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- PDB-6g6w: HUMAN PI3KDELTA IN COMPLEX WITH LIGAND LASW1976 -

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Basic information

Entry
Database: PDB / ID: 6g6w
TitleHUMAN PI3KDELTA IN COMPLEX WITH LIGAND LASW1976
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
KeywordsTRANSFERASE / PI3KDELTA KINASE / PROTEROS BIOSTRUCTURES GMBH
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 / positive regulation of neutrophil apoptotic process / Downstream TCR signaling / RHOG GTPase cycle / natural killer cell differentiation / 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 / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol 3-kinase regulator activity / 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 / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / G alpha (q) signalling events / 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 / Interleukin-3, Interleukin-5 and GM-CSF signaling / 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
Chem-EO5 / 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: 2.72 Å
AuthorsSegarra, V. / Hernandez, B. / Jestel, A. / Mortel, M. / Nagel, S.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of a Novel Inhaled PI3K delta Inhibitor for the Treatment of Respiratory Diseases.
Authors: Erra, M. / Taltavull, J. / Bernal, F.J. / Caturla, J.F. / Carrascal, M. / Pages, L. / Mir, M. / Espinosa, S. / Gracia, J. / Dominguez, M. / Sabate, M. / Paris, S. / Maldonado, M. / ...Authors: Erra, M. / Taltavull, J. / Bernal, F.J. / Caturla, J.F. / Carrascal, M. / Pages, L. / Mir, M. / Espinosa, S. / Gracia, J. / Dominguez, M. / Sabate, M. / Paris, S. / Maldonado, M. / Hernandez, B. / Bravo, M. / Calama, E. / Miralpeix, M. / Lehner, M.D. / Calbet, M.
History
DepositionApr 3, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 7, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 21, 2018Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 17, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.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)144,5923
Polymers144,0212
Non-polymers5711
Water1086
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4440 Å2
ΔGint-13 kcal/mol
Surface area50300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.452, 108.951, 142.481
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: 123010.609 Da / Num. of mol.: 1 / Fragment: N-terminal truncated
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: 21010.748 Da / Num. of mol.: 1 / Fragment: UNP residues 431-599
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-EO5 / ~{N}-[3-[4-[[(1~{S})-1-(5-methyl-4-oxidanylidene-3-phenyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino]-7~{H}-pyrrolo[ 2,3-d]pyrimidin-5-yl]-5-oxidanyl-phenyl]methanesulfonamide / LASW1976


Mass: 570.622 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H26N8O4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 2.66 Å3/Da / Density % sol: 53.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: PEG

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 25, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.72→86.57 Å / Num. obs: 38495 / % possible obs: 99.9 % / Redundancy: 8.1 % / Rmerge(I) obs: 0.038 / Net I/σ(I): 30.3
Reflection shellResolution: 2.72→2.97 Å / Redundancy: 8.2 % / Rmerge(I) obs: 0.44 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdbid 2WXR

2wxr


Resolution: 2.72→86.57 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.936 / SU B: 35.519 / SU ML: 0.323 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.016 / ESU R Free: 0.342
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2601 791 2.1 %RANDOM
Rwork0.2181 ---
obs0.219 37703 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 211.03 Å2 / Biso mean: 96.97 Å2 / Biso min: 44.68 Å2
Baniso -1Baniso -2Baniso -3
1--0.06 Å20 Å20 Å2
2--0.07 Å20 Å2
3----0.01 Å2
Refinement stepCycle: final / Resolution: 2.72→86.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8786 0 41 6 8833
Biso mean--78.01 79.31 -
Num. residues----1078
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.028854
X-RAY DIFFRACTIONr_bond_other_d0.0020.026137
X-RAY DIFFRACTIONr_angle_refined_deg1.251.96911982
X-RAY DIFFRACTIONr_angle_other_deg0.996314829
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1751069
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.55523.986424
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.069151557
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6321559
X-RAY DIFFRACTIONr_chiral_restr0.0680.21326
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0219770
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021820
LS refinement shellResolution: 2.72→2.791 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.418 54 -
Rwork0.301 2527 -
all-2581 -
obs--99.77 %
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)
14.42842.8807-2.83025.1468-1.58965.8806-0.2026-0.12940.20610.13270.2313-0.1386-0.10980.0803-0.02870.7213-0.08710.01410.7530.0110.217543.03817.631-11.275
22.16140.6827-0.14873.70581.15674.3840.103-0.10460.70580.16920.0768-0.0833-1.32730.2217-0.17971.1325-0.01610.07560.78920.07670.639222.68235.51517.49
31.66890.3624-0.52673.6033-0.10351.7392-0.1390.2336-0.3742-0.0987-0.01930.56890.441-0.32120.15831.1416-0.10020.010.9275-0.13290.51325.664-8.3657.136
43.2255-0.4465-0.88351.76190.36742.5911-0.05340.1665-0.4208-0.01310.03130.67080.2375-0.79610.0220.77560.0079-0.02920.82020.07610.4727-0.90510.54217.464
54.85760.2032-2.43042.3888-0.05074.87710.005-0.18960.06110.21330.0099-0.6481-0.16980.912-0.01480.7568-0.039-0.0750.89410.08490.404235.77916.74623.115
63.30610.9031.1221.77950.99985.13490.1473-0.5877-0.18480.6742-0.1592-0.0550.12530.23320.0121.0491-0.0419-0.01170.80850.10330.378121.63112.6945.749
72.27651.9562-4.06561.9088-3.75868.8215-0.2698-0.0907-0.2755-0.2454-0.1527-0.32540.34860.25920.42240.9836-0.05450.07530.8681-0.03030.483530.299-8.1916.681
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 DIFFRACTION7B440 - 599

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