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- PDB-4ovu: Crystal Structure of p110alpha in complex with niSH2 of p85alpha -

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Basic information

Entry
Database: PDB / ID: 4ovu
TitleCrystal Structure of p110alpha in complex with niSH2 of p85alpha
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsTRANSFERASE/TRANSFERASE REGULATOR / p110 / p85 / PI3KCA / PI3K / PIK3R1 / phosphatidilynositol 3 / 4 / 5 triphosphate / PIP2 / phosphatidylinositol 4 / 5 bisphosphate / lipid kinase / phosphoinositide / 3-kinase / signaling / phosphatidylinositol 3-kinase / TRANSFERASE-TRANSFERASE REGULATOR 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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 ...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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 4 / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, Domain 5 / 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 / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / 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 / Ubiquitin-like (UB roll) / Helix Hairpins / Alpha Horseshoe / Armadillo-type fold / Ubiquitin-like domain superfamily / Roll / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
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: 2.96 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)R37 CA043460 United States
CitationJournal: Oncotarget / Year: 2014
Title: Structural basis of nSH2 regulation and lipid binding in PI3K alpha.
Authors: Miller, M.S. / Schmidt-Kittler, O. / Bolduc, D.M. / Brower, E.T. / Chaves-Moreira, D. / Allaire, M. / Kinzler, K.W. / Jennings, I.G. / Thompson, P.E. / Cole, P.A. / Amzel, L.M. / Vogelstein, B. / Gabelli, S.B.
History
DepositionJan 14, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 3, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Author supporting evidence / Database references ...Author supporting evidence / Database references / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_audit_support / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_oper_list / software / struct_keywords
Item: _citation.country / _entity_src_gen.pdbx_alt_source_flag ..._citation.country / _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.country / _pdbx_audit_support.funding_organization / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _struct_keywords.text
Revision 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Sep 27, 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 / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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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


Theoretical massNumber of molelcules
Total (without water)161,4902
Polymers161,4902
Non-polymers00
Water32418
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7290 Å2
ΔGint-14 kcal/mol
Surface area57860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)114.692, 116.205, 149.086
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: 127822.578 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
#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 / Fragment: UNP residues 322-600
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRB1,PI3KR1,PIK3R1 / Plasmid: pFastbac HT-A / Cell line (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P27986
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 18 / 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: 2.89 Å3/Da / Density % sol: 57.39 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.8 / Details: NaFormate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 0.9788 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 30, 2009
RadiationProtocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9788 Å / Relative weight: 1
ReflectionResolution: 2.96→50 Å / Num. obs: 41914 / % possible obs: 99.6 % / Redundancy: 7.2 % / Rmerge(I) obs: 0.068 / Χ2: 1.669 / Net I/av σ(I): 36.874 / Net I/σ(I): 15.5 / Num. measured all: 300309
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.96-3.017.10.68620861.2841100
3.01-3.077.20.60320691.3391100
3.07-3.127.20.47520551.2821100
3.12-3.197.20.37520831.2751100
3.19-3.267.20.32720751.2871100
3.26-3.337.30.25120651.2971100
3.33-3.427.30.19620801.2981100
3.42-3.517.40.15620901.3671100
3.51-3.617.40.12320801.4141100
3.61-3.737.40.120801.5561100
3.73-3.867.40.08220801.623199.7
3.86-4.027.40.06720791.65199.9
4.02-4.27.30.06221001.873199.8
4.2-4.427.30.05321041.936199.9
4.42-4.77.30.04720982.135199.8
4.7-5.067.10.04821082.3031100
5.06-5.577.10.0521282.419199.9
5.57-6.376.90.04921282.357199.9
6.37-8.026.70.03421571.975199.4
8.02-506.50.02521691.748194.6

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.7.0029refinement
PDB_EXTRACT3.14data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2RD0

2rd0


Resolution: 2.96→37.79 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.897 / WRfactor Rfree: 0.2617 / WRfactor Rwork: 0.1853 / FOM work R set: 0.8076 / SU B: 38.039 / SU ML: 0.318 / SU R Cruickshank DPI: 0.4021 / SU Rfree: 0.4287 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.429 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2715 2122 5.1 %RANDOM
Rwork0.1912 39719 --
obs0.1952 41841 99.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 195.96 Å2 / Biso mean: 90.269 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-3.26 Å2-0 Å2-0 Å2
2--0.5 Å20 Å2
3----3.77 Å2
Refinement stepCycle: final / Resolution: 2.96→37.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10822 0 0 18 10840
Num. residues----1312
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01911067
X-RAY DIFFRACTIONr_angle_refined_deg1.6891.9614932
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.21651307
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.74324.293559
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.749152081
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.2861575
X-RAY DIFFRACTIONr_chiral_restr0.1240.21609
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0218338
LS refinement shellResolution: 2.96→3.037 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 141 -
Rwork0.279 2747 -
all-2888 -
obs--94.04 %
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)
10.94510.0104-0.07220.82730.14971.66110.07240.1781-0.04180.0668-0.06150.21540.0611-0.0595-0.01090.04950.02270.08910.04540.00850.220466.466862.672291.6248
20.1490.12330.22751.3070.07121.18570.12040.1662-0.2076-0.10040.10130.19780.5184-0.1112-0.22170.60360.06780.12740.6439-0.10360.742769.821637.874986.8341
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-28 - 1052
2X-RAY DIFFRACTION2B327 - 598

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