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- PDB-9cmk: Crystal structure of p110alpha-RAS binding domain (RBD) in comple... -

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Basic information

Entry
Database: PDB / ID: 9cmk
TitleCrystal structure of p110alpha-RAS binding domain (RBD) in complex with molecular glue D927
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsSIGNALING PROTEIN / RAS / PI3Kalpha / p110alpha / PIK3CA / RBD / glue / D927
Function / homology
Function and homology information


response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of actin filament organization / response to L-leucine / 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 / regulation of actin filament organization / response to L-leucine / 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 / Activated NTRK2 signals through PI3K / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex, class IB / positive regulation of protein localization to membrane / 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 / relaxation of cardiac muscle / 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 / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / 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 / response to dexamethasone / PI-3K cascade:FGFR1 / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / negative regulation of anoikis / RET signaling / PI3K events in ERBB2 signaling / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / protein kinase activator activity / intercalated disc / regulation of multicellular organism growth / 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 / Role of phospholipids in phagocytosis / GAB1 signalosome / 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 / cardiac muscle contraction / GPVI-mediated activation cascade / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR3 in disease / Tie2 Signaling / Signaling by FGFR2 in disease / response to muscle stretch / 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 / positive regulation of smooth muscle cell proliferation / Regulation of signaling by CBL / cellular response to glucose stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / platelet activation / VEGFA-VEGFR2 Pathway / cellular response to insulin stimulus / epidermal growth factor receptor signaling pathway / glucose metabolic process / Signaling by CSF1 (M-CSF) in myeloid cells
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: 1.75 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: Science / Year: 2025
Title: Molecular glues that facilitate RAS binding to PI3Kalpha promote glucose uptake without insulin
Authors: Czyzyk, D.J. / Yan, W. / Messing, S. / Gillette, W. / Esposito, D. / Nissley, D.V. / McCormick, F. / Simanshu, D.K.
History
DepositionJul 15, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 23, 2025Provider: repository / Type: Initial release

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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 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,33510
Polymers33,0032
Non-polymers1,3328
Water6,179343
1
A: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,1456
Polymers16,5011
Non-polymers6445
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,1904
Polymers16,5011
Non-polymers6893
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.092, 91.230, 46.800
Angle α, β, γ (deg.)90.00, 112.40, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 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: 16501.496 Da / Num. of mol.: 2
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 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 351 molecules

#2: Chemical ChemComp-A1ATF / 2-[3-fluoro-4-({(7P)-7-[2-(2-methoxyethoxy)phenyl]thieno[2,3-d]pyridazin-4-yl}amino)phenyl]acetamide


Mass: 452.501 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H21FN4O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-MRD / (4R)-2-METHYLPENTANE-2,4-DIOL


Mass: 118.174 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C6H14O2 / Comment: precipitant*YM
#5: Chemical ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C6H14O2 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 343 / 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: 2.44 Å3/Da / Density % sol: 49.7 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.4
Details: 0.1 M (MES/Imidazole), 0.06 M Divalent mix, 40 %v/v (MPD, PEG 1000, PEG 3350)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.97934 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 20, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97934 Å / Relative weight: 1
ReflectionResolution: 1.75→30 Å / Num. obs: 31272 / % possible obs: 99.7 % / Redundancy: 7 % / CC1/2: 0.997 / Rmerge(I) obs: 0.125 / Rpim(I) all: 0.056 / Net I/σ(I): 10.63
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2% possible all
1.75-1.866.81.0082.0150000.72199.7
1.86-1.987.20.6353.547380.86499.8
1.98-2.147.20.3975.5444030.95199.8
2.14-2.3570.2568.1640670.97699.8
2.35-2.626.80.1810.4736810.98799.8
2.62-3.027.20.1215.3332450.99399.6
3.02-3.697.10.07922.5527610.99699.6
3.69-5.186.60.05928.5321450.99799.6
5.18-3070.0529.5712320.99898.5

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Processing

Software
NameVersionClassification
PHENIX(1.21.1_5286: ???)refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→28.77 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2205 1553 4.97 %
Rwork0.1757 --
obs0.1779 31270 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.75→28.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2168 0 91 343 2602
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012330
X-RAY DIFFRACTIONf_angle_d1.0863156
X-RAY DIFFRACTIONf_dihedral_angle_d12.418894
X-RAY DIFFRACTIONf_chiral_restr0.072346
X-RAY DIFFRACTIONf_plane_restr0.008381
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.810.29391360.23472691X-RAY DIFFRACTION99
1.81-1.870.24561330.22462693X-RAY DIFFRACTION100
1.87-1.950.2671530.2082689X-RAY DIFFRACTION100
1.95-2.040.26471450.1822679X-RAY DIFFRACTION100
2.04-2.140.21771390.17672693X-RAY DIFFRACTION100
2.14-2.280.22191370.17192697X-RAY DIFFRACTION100
2.28-2.450.22341420.17442714X-RAY DIFFRACTION100
2.45-2.70.21931460.17892709X-RAY DIFFRACTION100
2.7-3.090.21161400.17872691X-RAY DIFFRACTION100
3.09-3.890.21031390.15852708X-RAY DIFFRACTION100
3.89-28.770.20211430.16692753X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 0.8679 Å / Origin y: 6.7268 Å / Origin z: 12.0271 Å
111213212223313233
T0.1271 Å2-0.0009 Å20.0029 Å2-0.1521 Å2-0.0052 Å2--0.109 Å2
L0.4726 °2-0.1774 °2-0.0416 °2-1.0888 °2-0.0647 °2--0.1314 °2
S0.0169 Å °-0.0008 Å °0.0086 Å °-0.0834 Å °-0.0131 Å °0.0308 Å °-0.0005 Å °0.0023 Å °-0.0033 Å °
Refinement TLS groupSelection details: all

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