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- PDB-6pyr: Human PI3Kdelta in complex with Compound 2-10 ((3S)-3-benzyl-3-me... -

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Basic information

Entry
Database: PDB / ID: 6pyr
TitleHuman PI3Kdelta in complex with Compound 2-10 ((3S)-3-benzyl-3-methyl-5-[5-(2-methylpyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-1,3-dihydro-2H-indol-2-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 differentiation / mast cell chemotaxis / natural killer cell differentiation / positive regulation of epithelial tube formation / perinuclear endoplasmic reticulum membrane / natural killer cell chemotaxis / regulation of toll-like receptor 4 signaling pathway / neutrophil extravasation / positive regulation of neutrophil apoptotic process ...B cell chemotaxis / mast cell differentiation / mast cell chemotaxis / natural killer cell differentiation / positive regulation of epithelial tube formation / perinuclear endoplasmic reticulum membrane / natural killer cell chemotaxis / regulation of toll-like receptor 4 signaling pathway / neutrophil extravasation / positive regulation of neutrophil apoptotic process / phosphatidylinositol kinase activity / phosphatidylinositol 3-kinase regulator activity / respiratory burst involved in defense response / positive regulation of focal adhesion disassembly / IRS-mediated signalling / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / myeloid leukocyte migration / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulatory subunit binding / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / T cell chemotaxis / natural killer cell activation / Activated NTRK3 signals through PI3K / cis-Golgi network / ErbB-3 class receptor binding / RHOF GTPase cycle / kinase activator activity / transmembrane receptor protein tyrosine kinase adaptor activity / RHOD GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / positive regulation of endoplasmic reticulum unfolded protein response / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / Nephrin family interactions / RND1 GTPase cycle / Costimulation by the CD28 family / positive regulation of leukocyte migration / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / MET activates PI3K/AKT signaling / RND2 GTPase cycle / PI3K/AKT activation / RND3 GTPase cycle / positive regulation of filopodium assembly / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / negative regulation of stress fiber assembly / growth hormone receptor signaling pathway / phosphatidylinositol 3-kinase / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / RHOV GTPase cycle / 1-phosphatidylinositol-3-kinase activity / negative regulation of cell-matrix adhesion / Signaling by ALK / RHOB GTPase cycle / mast cell degranulation / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / B cell activation / PI-3K cascade:FGFR2 / RHOJ GTPase cycle / PI-3K cascade:FGFR4 / RHOC GTPase cycle / PI-3K cascade:FGFR1 / negative regulation of osteoclast differentiation / intracellular glucose homeostasis / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / CDC42 GTPase cycle / RHOU GTPase cycle / PI3K events in ERBB2 signaling / T cell differentiation / RET signaling / insulin receptor substrate binding / RHOG GTPase cycle / Interleukin-3, Interleukin-5 and GM-CSF signaling / extrinsic apoptotic signaling pathway via death domain receptors / PI3K Cascade / RHOA GTPase cycle / RAC2 GTPase cycle / RAC3 GTPase cycle / Role of phospholipids in phagocytosis / GAB1 signalosome / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / positive regulation of lamellipodium assembly / Signaling by FGFR4 in disease / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR3 in disease
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-P5J / 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: 2.21 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)137,9273
Polymers137,4802
Non-polymers4471
Water1,20767
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4470 Å2
ΔGint-17 kcal/mol
Surface area52530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.471, 108.078, 142.346
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-P5J / (3S)-3-benzyl-3-methyl-5-[5-(2-methylpyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-1,3-dihydro-2H-indol-2-one


Mass: 446.503 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H22N6O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 67 / 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: 2.61 Å3/Da / Density % sol: 52.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 12-14% PEG6000, 100 mM MES/NaOH, pH 5.75, 5 mM DTT

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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: Jun 13, 2014
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: 2.21→86.08 Å / Num. obs: 70018 / % possible obs: 99.3 % / Redundancy: 4.7 % / Biso Wilson estimate: 69.395 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.04 / Rrim(I) all: 0.045 / Χ2: 0.982 / Net I/σ(I): 19.31
Reflection shellResolution: 2.21→2.46 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.598 / Mean I/σ(I) obs: 2.67 / Num. unique obs: 19050 / CC1/2: 0.994 / Rrim(I) all: 0.042 / % possible all: 99.7

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.6.0117refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.21→86.08 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.942 / SU B: 17.152 / SU ML: 0.201 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.249 / ESU R Free: 0.206
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2591 1467 2.1 %RANDOM
Rwork0.2207 ---
obs0.2216 68550 99.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 195.26 Å2 / Biso mean: 78.765 Å2 / Biso min: 39.56 Å2
Baniso -1Baniso -2Baniso -3
1-0.11 Å20 Å20 Å2
2--0.72 Å20 Å2
3----0.83 Å2
Refinement stepCycle: final / Resolution: 2.21→86.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8953 0 34 67 9054
Biso mean--57.97 61.17 -
Num. residues----1096
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.028785
X-RAY DIFFRACTIONr_bond_other_d0.0020.026150
X-RAY DIFFRACTIONr_angle_refined_deg1.0581.96311899
X-RAY DIFFRACTIONr_angle_other_deg0.948314738
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.11551085
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.78223.88384
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.951151493
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8371552
X-RAY DIFFRACTIONr_chiral_restr0.0590.21341
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219717
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021807
LS refinement shellResolution: 2.21→2.267 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.476 85 -
Rwork0.344 4717 -
all-4802 -
obs--99.67 %
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)
13.84091.5653-2.33713.7711-1.04744.8818-0.0552-0.13760.0910.18570.0997-0.1054-0.07220.1138-0.04460.3773-0.07890.01520.4317-0.02510.094743.40117.251-11.225
21.56240.673-0.22363.84852.23634.73990.2091-0.03710.5661-0.00220.122-0.0782-0.8930.1216-0.33110.5959-0.0120.10530.46570.05930.393622.71834.11617.198
31.24270.0638-0.42212.76720.37871.5988-0.15710.1665-0.2726-0.21470.03060.34760.4862-0.2730.12650.6895-0.110.03320.5764-0.07210.27655.631-8.5856.989
42.9907-0.1837-0.51251.5390.1941.3951-0.05750.109-0.2770.00280.06470.49510.1715-0.5195-0.00730.3927-0.0232-0.01140.46570.05950.2486-0.18810.5617.289
53.00270.4454-1.61871.2595-0.07344.529-0.0166-0.1436-0.13310.0522-0.0339-0.372-0.12190.70050.05040.3687-0.036-0.02570.46050.01740.219935.53215.90523.233
62.61470.94020.82511.6110.09414.85380.1031-0.3434-0.18960.3966-0.1174-0.1294-0.16170.30580.01420.5126-0.0238-0.0320.36760.0430.151321.90212.60145.426
72.37151.8639-4.22441.7065-3.64079.0111-0.154-0.1024-0.2149-0.1354-0.0842-0.16460.26330.33140.23810.5377-0.02220.06820.4634-0.03510.255529.998-8.1856.189
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 - 1032
7X-RAY DIFFRACTION7B431 - 599

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