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- PDB-6ocu: HUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 29 -

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Basic information

Entry
Database: PDB / ID: 6ocu
TitleHUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 29
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Keywordstransferase/transferase inhibitor / PI3KDELTA KINASE / TRANSFERASE / transferase-transferase inhibitor complex
Function / homology
Function and homology information


B cell chemotaxis / Signaling by ALK / MET activates PI3K/AKT signaling / RHOC GTPase cycle / CDC42 GTPase cycle / RAC1 GTPase cycle / RAC2 GTPase cycle / RHOD GTPase cycle / RHOJ GTPase cycle / RAC3 GTPase cycle ...B cell chemotaxis / Signaling by ALK / MET activates PI3K/AKT signaling / RHOC GTPase cycle / CDC42 GTPase cycle / RAC1 GTPase cycle / RAC2 GTPase cycle / RHOD GTPase cycle / RHOJ GTPase cycle / RAC3 GTPase cycle / RHOF GTPase cycle / FLT3 Signaling / RND3 GTPase cycle / RND2 GTPase cycle / RND1 GTPase cycle / PI3K events in ERBB4 signaling / Interleukin-7 signaling / GAB1 signalosome / PI3K events in ERBB2 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / IRS-mediated signalling / GPVI-mediated activation cascade / Signaling by SCF-KIT / Downstream signal transduction / PI3K/AKT activation / Role of phospholipids in phagocytosis / Tie2 Signaling / Role of LAT2/NTAL/LAB on calcium mobilization / Costimulation by the CD28 family / CD28 dependent PI3K/Akt signaling / RAF/MAP kinase cascade / Interleukin receptor SHC signaling / 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 / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Synthesis of PIPs at the plasma membrane / RHOA GTPase cycle / DAP12 signaling / RHOU GTPase cycle / RHOV GTPase cycle / mast cell differentiation / mast cell chemotaxis / Regulation of signaling by CBL / Downstream TCR signaling / natural killer cell differentiation / RHOG GTPase cycle / positive regulation of epithelial tube formation / RET signaling / natural killer cell chemotaxis / Interleukin-3, Interleukin-5 and GM-CSF signaling / VEGFA-VEGFR2 Pathway / neutrophil extravasation / positive regulation of neutrophil apoptotic process / phosphatidylinositol 3-kinase regulator activity / respiratory burst involved in defense response / phosphatidylinositol 3-kinase activator activity / 1-phosphatidylinositol-3-kinase regulator activity / T cell chemotaxis / natural killer cell activation / ErbB-3 class receptor binding / transmembrane receptor protein tyrosine kinase adaptor activity / positive regulation of endoplasmic reticulum unfolded protein response / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / Extra-nuclear estrogen signaling / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / G alpha (q) signalling events / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / B cell activation / intracellular glucose homeostasis / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / T cell differentiation / RET signaling / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / positive regulation of endothelial cell proliferation / insulin-like growth factor receptor binding / T cell activation / response to endoplasmic reticulum stress / positive regulation of endothelial cell migration / substrate adhesion-dependent cell spreading / B cell differentiation
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. / 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) / Rho GTPase activation protein / 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
Chem-M5D / 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 (cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.77 Å
AuthorsLesburg, C.A. / Augustin, M.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Discovery and optimization of heteroaryl piperazines as potent and selective PI3K delta inhibitors.
Authors: Zhou, H. / McGowan, M.A. / Lipford, K. / Christopher, M. / Fradera, X. / Witter, D. / Lesburg, C.A. / Li, C. / Methot, J.L. / Lampe, J. / Achab, A. / Shaffer, L. / Goldenblatt, P. / Shah, S. ...Authors: Zhou, H. / McGowan, M.A. / Lipford, K. / Christopher, M. / Fradera, X. / Witter, D. / Lesburg, C.A. / Li, C. / Methot, J.L. / Lampe, J. / Achab, A. / Shaffer, L. / Goldenblatt, P. / Shah, S. / Bass, A. / Schroeder, G. / Chen, D. / Zeng, H. / Augustin, M.A. / Katz, J.D.
History
DepositionMar 25, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.year
Revision 1.2Mar 13, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)142,9663
Polymers142,6012
Non-polymers3651
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4260 Å2
ΔGint-14 kcal/mol
Surface area51540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.998, 109.407, 142.592
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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 / 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: 119633.023 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-4,5-bisphosphate 3-kinase
#2: Protein Phosphatidylinositol 3-kinase regulatory subunit alpha / PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit ...PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha / PtdIns-3-kinase regulatory subunit p85-alpha


Mass: 22968.010 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: PIK3R1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P23727
#3: Chemical ChemComp-M5D / 5-{(3R)-3-methyl-4-[(1R,2R)-2-methylcyclopropane-1-carbonyl]piperazin-1-yl}-3-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carbonitrile


Mass: 365.432 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23N7O / Feature type: SUBJECT OF INVESTIGATION

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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: 2.67 Å3/Da / Density % sol: 54.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 16% PEG6000 0.10 M KCl 0.10 M MES pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 30, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.77→86.8 Å / Num. obs: 36583 / % possible obs: 99.1 % / Redundancy: 4 % / Rmerge(I) obs: 0.052 / Rrim(I) all: 0.06 / Net I/σ(I): 16.32
Reflection shellResolution: 2.77→3.02 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.599 / Mean I/σ(I) obs: 2.25 / Num. unique obs: 8247 / Rrim(I) all: 0.684 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
PDB_EXTRACT3.24data extraction
XSCALEdata scaling
MOLREPphasing
XDS/XSCALEdata collection
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: NONE

Resolution: 2.77→86.8 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.872 / SU B: 43.744 / SU ML: 0.382 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.525 / ESU R Free: 0.394
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2873 755 2.1 %RANDOM
Rwork0.2192 ---
obs0.2205 35828 99.09 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 232.09 Å2 / Biso mean: 97.984 Å2 / Biso min: 41.8 Å2
Baniso -1Baniso -2Baniso -3
1-3.95 Å20 Å2-0 Å2
2--2.2 Å2-0 Å2
3----6.16 Å2
Refinement stepCycle: final / Resolution: 2.77→86.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8776 0 27 0 8803
Biso mean--82.74 --
Num. residues----1074
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0198789
X-RAY DIFFRACTIONr_bond_other_d0.0020.028366
X-RAY DIFFRACTIONr_angle_refined_deg1.1061.96711888
X-RAY DIFFRACTIONr_angle_other_deg0.876319177
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.42751062
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.19724415
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.059151544
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4751559
X-RAY DIFFRACTIONr_chiral_restr0.0590.21322
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.029854
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022047
LS refinement shellResolution: 2.77→2.842 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.536 50 -
Rwork0.364 2639 -
all-2689 -
obs--99.48 %
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)
15.35521.6843-2.61814.6325-2.24636.766-0.1563-0.17560.19250.21710.1106-0.0853-0.0744-0.17650.04560.069-0.059-0.00510.1756-0.00130.057343.44217.389-11.15
22.15780.7426-0.12045.23051.95674.98310.1406-0.09530.64030.07350.0508-0.1151-1.32850.1989-0.19130.4427-0.03120.08980.27270.11050.419922.74234.36916.934
31.68820.4875-0.5254.04420.05791.7524-0.16310.1554-0.3527-0.21250.01510.5330.5089-0.30920.14790.3944-0.1046-0.0050.3765-0.12220.33265.794-8.427.038
44.18640.0708-0.86152.08250.15182.5104-0.07170.1544-0.38770.02350.06280.62080.1294-0.70610.00880.0362-0.0035-0.02170.27320.03130.2793-0.44810.63517.382
53.75340.3065-1.51311.9128-0.31934.92160.1363-0.22410.01750.1167-0.1338-0.6688-0.31540.9228-0.00260.0295-0.0642-0.03220.36490.07570.303935.56117.12323.297
63.13450.85661.02381.7692-0.00635.43510.2415-0.4709-0.17460.7407-0.2012-0.1389-0.01790.2139-0.04040.3168-0.0558-0.06540.2940.05820.207121.64312.95245.599
72.06961.7867-3.78481.7686-3.44047.7155-0.2302-0.0464-0.2145-0.1674-0.1196-0.2530.20920.25050.34990.2437-0.06630.05310.2731-0.01160.290830.264-8.437.427
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 - 1028
7X-RAY DIFFRACTION7B432 - 599

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