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- PDB-9b4u: Crystal structure of p110alpha-RBD covalently bound to a breaker ... -

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Basic information

Entry
Database: PDB / ID: 9b4u
TitleCrystal structure of p110alpha-RBD covalently bound to a breaker compound BBO-10203 via Cys242
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsONCOPROTEIN / p110alpha / PIK3CA / PI3Kalpha / RBD / breaker / PI3K-RAS / 10203
Function / homology
Function and homology information


response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / IRS-mediated signalling / autosome genomic imprinting / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure ...response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / IRS-mediated signalling / autosome genomic imprinting / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure / regulation of cellular respiration / positive regulation of protein localization to membrane / Activated NTRK2 signals through PI3K / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / 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 / phosphatidylinositol 3-kinase complex, class IA / Nephrin family interactions / anoikis / Signaling by LTK in cancer / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by LTK / MET activates PI3K/AKT signaling / PI3K/AKT activation / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / vascular endothelial growth factor signaling pathway / relaxation of cardiac muscle / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of macroautophagy / PI-3K cascade:FGFR2 / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / response to dexamethasone / negative regulation of anoikis / RET signaling / PI3K events in ERBB2 signaling / protein kinase activator activity / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / regulation of multicellular organism growth / intercalated disc / CD28 dependent PI3K/Akt signaling / positive regulation of TOR signaling / Role of LAT2/NTAL/LAB on calcium mobilization / RAC2 GTPase cycle / Interleukin receptor SHC signaling / GAB1 signalosome / Role of phospholipids in phagocytosis / adipose tissue development / phagocytosis / endothelial cell migration / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Signaling by FGFR4 in disease / positive regulation of lamellipodium assembly / energy homeostasis / Signaling by FLT3 ITD and TKD mutants / cardiac muscle contraction / GPVI-mediated activation cascade / Signaling by FGFR3 in disease / Tie2 Signaling / Signaling by FGFR2 in disease / response to muscle stretch / T cell costimulation / RAC1 GTPase cycle / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Downstream signal transduction / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / liver development / response to activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Regulation of signaling by CBL / positive regulation of smooth muscle cell proliferation / cellular response to glucose stimulus / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / platelet activation / VEGFA-VEGFR2 Pathway / epidermal growth factor receptor signaling pathway / cellular response to insulin stimulus / glucose metabolic process
Similarity search - Function
PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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 ...PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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 / 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 3/4-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 / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.21 Å
AuthorsCzyzyk, D.J. / Simanshu, D.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)75N91019D00024 United States
CitationJournal: Science / Year: 2025
Title: BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3K alpha interaction.
Authors: Simanshu, D.K. / Xu, R. / Stice, J.P. / Czyzyk, D.J. / Feng, S. / Denson, J.P. / Riegler, E. / Yang, Y. / Zhang, C. / Donovan, S. / Smith, B.P. / Abreu-Blanco, M. / Chen, M. / Feng, C. / Fu, ...Authors: Simanshu, D.K. / Xu, R. / Stice, J.P. / Czyzyk, D.J. / Feng, S. / Denson, J.P. / Riegler, E. / Yang, Y. / Zhang, C. / Donovan, S. / Smith, B.P. / Abreu-Blanco, M. / Chen, M. / Feng, C. / Fu, L. / Rabara, D. / Young, L.C. / Dyba, M. / Yan, W. / Lin, K. / Ghorbanpoorvalukolaie, S. / Larsen, E.K. / Malik, W. / Champagne, A. / Parker, K. / Ju, J.H. / Jeknic, S. / Esposito, D. / Turner, D.M. / Lightstone, F.C. / Wang, B. / Wehn, P.M. / Wang, K. / Stephen, A.G. / Maciag, A.E. / Hata, A.N. / Sinkevicius, K.W. / Nissley, D.V. / Wallace, E.M. / McCormick, F. / Beltran, P.J.
History
DepositionMar 21, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 25, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
B: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8854
Polymers33,6002
Non-polymers1,2852
Water1,56787
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)78.041, 71.613, 62.090
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-1156-

HOH

21B-1119-

HOH

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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: 16799.793 Da / Num. of mol.: 2 / Fragment: Ras Binding Domain (RBD)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: Escherichia coli (E. coli)
References: UniProt: P42336, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A1AIR / 1-[(4R,8R)-2-[(4M,7P)-7-[2,4-difluoro-6-(2-methoxyethoxy)phenyl]-4-(1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl]-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl]propan-1-one


Mass: 642.718 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C34H32F2N6O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 87 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.58 Å3/Da / Density % sol: 52.36 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.9 / Details: 0.1 M Tris, 0.2 M CaCl2, 24 % PEG 6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 17, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.21→48.59 Å / Num. obs: 18081 / % possible obs: 99.8 % / Redundancy: 13.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.063 / Rrim(I) all: 0.066 / Net I/σ(I): 23.35
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.21-2.341.05228220.9281.0971
2.34-2.50.57127370.9740.5931
2.5-2.70.30725150.9890.3191
2.7-2.960.15523360.9970.1611
2.96-3.30.08321090.9980.0861
3.3-3.810.05718950.9990.0591
3.81-4.660.04216150.9990.0441
4.66-6.560.0412800.9990.0421
6.56-48.590.0317720.9980.0321

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Processing

Software
NameVersionClassification
PHENIX(1.21_5207: ???)refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.21→48.59 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 32.57 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2692 898 4.98 %
Rwork0.229 --
obs0.2309 18038 99.55 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.21→48.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2235 0 92 87 2414
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022397
X-RAY DIFFRACTIONf_angle_d0.5833265
X-RAY DIFFRACTIONf_dihedral_angle_d12.691893
X-RAY DIFFRACTIONf_chiral_restr0.044351
X-RAY DIFFRACTIONf_plane_restr0.004400
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.21-2.340.3371380.29612757X-RAY DIFFRACTION99
2.34-2.520.40281480.34972822X-RAY DIFFRACTION99
2.52-2.780.37781530.30222825X-RAY DIFFRACTION100
2.78-3.180.29831470.27912833X-RAY DIFFRACTION100
3.18-4.010.2311520.21752882X-RAY DIFFRACTION100
4.01-48.590.23571600.18393021X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -17.6249 Å / Origin y: 5.3817 Å / Origin z: -22.5205 Å
111213212223313233
T0.3569 Å2-0.0706 Å2-0.0056 Å2-0.332 Å20.0063 Å2--0.4337 Å2
L0.9211 °20.2184 °20.2139 °2-1.2821 °2-0.2006 °2--3.5991 °2
S0.0696 Å °-0.2282 Å °-0.044 Å °0.281 Å °-0.1161 Å °-0.0793 Å °0.033 Å °0.1618 Å °0.0515 Å °
Refinement TLS groupSelection details: all

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