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- PDB-5sxf: Crystal Structure of PI3Kalpha in complex with fragment 9 -

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Basic information

Entry
Database: PDB / ID: 5sxf
TitleCrystal Structure of PI3Kalpha in complex with fragment 9
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-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / 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 / IRS-mediated signalling ...perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / 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 / IRS-mediated signalling / positive regulation of focal adhesion disassembly / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase activator activity / autosome genomic imprinting / 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 / positive regulation of endoplasmic reticulum unfolded protein response / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / negative regulation of fibroblast apoptotic process / cis-Golgi network / ErbB-3 class receptor binding / kinase activator activity / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / regulation of cellular respiration / RHOF GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / RHOD GTPase cycle / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / enzyme-substrate adaptor activity / Nephrin family interactions / anoikis / Signaling by LTK in cancer / Costimulation by the CD28 family / RND1 GTPase cycle / Signaling by LTK / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / relaxation of cardiac muscle / MET activates PI3K/AKT signaling / positive regulation of leukocyte migration / PI3K/AKT activation / RND2 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / positive regulation of filopodium assembly / RND3 GTPase cycle / growth hormone receptor signaling pathway / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / negative regulation of stress fiber assembly / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / natural killer cell mediated cytotoxicity / 1-phosphatidylinositol-3-kinase activity / RHOV GTPase cycle / negative regulation of cell-matrix adhesion / Signaling by ALK / negative regulation of macroautophagy / RHOB GTPase cycle / GP1b-IX-V activation signalling / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / protein kinase activator activity / PI-3K cascade:FGFR4 / response to dexamethasone / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / negative regulation of osteoclast differentiation / intracellular glucose homeostasis / phosphatidylinositol-mediated signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / CD28 dependent PI3K/Akt signaling / RHOU GTPase cycle / CDC42 GTPase cycle / PI3K events in ERBB2 signaling / negative regulation of anoikis / PI3K Cascade / RET signaling / intercalated disc / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / T cell differentiation / RHOG GTPase cycle / regulation of multicellular organism growth / extrinsic apoptotic signaling pathway via death domain receptors / endothelial cell migration / positive regulation of TOR signaling / RHOA GTPase cycle
Similarity search - Function
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 / Rho GTPase-activating protein domain ...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 / 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. / 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 / Rho GTPase activation protein / 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- and 4-kinases signature 2. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / 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
HYDROXYPHENYL PROPIONIC 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: 3.46 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 9, 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 9, 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)161,7363
Polymers161,5702
Non-polymers1661
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6430 Å2
ΔGint-9 kcal/mol
Surface area56290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)112.346, 115.920, 147.185
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: 127902.547 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 / Fragment: residues 322-600
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-HPP / HYDROXYPHENYL PROPIONIC ACID


Mass: 166.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H10O3
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: 2.97 Å3/Da / Density % sol: 58.55 % / Mosaicity: 0.692 ° / Mosaicity esd: 0.008 °
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: 3.45→91.07 Å / Num. obs: 25565 / % possible obs: 100 % / Redundancy: 7.3 % / Rmerge(I) obs: 0.112 / Net I/av σ(I): 21.1 / Net I/σ(I): 7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Diffraction-ID% possible all
3.45-3.517.40.9380.8181100
3.51-3.577.50.8150.8551100
3.57-3.647.50.6040.8941100
3.64-3.727.40.4910.9291100
3.72-3.87.50.4180.9441100
3.8-3.897.40.3410.9611100
3.89-3.987.40.280.9781100
3.98-4.097.40.2450.9861100
4.09-4.217.40.1980.9851100
4.21-4.357.40.1760.9891100
4.35-4.57.40.1380.9911100
4.5-4.687.30.1250.9941100
4.68-4.897.30.1210.9931100
4.89-5.157.30.1150.9931100
5.15-5.477.30.1130.9941100
5.47-5.97.20.120.992199.9
5.9-6.497.10.1040.9941100
6.49-7.4370.0750.9961100
7.43-9.3570.0460.9991100
9.35-506.60.0420.999199.7

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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: 3.46→91.07 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.894 / SU B: 29.325 / SU ML: 0.442 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.605
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2668 1314 5.2 %RANDOM
Rwork0.1946 ---
obs0.1983 24200 98.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 308.9 Å2 / Biso mean: 127.991 Å2 / Biso min: 59.85 Å2
Baniso -1Baniso -2Baniso -3
1-4.56 Å20 Å20 Å2
2--1.13 Å20 Å2
3----5.69 Å2
Refinement stepCycle: final / Resolution: 3.46→91.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9970 0 12 0 9982
Biso mean--178.68 --
Num. residues----1207
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.01910189
X-RAY DIFFRACTIONr_bond_other_d0.0020.029812
X-RAY DIFFRACTIONr_angle_refined_deg1.4831.96413727
X-RAY DIFFRACTIONr_angle_other_deg0.971322593
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.25751192
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.66324.219512
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.063151927
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0951572
X-RAY DIFFRACTIONr_chiral_restr0.0790.21484
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02111289
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022371
X-RAY DIFFRACTIONr_mcbond_it8.1612.4414813
X-RAY DIFFRACTIONr_mcbond_other8.14712.444812
X-RAY DIFFRACTIONr_mcangle_it12.71818.6235990
LS refinement shellResolution: 3.457→3.546 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.337 102 -
Rwork0.29 1489 -
all-1591 -
obs--85.13 %

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