+Open data
-Basic information
Entry | Database: PDB / ID: 8ilr | ||||||||||||||||||||||||||||||||||||
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Title | Cryo-EM structure of PI3Kalpha in complex with compound 16 | ||||||||||||||||||||||||||||||||||||
Components |
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Keywords | STRUCTURAL PROTEIN / Phosphoinositide 3-kinase / drug target / ligand / binding pocket / chemical scaffold | ||||||||||||||||||||||||||||||||||||
Function / homology | Function and homology information perinuclear endoplasmic reticulum membrane / response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of toll-like receptor 4 signaling pathway / response to L-leucine / phosphatidylinositol kinase activity / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling ...perinuclear endoplasmic reticulum membrane / response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of toll-like receptor 4 signaling pathway / response to L-leucine / phosphatidylinositol kinase activity / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling / cellular response to hydrostatic pressure / positive regulation of focal adhesion disassembly / 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 protein localization to membrane / Activated NTRK3 signals through PI3K / negative regulation of fibroblast apoptotic process / cis-Golgi network / ErbB-3 class receptor binding / phosphatidylinositol 3-kinase complex, class IB / kinase activator activity / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / RHOF GTPase cycle / regulation of cellular respiration / RHOD GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / positive regulation of endoplasmic reticulum unfolded protein response / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex / Nephrin family interactions / relaxation of cardiac muscle / anoikis / Signaling by LTK in cancer / positive regulation of leukocyte migration / RND1 GTPase cycle / Costimulation by the CD28 family / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / Signaling by LTK / RND2 GTPase cycle / MET activates PI3K/AKT signaling / phosphatidylinositol-4,5-bisphosphate 3-kinase / PI3K/AKT activation / RND3 GTPase cycle / positive regulation of filopodium assembly / phosphatidylinositol 3-kinase / vascular endothelial growth factor signaling pathway / growth hormone receptor signaling pathway / RHOB GTPase cycle / negative regulation of stress fiber assembly / natural killer cell mediated cytotoxicity / phosphatidylinositol-3-phosphate biosynthetic process / insulin binding / RHOV GTPase cycle / 1-phosphatidylinositol-3-kinase activity / negative regulation of cell-matrix adhesion / Signaling by ALK / negative regulation of macroautophagy / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR2 / protein kinase activator activity / PI-3K cascade:FGFR4 / response to dexamethasone / RHOC GTPase cycle / RHOJ GTPase cycle / PI-3K cascade:FGFR1 / intracellular glucose homeostasis / negative regulation of osteoclast differentiation / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / CD28 dependent PI3K/Akt signaling / phosphatidylinositol phosphate biosynthetic process / CDC42 GTPase cycle / RHOU GTPase cycle / T cell differentiation / PI3K events in ERBB2 signaling / intercalated disc / negative regulation of anoikis / RET signaling / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / RHOG GTPase cycle / extrinsic apoptotic signaling pathway via death domain receptors / RHOA GTPase cycle / regulation of multicellular organism growth / PI3K Cascade / endothelial cell migration / positive regulation of TOR signaling Similarity search - Function | ||||||||||||||||||||||||||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||||||||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.05 Å | ||||||||||||||||||||||||||||||||||||
Authors | Zhou, 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
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8ilr.cif.gz | 279.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8ilr.ent.gz | 213.6 KB | Display | PDB format |
PDBx/mmJSON format | 8ilr.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8ilr_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 8ilr_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 8ilr_validation.xml.gz | 54.5 KB | Display | |
Data in CIF | 8ilr_validation.cif.gz | 79.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/il/8ilr ftp://data.pdbj.org/pub/pdb/validation_reports/il/8ilr | HTTPS FTP |
-Related structure data
Related structure data | 35543MC 8ilsC 8ilvC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | 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 |
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#2: Protein | 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 / |
#4: Water | ChemComp-HOH / |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Human PI3Kalpha in complex with compound 16 / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Trichoplusia ni (cabbage looper) / Strain: Sf-9 |
Buffer solution | pH: 7.6 |
Specimen | Conc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm |
Image recording | Electron dose: 70 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 390977 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Target criteria: Correlation coefficient | ||||||||||||||||||||||||
Atomic model building | PDB-ID: 7MYN Accession code: 7MYN / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||
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