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- PDB-8s3r: HUMAN PI3KDELTA IN COMPLEX WITH PYRIDAZINONE INHIBITOR 7 -

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Basic information

Entry
Database: PDB / ID: 8s3r
TitleHUMAN PI3KDELTA IN COMPLEX WITH PYRIDAZINONE INHIBITOR 7
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / PI3KDELTA KINASE / PI3KDELTA KINASE INHIBITOR
Function / homology
Function and homology information


B cell chemotaxis / RHOC GTPase cycle / PI3K events in ERBB4 signaling / Interleukin-7 signaling / GAB1 signalosome / PI3K events in ERBB2 signaling / MET activates PI3K/AKT signaling / CDC42 GTPase cycle / RHOD GTPase cycle / RHOJ GTPase cycle ...B cell chemotaxis / RHOC GTPase cycle / PI3K events in ERBB4 signaling / Interleukin-7 signaling / GAB1 signalosome / PI3K events in ERBB2 signaling / MET activates PI3K/AKT signaling / CDC42 GTPase cycle / RHOD GTPase cycle / RHOJ GTPase cycle / RAC3 GTPase cycle / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / FLT3 Signaling / RND2 GTPase cycle / RND1 GTPase cycle / IRS-mediated signalling / GPVI-mediated activation cascade / Signaling by SCF-KIT / Downstream signal transduction / PI3K/AKT activation / Signaling by ALK / Role of phospholipids in phagocytosis / Tie2 Signaling / Role of LAT2/NTAL/LAB on calcium mobilization / CD28 dependent PI3K/Akt signaling / RAC1 GTPase cycle / RAC2 GTPase cycle / Interleukin receptor SHC signaling / RND3 GTPase cycle / Co-stimulation by ICOS / PI-3K cascade:FGFR1 / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR3 / PI-3K cascade:FGFR4 / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / PI3K Cascade / PIP3 activates AKT signaling / GP1b-IX-V activation signalling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Synthesis of PIPs at the plasma membrane / RHOA GTPase cycle / RHOF GTPase cycle / DAP12 signaling / RHOU GTPase cycle / RHOV GTPase cycle / mast cell differentiation / mast cell chemotaxis / Regulation of signaling by CBL / positive regulation of neutrophil apoptotic process / Downstream TCR signaling / natural killer cell differentiation / RHOG GTPase cycle / positive regulation of epithelial tube formation / natural killer cell chemotaxis / neutrophil extravasation / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / VEGFA-VEGFR2 Pathway / respiratory burst involved in defense response / phosphatidylinositol 3-kinase regulator activity / phosphatidylinositol 3-kinase activator activity / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol 3-kinase complex / T cell chemotaxis / ErbB-3 class receptor binding / transmembrane receptor protein tyrosine kinase adaptor activity / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Co-stimulation by ICOS / phosphatidylinositol 3-kinase complex, class IA / natural killer cell activation / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / vascular endothelial growth factor signaling pathway / Extra-nuclear estrogen signaling / 1-phosphatidylinositol-3-kinase activity / G alpha (q) signalling events / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / phosphatidylinositol-mediated signaling / intracellular glucose homeostasis / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / B cell activation / RET signaling / insulin receptor substrate binding / T cell differentiation / Interleukin-3, Interleukin-5 and GM-CSF signaling / CD28 dependent PI3K/Akt signaling / Interleukin receptor SHC signaling / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase binding / insulin-like growth factor receptor binding / positive regulation of endothelial cell proliferation / neutrophil chemotaxis / positive regulation of endothelial cell migration / substrate adhesion-dependent cell spreading
Similarity search - Function
PI3Kdelta, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain ...PI3Kdelta, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / 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. / Rho GTPase activation protein / 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 3/4-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 / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Src homology 3 domains / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform / Phosphatidylinositol 3-kinase regulatory subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Bos taurus (domestic cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.28 Å
AuthorsPala, D. / Bruno, P. / Capelli, A.M. / Biagetti, M.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and Optimization of Pyridazinones as PI3K delta Selective Inhibitors for Administration by Inhalation.
Authors: Bruno, P. / Micoli, A. / Corsi, M. / Pala, D. / Guariento, S. / Fiorelli, C. / Ronchi, P. / Fioni, A. / Gallo, P.M. / Marenghi, G. / Bertolini, S. / Capacchi, S. / Mileo, V. / Biagetti, M. / Capelli, A.M.
History
DepositionFeb 20, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 24, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
B: Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,9893
Polymers137,4802
Non-polymers5091
Water1,24369
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4310 Å2
ΔGint-15 kcal/mol
Surface area50360 Å2
Unit cell
Length a, b, c (Å)90.121, 108.350, 142.411
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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: 116600.633 Da / Num. of mol.: 1 / Fragment: PI3-KINASE P110 DELTA AND P85 FRAGMENT
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CD / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O00329, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase
#2: Protein Phosphatidylinositol 3-kinase regulatory subunit alpha / PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory ...PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha / PI3-kinase subunit p85-alpha / PtdIns-3-kinase regulatory subunit p85-alpha


Mass: 20879.555 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: PIK3R1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P23727
#3: Chemical ChemComp-A1H48 / 5-[(1~{S})-1-[4-azanyl-3-(5-oxidanylpyridin-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-4-cyclopentyl-2-(phenylmethyl)pyridazin-3-one


Mass: 508.574 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H28N8O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / 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: 2.53 Å3/Da / Density % sol: 51.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 16% PEG6000, 0.10 M KCL, 0.10 M MES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99988 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 27, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99988 Å / Relative weight: 1
ReflectionResolution: 2.28→86.23 Å / Num. obs: 62597 / % possible obs: 97.4 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.061 / Net I/σ(I): 10.15
Reflection shellResolution: 2.28→2.53 Å / Rmerge(I) obs: 0.446 / Num. unique obs: 16598

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0049refinement
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.28→86.23 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.932 / SU B: 21.144 / SU ML: 0.23 / Cross valid method: THROUGHOUT / ESU R: 0.27 / ESU R Free: 0.236 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26963 1312 2.1 %RANDOM
Rwork0.20308 ---
obs0.20446 61285 97.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 74.287 Å2
Baniso -1Baniso -2Baniso -3
1-2.96 Å2-0 Å20 Å2
2---0.01 Å2-0 Å2
3----2.95 Å2
Refinement stepCycle: LAST / Resolution: 2.28→86.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8811 0 38 69 8918
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0198833
X-RAY DIFFRACTIONr_bond_other_d0.0010.028454
X-RAY DIFFRACTIONr_angle_refined_deg1.8031.9711947
X-RAY DIFFRACTIONr_angle_other_deg2.594319375
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.75351070
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.6823.941406
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.148151561
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.2281558
X-RAY DIFFRACTIONr_chiral_restr0.1050.21332
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.029884
X-RAY DIFFRACTIONr_gen_planes_other0.0090.022053
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_it9.6095.284310
X-RAY DIFFRACTIONr_mcbond_other9.5985.2784309
X-RAY DIFFRACTIONr_mcangle_it11.548.8375370
X-RAY DIFFRACTIONr_mcangle_other11.5488.845371
X-RAY DIFFRACTIONr_scbond_it13.0966.1724523
X-RAY DIFFRACTIONr_scbond_other13.0956.1724524
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other15.8959.9266578
X-RAY DIFFRACTIONr_long_range_B_refined16.72824.2369990
X-RAY DIFFRACTIONr_long_range_B_other16.72924.2349989
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.28→2.339 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.41 102 -
Rwork0.341 4411 -
obs--96.18 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.50011.5209-1.78954.3673-0.74654.4159-0.0942-0.12110.12830.23030.0923-0.0485-0.05890.06780.0020.0439-0.0607-0.00610.3164-0.03780.011843.33117.128-11.338
21.62260.3758-0.16913.75132.09714.93520.2337-0.08030.50680.0610.0719-0.1132-0.89230.051-0.30560.2498-0.01960.11070.30270.06680.229422.54733.85216.901
31.20290.0462-0.32743.33050.32811.3522-0.10550.0844-0.3233-0.25460.01380.3710.4896-0.23880.09170.362-0.0889-0.0090.4312-0.05740.19285.96-9.1247.204
43.18680.0896-0.39872.18580.27681.2993-0.02210.0009-0.27190.04530.04920.64890.1532-0.5074-0.02710.0306-0.0160.00010.37840.08450.239-0.74110.42517.413
52.52930.4071-1.06451.3955-0.48754.33050.1053-0.1625-0.08980.0476-0.1157-0.4699-0.07740.7850.01040.0106-0.0267-0.01660.36480.03230.166835.79415.91622.854
62.89250.60930.70671.1904-0.21784.36730.1802-0.3667-0.17510.4682-0.1267-0.1349-0.0710.2764-0.05360.2021-0.039-0.0180.28460.04760.089621.89912.43845.679
71.84821.4253-3.15751.313-2.8116.8837-0.1238-0.0509-0.1326-0.1393-0.0485-0.12470.22490.25190.17230.1943-0.02170.05520.2831-0.04710.199130.297-8.0356.111
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A17 - 108
2X-RAY DIFFRACTION2A109 - 278
3X-RAY DIFFRACTION3A279 - 474
4X-RAY DIFFRACTION4A475 - 675
5X-RAY DIFFRACTION5A676 - 830
6X-RAY DIFFRACTION6A831 - 1031
7X-RAY DIFFRACTION7B2 - 599

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