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- PDB-9b4t: Crystal structure of the MRAS-p110alpha complex -

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Basic information

Entry
Database: PDB / ID: 9b4t
TitleCrystal structure of the MRAS-p110alpha complex
Components
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
  • Ras-related protein M-Ras
KeywordsONCOPROTEIN / RAS / RRAS3 / MRAS / p110alpha / PIK3CA / PI3Kalpha / PI3Ka / PI3K
Function / homology
Function and homology information


protein phosphatase type 1 complex / response to muscle inactivity / negative regulation of actin filament depolymerization / GTP-dependent protein binding / response to L-leucine / regulation of actin filament organization / response to butyrate / IRS-mediated signalling / autosome genomic imprinting / phosphatidylinositol 3-kinase complex ...protein phosphatase type 1 complex / response to muscle inactivity / negative regulation of actin filament depolymerization / GTP-dependent protein binding / 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 / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / 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 / RAC2 GTPase cycle / Role of LAT2/NTAL/LAB on calcium mobilization / 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 / cellular response to leukemia inhibitory factor / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / liver development / small monomeric GTPase / response to activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Regulation of signaling by CBL / positive regulation of smooth muscle cell proliferation / RAF activation / cellular response to glucose stimulus / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII
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. / Small GTPase, Ras-type / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / small GTPase Ras family profile. / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / C2 domain superfamily / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-5H5 / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / Ras-related protein M-Ras / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 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: Nat Commun / Year: 2025
Title: Structural insights into isoform-specific RAS-PI3K alpha interactions and the role of RAS in PI3K alpha activation.
Authors: Czyzyk, D. / Yan, W. / Messing, S. / Gillette, W. / Tsuji, T. / Yamaguchi, M. / Furuzono, S. / Turner, D.M. / Esposito, D. / Nissley, D.V. / McCormick, F. / Simanshu, D.K.
History
DepositionMar 21, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 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: Ras-related protein M-Ras
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,3475
Polymers132,4182
Non-polymers9293
Water48627
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2800 Å2
ΔGint-18 kcal/mol
Surface area47020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.935, 105.936, 114.493
Angle α, β, γ (deg.)90.00, 97.50, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform / PI3-kinase subunit alpha / PI3K-alpha / PI3Kalpha / PtdIns-3-kinase subunit alpha / ...PI3-kinase subunit alpha / PI3K-alpha / PI3Kalpha / PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha / PtdIns-3-kinase subunit p110-alpha / p110alpha / Phosphoinositide 3-kinase alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 112033.430 Da / Num. of mol.: 1 / Mutation: W1057A, I1058A, F1059A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: Trichoplusia (butterflies/moths)
References: UniProt: P42336, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Protein Ras-related protein M-Ras / Ras-related protein R-Ras3


Mass: 20384.250 Da / Num. of mol.: 1 / Mutation: Q35A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MRAS, RRAS3 / Production host: Escherichia coli (E. coli) / References: UniProt: O14807, small monomeric GTPase

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Non-polymers , 4 types, 30 molecules

#3: Chemical ChemComp-5H5 / (2S)-2-({2-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl}oxy)propanamide / GDC-0326


Mass: 382.416 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22N6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O13P3 / Feature type: SUBJECT OF INVESTIGATION
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 27 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.67 Å3/Da / Density % sol: 53.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.1 M (Tris/Bicine) 1.2%w/v cholic acid mix, 50%v/v (40%v/v ethylene glycol, 20%w/v PEG 8000)

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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: 2.75→50.03 Å / Num. obs: 35877 / % possible obs: 98.7 % / Redundancy: 7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.078 / Rrim(I) all: 0.084 / Net I/σ(I): 13.48
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.75-2.921.11957130.871.2051
2.92-3.120.61154480.9590.6581
3.12-3.370.3450550.9810.3681
3.37-3.690.1846230.9920.1941
3.69-4.120.10142150.9970.1091
4.12-4.750.06937520.9980.0751
4.75-5.810.05931670.9980.0641
5.81-8.160.05125000.9980.0551
8.16-50.030.03414040.9990.0371

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Processing

Software
NameVersionClassification
PHENIX(1.21_5207: ???)refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.75→50.03 Å / SU ML: 0.5 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 34.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2619 1787 5 %
Rwork0.2135 --
obs0.2158 35732 98.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.75→50.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8626 0 61 27 8714
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0028878
X-RAY DIFFRACTIONf_angle_d0.40612014
X-RAY DIFFRACTIONf_dihedral_angle_d11.6813366
X-RAY DIFFRACTIONf_chiral_restr0.0381317
X-RAY DIFFRACTIONf_plane_restr0.0031533
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.75-2.830.49951360.45472582X-RAY DIFFRACTION96
2.83-2.910.39421360.37572554X-RAY DIFFRACTION98
2.91-30.32961350.32112604X-RAY DIFFRACTION98
3-3.110.33781370.28462619X-RAY DIFFRACTION98
3.11-3.230.30431370.27772586X-RAY DIFFRACTION98
3.23-3.380.3281350.28562580X-RAY DIFFRACTION98
3.38-3.560.34131350.25772557X-RAY DIFFRACTION97
3.56-3.780.30271390.2252625X-RAY DIFFRACTION99
3.78-4.080.22961380.20982635X-RAY DIFFRACTION99
4.08-4.490.24981400.19822641X-RAY DIFFRACTION99
4.49-5.130.22841360.17672595X-RAY DIFFRACTION98
5.13-6.460.28781420.20812682X-RAY DIFFRACTION100
6.47-50.030.19531410.16812685X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: -1.6934 Å / Origin y: -12.2223 Å / Origin z: 37.8298 Å
111213212223313233
T0.6517 Å20.0024 Å2-0.0368 Å2-0.8096 Å2-0.0261 Å2--0.6542 Å2
L0.8789 °2-0.2281 °2-0.2751 °2-1.0712 °2-0.1974 °2--1.7841 °2
S0.0273 Å °0.0975 Å °-0.0197 Å °0.0458 Å °0.0764 Å °0.051 Å °-0.204 Å °0.133 Å °-0.1024 Å °
Refinement TLS groupSelection details: all

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