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- PDB-5swr: Crystal Structure of PI3Kalpha in complex with fragments 20 and 26 -

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Basic information

Entry
Database: PDB / ID: 5swr
TitleCrystal Structure of PI3Kalpha in complex with fragments 20 and 26
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / lipid kinase / phosphoinositide / 3-kinase / signaling / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / negative regulation of actin filament depolymerization / phosphatidylinositol kinase activity / response to L-leucine / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / positive regulation of focal adhesion disassembly ...perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / negative regulation of actin filament depolymerization / phosphatidylinositol kinase activity / response to L-leucine / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / positive regulation of focal adhesion disassembly / IRS-mediated signalling / phosphatidylinositol 3-kinase activator activity / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / interleukin-18-mediated signaling pathway / myeloid leukocyte migration / autosome genomic imprinting / phosphatidylinositol 3-kinase complex / T follicular helper cell differentiation / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase regulatory subunit binding / regulation of cellular respiration / neurotrophin TRKA receptor binding / positive regulation of protein localization to membrane / Activated NTRK2 signals through PI3K / cis-Golgi network / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / ErbB-3 class receptor binding / transmembrane receptor protein tyrosine kinase adaptor activity / phosphatidylinositol 3-kinase complex, class IB / vasculature development / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by cytosolic FGFR1 fusion mutants / Co-stimulation by ICOS / cardiac muscle cell contraction / RHOD GTPase cycle / RHOF GTPase cycle / phosphatidylinositol 3-kinase complex, class IA / kinase activator activity / Nephrin family interactions / anoikis / Signaling by LTK in cancer / phosphatidylinositol-3-phosphate biosynthetic process / positive regulation of leukocyte migration / Signaling by LTK / MET activates PI3K/AKT signaling / PI3K/AKT activation / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / negative regulation of stress fiber assembly / RND1 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / positive regulation of filopodium assembly / RND2 GTPase cycle / phosphatidylinositol 3-kinase / vascular endothelial growth factor signaling pathway / RND3 GTPase cycle / relaxation of cardiac muscle / insulin binding / growth hormone receptor signaling pathway / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / RHOV GTPase cycle / PI-3K cascade:FGFR3 / RHOB GTPase cycle / natural killer cell mediated cytotoxicity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of macroautophagy / GP1b-IX-V activation signalling / PI-3K cascade:FGFR2 / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / intracellular glucose homeostasis / phosphatidylinositol phosphate biosynthetic process / negative regulation of osteoclast differentiation / Synthesis of PIPs at the plasma membrane / response to dexamethasone / RHOU GTPase cycle / CDC42 GTPase cycle / negative regulation of anoikis / RET signaling / PI3K events in ERBB2 signaling / protein kinase activator activity / insulin receptor substrate binding / T cell differentiation / Interleukin-3, Interleukin-5 and GM-CSF signaling / extrinsic apoptotic signaling pathway via death domain receptors / PI3K Cascade / RHOG GTPase cycle / regulation of multicellular organism growth / intercalated disc / negative regulation of cell-matrix adhesion / CD28 dependent PI3K/Akt signaling / RHOA GTPase cycle / positive regulation of TOR signaling / RAC2 GTPase cycle
Similarity search - Function
Helix Hairpins - #1490 / PI3Kalpha, 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 ...Helix Hairpins - #1490 / PI3Kalpha, 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 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. / C2 domain / 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 / SH2 domain superfamily / Src homology 3 domains / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Helix Hairpins / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
6-hydroxy-3,4-dihydronaphthalen-1(2H)-one / 2-HYDROXYBENZOIC ACID / Phosphatidylinositol 3-kinase regulatory subunit alpha / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 3.31 Å
AuthorsGabelli, S.B. / Vogelstein, B. / Miller, M.S. / Amzel, L.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA062924 and CA043460 United States
CitationJournal: Bioorg. Med. Chem. / Year: 2017
Title: Identification of allosteric binding sites for PI3K alpha oncogenic mutant specific inhibitor design.
Authors: Miller, M.S. / Maheshwari, S. / McRobb, F.M. / Kinzler, K.W. / Amzel, L.M. / Vogelstein, B. / Gabelli, S.B.
History
DepositionAug 8, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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 alpha isoform
B: Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)162,0216
Polymers161,6492
Non-polymers3714
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8250 Å2
ΔGint-34 kcal/mol
Surface area60540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)114.236, 116.331, 149.299
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 alpha isoform / PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic ...PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha / p110alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 127982.531 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Plasmid: pFastbac HT-A / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P42336, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein 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: 33666.961 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Plasmid: pFastbac HT-A / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P27986
#3: Chemical ChemComp-718 / 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one


Mass: 162.185 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H10O2
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-SAL / 2-HYDROXYBENZOIC ACID / SALICYLIC ACID


Mass: 138.121 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H6O3
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: 3.07 Å3/Da / Density % sol: 59.95 % / Mosaicity: 0.484 ° / Mosaicity esd: 0.007 °
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: NaFormate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Oct 17, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.3→91.76 Å / Num. obs: 30235 / % possible obs: 99.7 % / Redundancy: 7.2 % / Rmerge(I) obs: 0.097 / Net I/av σ(I): 27.462 / Net I/σ(I): 9.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
3.3-3.426.50.639198.8
3.42-3.557.30.445199.8
3.55-3.727.40.293199.8
3.72-3.917.50.214199.7
3.91-4.167.40.158199.8
4.16-4.487.40.118199.8
4.48-4.937.30.096199.9
4.93-5.647.20.093199.9
5.64-7.170.0851100
7.1-506.80.052199.6

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
REFMAC5.8.0135refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4OVU

4ovu


Resolution: 3.31→91.76 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.887 / SU B: 24.478 / SU ML: 0.402 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.565
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2726 1547 5.1 %RANDOM
Rwork0.1977 ---
obs0.2014 28638 99.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 246.22 Å2 / Biso mean: 119.805 Å2 / Biso min: 55.54 Å2
Baniso -1Baniso -2Baniso -3
1-1.88 Å20 Å20 Å2
2--1.27 Å20 Å2
3----3.15 Å2
Refinement stepCycle: final / Resolution: 3.31→91.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10768 0 24 0 10792
Biso mean--152.57 --
Num. residues----1305
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.01911020
X-RAY DIFFRACTIONr_bond_other_d0.0020.0210561
X-RAY DIFFRACTIONr_angle_refined_deg1.4491.96514857
X-RAY DIFFRACTIONr_angle_other_deg0.977324323
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.27151292
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.08724.252555
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.08152067
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.1041577
X-RAY DIFFRACTIONr_chiral_restr0.0830.21595
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02112254
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022571
X-RAY DIFFRACTIONr_mcbond_it7.26311.6785207
X-RAY DIFFRACTIONr_mcbond_other7.2511.6775206
X-RAY DIFFRACTIONr_mcangle_it11.32317.4846486
LS refinement shellResolution: 3.308→3.393 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.336 114 -
Rwork0.263 1961 -
all-2075 -
obs--93.98 %

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