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- PDB-6pyu: Human PI3Kdelta in complex with Compound 4-2 ((3S)-1'-(cyclopropa... -

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Basic information

Entry
Database: PDB / ID: 6pyu
TitleHuman PI3Kdelta in complex with Compound 4-2 ((3S)-1'-(cyclopropanecarbonyl)-5-(quinoxalin-6-yl)spiro[indole-3,2'-pyrrolidin]-2(1H)-one)
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 / mast cell chemotaxis / mast cell differentiation / natural killer cell differentiation / natural killer cell chemotaxis / perinuclear endoplasmic reticulum membrane / neutrophil extravasation / regulation of toll-like receptor 4 signaling pathway / phosphatidylinositol kinase activity / positive regulation of epithelial tube formation ...B cell chemotaxis / mast cell chemotaxis / mast cell differentiation / natural killer cell differentiation / natural killer cell chemotaxis / perinuclear endoplasmic reticulum membrane / neutrophil extravasation / regulation of toll-like receptor 4 signaling pathway / phosphatidylinositol kinase activity / positive regulation of epithelial tube formation / phosphatidylinositol 3-kinase regulator activity / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol 3-kinase activator activity / respiratory burst involved in defense response / T follicular helper cell differentiation / IRS-mediated signalling / interleukin-18-mediated signaling pathway / phosphatidylinositol 3-kinase regulatory subunit binding / myeloid leukocyte migration / PI3K events in ERBB4 signaling / neurotrophin TRKA receptor binding / positive regulation of neutrophil apoptotic process / positive regulation of focal adhesion disassembly / T cell chemotaxis / cis-Golgi network / Activated NTRK2 signals through PI3K / ErbB-3 class receptor binding / transmembrane receptor protein tyrosine kinase adaptor activity / negative regulation of stress fiber assembly / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex / Co-stimulation by ICOS / RHOD GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / natural killer cell activation / Nephrin family interactions / RHOF GTPase cycle / kinase activator activity / Signaling by LTK in cancer / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by LTK / positive regulation of leukocyte migration / RND1 GTPase cycle / RND2 GTPase cycle / positive regulation of filopodium assembly / RND3 GTPase cycle / phosphatidylinositol 3-kinase complex, class IA / MET activates PI3K/AKT signaling / PI3K/AKT activation / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / growth hormone receptor signaling pathway / phosphatidylinositol 3-kinase / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by ALK / RHOV GTPase cycle / 1-phosphatidylinositol-3-kinase activity / vascular endothelial growth factor signaling pathway / RHOB GTPase cycle / natural killer cell mediated cytotoxicity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / mast cell degranulation / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / RHOJ GTPase cycle / RHOC GTPase cycle / negative regulation of osteoclast differentiation / phosphatidylinositol phosphate biosynthetic process / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / RHOU GTPase cycle / CDC42 GTPase cycle / RET signaling / B cell activation / T cell differentiation / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / RHOG GTPase cycle / PI3K events in ERBB2 signaling / PI3K Cascade / negative regulation of cell-matrix adhesion / extrinsic apoptotic signaling pathway via death domain receptors / Role of LAT2/NTAL/LAB on calcium mobilization / RAC3 GTPase cycle / RHOA GTPase cycle / CD28 dependent PI3K/Akt signaling / RAC2 GTPase cycle / Interleukin receptor SHC signaling / Role of phospholipids in phagocytosis / enzyme-substrate adaptor activity / GAB1 signalosome / phosphatidylinositol 3-kinase binding / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / GPVI-mediated activation cascade
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 / Phosphatidylinositol 3-kinase, accessory domain (PIK) ...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 / Phosphatidylinositol 3-kinase, accessory domain (PIK) / 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 domain / 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 / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Src homology 3 (SH3) domain profile. / SH3 domain / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-P5V / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform / Phosphatidylinositol 3-kinase regulatory subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.54 Å
AuthorsLesburg, C.A. / Augustin, M.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Design of selective PI3K delta inhibitors using an iterative scaffold-hopping workflow.
Authors: Fradera, X. / Methot, J.L. / Achab, A. / Christopher, M. / Altman, M.D. / Zhou, H. / McGowan, M.A. / Kattar, S.D. / Wilson, K. / Garcia, Y. / Augustin, M.A. / Lesburg, C.A. / Shah, S. / ...Authors: Fradera, X. / Methot, J.L. / Achab, A. / Christopher, M. / Altman, M.D. / Zhou, H. / McGowan, M.A. / Kattar, S.D. / Wilson, K. / Garcia, Y. / Augustin, M.A. / Lesburg, C.A. / Shah, S. / Goldenblatt, P. / Katz, J.D.
History
DepositionJul 30, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
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)137,8653
Polymers137,4802
Non-polymers3841
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4320 Å2
ΔGint-14 kcal/mol
Surface area51680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.439, 108.587, 142.279
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: 116600.633 Da / Num. of mol.: 1 / Fragment: UNP residues 17-1034
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: 20879.555 Da / Num. of mol.: 1 / Fragment: UNP residues 131-299
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P27986
#3: Chemical ChemComp-P5V / (3S)-1'-(cyclopropanecarbonyl)-5-(quinoxalin-6-yl)spiro[indole-3,2'-pyrrolidin]-2(1H)-one


Mass: 384.431 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H20N4O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 2.63 Å3/Da / Density % sol: 53.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: not available

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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: Feb 13, 2015
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.54→86.39 Å / Num. obs: 46030 / % possible obs: 98.1 % / Redundancy: 6 % / Biso Wilson estimate: 79.269 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.093 / Rrim(I) all: 0.102 / Χ2: 0.941 / Net I/σ(I): 11.78
Reflection shellResolution: 2.54→2.79 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.987 / Mean I/σ(I) obs: 18.3 / Num. unique obs: 11174 / CC1/2: 0.985 / Rrim(I) all: 0.11 / % possible all: 98.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.54→86.39 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.916 / SU B: 31.898 / SU ML: 0.311 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.53 / ESU R Free: 0.324
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2916 955 2.1 %RANDOM
Rwork0.2397 ---
obs0.2408 45628 98.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 253.08 Å2 / Biso mean: 106.112 Å2 / Biso min: 38.09 Å2
Baniso -1Baniso -2Baniso -3
1-3.9 Å20 Å2-0 Å2
2--3.09 Å2-0 Å2
3----6.99 Å2
Refinement stepCycle: final / Resolution: 2.54→86.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8886 0 29 12 8927
Biso mean--76.13 66.74 -
Num. residues----1090
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0198698
X-RAY DIFFRACTIONr_bond_other_d0.0050.028213
X-RAY DIFFRACTIONr_angle_refined_deg1.2141.96511797
X-RAY DIFFRACTIONr_angle_other_deg0.898318743
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.73251078
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.24623.912386
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.907151448
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4441554
X-RAY DIFFRACTIONr_chiral_restr0.0670.21333
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0219833
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022019
LS refinement shellResolution: 2.54→2.606 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.491 64 -
Rwork0.413 3289 -
all-3353 -
obs--97.84 %
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)
14.67850.9086-2.753.5708-1.12555.5838-0.1088-0.16460.18450.14330.0974-0.0628-0.05050.00230.01140.038-0.02570.00770.0696-0.01830.18443.4117.148-11.265
21.43280.5249-0.02793.952.34274.27850.0792-0.07670.4793-0.00830.1413-0.0359-0.77220.0497-0.22060.20730.01490.07760.10350.06880.443822.61234.4617.55
31.18470.1963-0.5512.81040.17381.6398-0.19280.1802-0.2757-0.15560.09320.31060.4982-0.29280.09950.2935-0.1188-0.00460.2297-0.07830.38475.85-8.3927.032
43.28610.1474-0.9391.45920.31261.9384-0.10980.1793-0.22940.04580.0540.43890.1965-0.6240.05580.0223-0.0629-0.00650.2290.06540.3259-0.39110.51217.61
52.80780.0542-1.28991.4874-0.19654.06660.0199-0.2301-0.01650.09720.0011-0.4691-0.13280.7853-0.0210.0325-0.0395-0.03410.17020.01810.310835.80116.46623.124
62.85810.4731.02361.29060.13884.07170.102-0.4015-0.08760.5184-0.0948-0.0780.05860.2065-0.00730.2114-0.0226-0.02680.09180.03740.264721.88812.66545.549
71.67911.3926-2.9641.3827-2.8556.5052-0.113-0.0701-0.1427-0.0985-0.1069-0.13780.17760.26680.21990.1738-0.02710.03250.0732-0.0390.307929.214-8.9328.05
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 - 1034
7X-RAY DIFFRACTION7B432 - 599

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