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- PDB-8ilr: Cryo-EM structure of PI3Kalpha in complex with compound 16 -

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Basic information

Entry
Database: PDB / ID: 8ilr
TitleCryo-EM structure of PI3Kalpha in complex with compound 16
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsSTRUCTURAL PROTEIN / Phosphoinositide 3-kinase / drug target / ligand / binding pocket / chemical scaffold
Function / homology
Function and homology information


perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / phosphatidylinositol kinase activity / regulation of actin filament organization / negative regulation of actin filament depolymerization / response to L-leucine / positive regulation of focal adhesion disassembly / response to butyrate / 1-phosphatidylinositol-3-kinase regulator activity ...perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / phosphatidylinositol kinase activity / regulation of actin filament organization / negative regulation of actin filament depolymerization / response to L-leucine / positive regulation of focal adhesion disassembly / response to butyrate / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / T follicular helper cell differentiation / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase regulatory subunit binding / autosome genomic imprinting / myeloid leukocyte migration / regulation of cellular respiration / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / cis-Golgi network / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / transmembrane receptor protein tyrosine kinase adaptor activity / ErbB-3 class receptor binding / 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 / RHOD GTPase cycle / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / RHOF GTPase cycle / Nephrin family interactions / kinase activator activity / Signaling by LTK in cancer / anoikis / phosphatidylinositol-3-phosphate biosynthetic process / positive regulation of leukocyte migration / Signaling by LTK / MET activates PI3K/AKT signaling / relaxation of cardiac muscle / 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 / RND3 GTPase cycle / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / growth hormone receptor signaling pathway / insulin binding / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / PI-3K cascade:FGFR3 / RHOV GTPase cycle / RHOB GTPase cycle / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / natural killer cell mediated cytotoxicity / GP1b-IX-V activation signalling / negative regulation of macroautophagy / PI-3K cascade:FGFR2 / response to dexamethasone / PI-3K cascade:FGFR4 / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / phosphatidylinositol phosphate biosynthetic process / intracellular glucose homeostasis / negative regulation of osteoclast differentiation / Synthesis of PIPs at the plasma membrane / RHOU GTPase cycle / RET signaling / CDC42 GTPase cycle / negative regulation of anoikis / PI3K events in ERBB2 signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / insulin receptor substrate binding / intercalated disc / T cell differentiation / RHOG GTPase cycle / negative regulation of cell-matrix adhesion / extrinsic apoptotic signaling pathway via death domain receptors / regulation of multicellular organism growth / protein kinase activator activity / CD28 dependent PI3K/Akt signaling / RHOA GTPase cycle / Role of LAT2/NTAL/LAB on calcium mobilization / RAC2 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. / 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. / 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 / 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
Chem-7TZ / Phosphatidylinositol 3-kinase regulatory subunit alpha / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.05 Å
AuthorsZhou, Q. / Liu, X. / Neri, D. / Li, W. / Favalli, N. / Bassi, G. / Yang, S. / Yang, D. / Vogt, P.K. / Wang, M.-W.
Funding support China, United States, 11items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81872915 China
National Natural Science Foundation of China (NSFC)82121005 China
National Natural Science Foundation of China (NSFC)81973373 China
National Natural Science Foundation of China (NSFC)21704064 China
Other government2018ZX09735-001
Other government2018ZX09711002-002-005
Other government2021ZD0203400
Other government2018YFA0507000
Other governmentZDKJ2021028
Other governmentNNCAS-2017-1-CC
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)R35 CA197582 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: Structural insights into the interaction of three Y-shaped ligands with PI3Kα.
Authors: Qingtong Zhou / Xiao Liu / Dario Neri / Wenxin Li / Nicholas Favalli / Gabriele Bassi / Su Yang / Dehua Yang / Peter K Vogt / Ming-Wei Wang /
Abstract: Class IA phosphoinositide 3-kinase alpha (PI3Kα) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently ...Class IA phosphoinositide 3-kinase alpha (PI3Kα) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently on the market or under development have safety concerns due to a lack of selectivity. Therefore, other chemical scaffolds or unique mechanisms of catalytic kinase inhibition are needed. Here, we report the cryo-electron microscopy structures of wild-type PI3Kα, the dimer of p110α and p85α, in complex with three Y-shaped ligands [cpd16 (compound 16), cpd17 (compound 17), and cpd18 (compound 18)] of different affinities and no inhibitory effect on the kinase activity. Unlike ATP-competitive inhibitors, cpd17 adopts a Y-shaped conformation with one arm inserted into a binding pocket formed by R770 and W780 and the other arm lodged in the ATP-binding pocket at an angle that is different from that of the ATP phosphate tail. Such a special interaction induces a conformation of PI3Kα resembling that of the unliganded protein. These observations were confirmed with two isomers (cpd16 and cpd18). Further analysis of these Y-shaped ligands revealed the structural basis of differential binding affinities caused by stereo- or regiochemical modifications. Our results may offer a different direction toward the design of therapeutic agents against PI3Kα.
History
DepositionMar 4, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 30, 2023Provider: 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 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)211,9743
Polymers211,4462
Non-polymers5291
Water1267
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#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: 127822.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P42336, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Protein Phosphatidylinositol 3-kinase regulatory subunit alpha / PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory ...PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha / PI3-kinase subunit p85-alpha / PtdIns-3-kinase regulatory subunit p85-alpha


Mass: 83623.203 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P27986
#3: Chemical ChemComp-7TZ / N-[(2S)-1-(ethylamino)-1-oxidanylidene-3-[4-(2-quinoxalin-6-ylethynyl)phenyl]propan-2-yl]-2,3-dimethyl-quinoxaline-6-carboxamide


Mass: 528.604 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H28N6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human PI3Kalpha in complex with compound 16 / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper) / Strain: Sf-9
Buffer solutionpH: 7.6
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
7PHENIX1.18.2-3874model fitting
13PHENIX1.18.2-3874model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 390977 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Target criteria: Correlation coefficient
Atomic model buildingPDB-ID: 7MYN

7myn


Accession code: 7MYN / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00210588
ELECTRON MICROSCOPYf_angle_d0.3614281
ELECTRON MICROSCOPYf_dihedral_angle_d3.5011375
ELECTRON MICROSCOPYf_chiral_restr0.0361538
ELECTRON MICROSCOPYf_plane_restr0.0041834

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