt_other_torsion21.72
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion881SEMIHARMONIC5
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_contact8451SEMIHARMONIC4
LS refinement shellResolution: 3.06→3.23 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.3518 146 5.15 %
Rwork0.1819 2688 -
all0.1904 2834 -
obs--99.79 %
Refinement TLS params.Method: refined / Origin x: -20.1093 Å / Origin y: -14.7007 Å / Origin z: 28.8532 Å
111213212223313233
T-0.1377 Å20.0513 Å20.0576 Å2--0.2658 Å2-0.0506 Å2---0.1831 Å2
L1.1501 °2-0.1694 °2-0.1653 °2-0.7842 °20.2108 °2--1.6138 °2
S-0.0121 Å °0.0876 Å °0.0554 Å °0.0374 Å °-0.0887 Å °0.0145 Å °0.0211 Å °-0.3242 Å °0.1007 Å °
Refinement TLS groupSelection details: { A|* }

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