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- PDB-5swt: Crystal Structure of PI3Kalpha in complex with fragments 17 and 27 -

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Basic information

Entry
Database: PDB / ID: 5swt
TitleCrystal Structure of PI3Kalpha in complex with fragments 17 and 27
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 / phosphatidylinositol 3-kinase activator activity / IRS-mediated signalling / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / cellular response to hydrostatic pressure / interleukin-18-mediated signaling pathway / T follicular helper cell differentiation / myeloid leukocyte migration / phosphatidylinositol 3-kinase complex / autosome genomic imprinting / PI3K events in ERBB4 signaling / 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 / ErbB-3 class receptor binding / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / transmembrane receptor protein tyrosine kinase adaptor activity / phosphatidylinositol 3-kinase complex, class IB / kinase activator activity / vasculature development / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by cytosolic FGFR1 fusion mutants / cardiac muscle cell contraction / RHOD GTPase cycle / RHOF GTPase cycle / phosphatidylinositol 3-kinase complex, class IA / Nephrin family interactions / anoikis / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by LTK in cancer / Regulation of T cell activation by CD28 family / positive regulation of leukocyte migration / enzyme-substrate adaptor activity / Signaling by LTK / MET activates PI3K/AKT signaling / growth hormone receptor signaling pathway / PI3K/AKT activation / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / RND1 GTPase cycle / negative regulation of stress fiber assembly / positive regulation of filopodium assembly / phosphatidylinositol-4,5-bisphosphate 3-kinase / RND2 GTPase cycle / phosphatidylinositol 3-kinase / vascular endothelial growth factor signaling pathway / RND3 GTPase cycle / relaxation of cardiac muscle / insulin binding / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / natural killer cell mediated cytotoxicity / GP1b-IX-V activation signalling / RHOB GTPase cycle / negative regulation of macroautophagy / RHOV GTPase cycle / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / phosphatidylinositol-mediated signaling / intracellular glucose homeostasis / negative regulation of osteoclast differentiation / phosphatidylinositol phosphate biosynthetic process / response to dexamethasone / Synthesis of PIPs at the plasma membrane / CD28 dependent PI3K/Akt signaling / RHOU GTPase cycle / PI3K events in ERBB2 signaling / CDC42 GTPase cycle / negative regulation of anoikis / RET signaling / T cell differentiation / Interleukin-3, Interleukin-5 and GM-CSF signaling / protein kinase activator activity / insulin receptor substrate binding / extrinsic apoptotic signaling pathway via death domain receptors / PI3K Cascade / RHOG GTPase cycle / regulation of multicellular organism growth / intercalated disc / endothelial cell migration / RHOA GTPase cycle / negative regulation of cell-matrix adhesion
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 / Src homology 3 domains / SH2 domain superfamily / 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
pyridin-3-ol / 3-fluoro-4-methoxyaniline / 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: 3.49 Å
AuthorsGabelli, S.B. / Vogelstein, B. / Miller, M.S. / Amzel, L.M.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA062924 and CA043460 United States
Alexander and Margaret Stewart Trust 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 23, 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)161,8864
Polymers161,6492
Non-polymers2362
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7280 Å2
ΔGint-16 kcal/mol
Surface area60900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)114.449, 115.944, 149.265
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-71A / pyridin-3-ol


Mass: 95.099 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H5NO
#4: Chemical ChemComp-71B / 3-fluoro-4-methoxyaniline


Mass: 141.143 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H8FNO
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: 59.89 % / Mosaicity: 0.525 ° / Mosaicity esd: 0.009 °
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: 3.49→91.57 Å / Num. obs: 25886 / % possible obs: 100 % / Redundancy: 7.3 % / Rmerge(I) obs: 0.123 / Net I/av σ(I): 19.167 / Net I/σ(I): 6.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
3.5-3.637.50.9731100
3.63-3.777.40.7461100
3.77-3.947.40.4961100
3.94-4.157.40.3251100
4.15-4.417.40.2161100
4.41-4.757.40.1541100
4.75-5.237.30.1311100
5.23-5.987.30.1221100
5.98-7.537.10.0941100
7.53-506.70.051199.9

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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: 3.49→91.57 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.882 / SU B: 35.479 / SU ML: 0.519 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.674
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2846 1325 5.1 %RANDOM
Rwork0.2083 ---
obs0.2121 24456 99.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 289.34 Å2 / Biso mean: 141.156 Å2 / Biso min: 70.4 Å2
Baniso -1Baniso -2Baniso -3
1-4.1 Å20 Å20 Å2
2---6.38 Å20 Å2
3---2.28 Å2
Refinement stepCycle: final / Resolution: 3.49→91.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10801 0 17 0 10818
Biso mean--140.48 --
Num. residues----1308
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.01911047
X-RAY DIFFRACTIONr_bond_other_d0.0020.0210612
X-RAY DIFFRACTIONr_angle_refined_deg1.3351.96414890
X-RAY DIFFRACTIONr_angle_other_deg0.959324432
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.13551295
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.27824.198555
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.728152079
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.3111578
X-RAY DIFFRACTIONr_chiral_restr0.0770.21604
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.02112263
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022580
X-RAY DIFFRACTIONr_mcbond_it7.25913.885219
X-RAY DIFFRACTIONr_mcbond_other7.25313.8795218
X-RAY DIFFRACTIONr_mcangle_it11.58520.796501
LS refinement shellResolution: 3.487→3.577 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.316 103 -
Rwork0.286 1661 -
all-1764 -
obs--93.28 %

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