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- PDB-9l3r: Human PI3KDELTA in complex with Zandelisib -

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Basic information

Entry
Database: PDB / ID: 9l3r
TitleHuman PI3KDELTA in complex with Zandelisib
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE/INHIBITOR / Inhibitor / TRANSFERASE / TRANSFERASE-INHIBITOR complex
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 chemotaxis / mast cell differentiation / Regulation of signaling by CBL / Downstream TCR signaling / positive regulation of neutrophil apoptotic process / RHOG GTPase cycle / positive regulation of epithelial tube formation / natural killer cell differentiation / natural killer cell chemotaxis / neutrophil extravasation / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / VEGFA-VEGFR2 Pathway / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol 3-kinase activator activity / respiratory burst involved in defense response / phosphatidylinositol 3-kinase complex / T cell chemotaxis / transmembrane receptor protein tyrosine kinase adaptor activity / ErbB-3 class receptor binding / 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 / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / Extra-nuclear estrogen signaling / G alpha (q) signalling events / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / mast cell degranulation / phosphatidylinositol-mediated signaling / intracellular glucose homeostasis / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / B cell activation / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / T cell differentiation / CD28 dependent PI3K/Akt signaling / Interleukin receptor SHC signaling / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase binding / T cell costimulation / insulin-like growth factor receptor binding / positive regulation of endothelial cell proliferation / neutrophil chemotaxis / positive regulation of endothelial cell migration
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 / Src homology 3 domains / SH2 domain superfamily / 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: 2.5 Å
AuthorsNagiri, C. / Aburai, K. / Takahashi, Y. / Saito, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Am J Cancer Res / Year: 2025
Title: A long-lasting PI3K delta inhibitor zandelisib forms a water-shielded hydrogen bond with p110 delta and demonstrates sustained inhibitory effects.
Authors: Kunieda, K. / Nagiri, C. / Watanabe, M. / Yoshida, T. / Zou, J. / Kaneda, A. / Takahashi, Y. / Aburai, K. / Saito, J.I. / Umehara, H. / Otsu, Y. / Ishii, T.
History
DepositionDec 19, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 11, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 2, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_id_ISSN ..._citation.country / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name

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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)141,3613
Polymers140,7842
Non-polymers5771
Water88349
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4430 Å2
ΔGint-16 kcal/mol
Surface area50370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.890, 109.080, 142.440
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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: 119633.023 Da / Num. of mol.: 1
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: 21150.889 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-A1L62 / Zandelisib / 4-[2-[bis(fluoranyl)methyl]benzimidazol-1-yl]-~{N}-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-6-morpholin-4-yl-1,3,5-triazin-2-amine / ME-401 / 4-[2-(difluoromethyl)benzimidazol-1-yl]-N-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-6-morpholin-4-yl-1,3,5-triazin-2-amine


Mass: 576.683 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H38F2N8O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 49 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.51 Å3/Da / Density % sol: 51.03 %
Crystal growTemperature: 283.15 K / Method: vapor diffusion, sitting drop / pH: 5.8
Details: 10% PEG 4000, 100 mM KCl, 1 mM TCEP neutral pH, 10 mM CaCl2, 100 mM MES pH 5.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99999 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 5, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.5→45.45 Å / Num. obs: 49670 / % possible obs: 99.9 % / Redundancy: 6.7 % / CC1/2: 1 / Rmerge(I) obs: 0.041 / Rpim(I) all: 0.017 / Rrim(I) all: 0.045 / Net I/σ(I): 18.7
Reflection shellResolution: 2.5→2.58 Å / Redundancy: 6.7 % / Rmerge(I) obs: 1.193 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 4525 / CC1/2: 0.858 / Rpim(I) all: 0.499 / Rrim(I) all: 1.296 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX1.19.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6PYR

6pyr


Resolution: 2.5→45.45 Å / SU ML: 0.4217 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 36.0235
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2776 2399 4.84 %
Rwork0.2304 47178 -
obs0.2327 49577 99.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 97.2 Å2
Refinement stepCycle: LAST / Resolution: 2.5→45.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8847 0 42 49 8938
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00279085
X-RAY DIFFRACTIONf_angle_d0.559212296
X-RAY DIFFRACTIONf_chiral_restr0.03851369
X-RAY DIFFRACTIONf_plane_restr0.00371575
X-RAY DIFFRACTIONf_dihedral_angle_d6.81691220
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.550.43821490.37712722X-RAY DIFFRACTION99.34
2.55-2.610.35611400.34862735X-RAY DIFFRACTION99.27
2.61-2.670.38191330.37172718X-RAY DIFFRACTION99.76
2.67-2.730.39671450.35772725X-RAY DIFFRACTION99.55
2.73-2.810.36861340.34312731X-RAY DIFFRACTION99.44
2.81-2.890.40131360.30312748X-RAY DIFFRACTION99.72
2.89-2.980.32371380.29722741X-RAY DIFFRACTION99.72
2.98-3.090.38891380.3092777X-RAY DIFFRACTION99.73
3.09-3.210.36191250.30112768X-RAY DIFFRACTION99.66
3.21-3.360.40351460.30672761X-RAY DIFFRACTION99.93
3.36-3.540.31741430.2642770X-RAY DIFFRACTION100
3.54-3.760.30181400.2392777X-RAY DIFFRACTION99.93
3.76-4.050.27281480.23392777X-RAY DIFFRACTION100
4.05-4.460.23481440.19962801X-RAY DIFFRACTION99.97
4.46-5.10.21571480.18512806X-RAY DIFFRACTION99.97
5.1-6.420.26121500.21512850X-RAY DIFFRACTION100
6.42-45.450.23111420.18172971X-RAY DIFFRACTION99.68
Refinement TLS params.Method: refined / Origin x: 20.7162134265 Å / Origin y: 9.65232915553 Å / Origin z: 17.559309381 Å
111213212223313233
T0.540820573652 Å2-0.000592222366243 Å2-0.030026915474 Å2-0.552847296522 Å2-0.00425892618246 Å2--0.631961189511 Å2
L0.879475756808 °20.323215339152 °2-0.50131027741 °2-0.923420883474 °2-0.403190111907 °2--1.56160041264 °2
S-0.0974836214812 Å °-0.0413871154564 Å °-0.0392357751408 Å °0.0433419132092 Å °0.030936829258 Å °0.0195388047272 Å °-0.0306846767294 Å °0.0497498369489 Å °0.067218013263 Å °
Refinement TLS groupSelection details: all

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