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Yorodumi- PDB-8w9a: CryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-79... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8w9a | ||||||
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Title | CryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-7909 binding at an allosteric site | ||||||
Components |
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Keywords | ONCOPROTEIN / PI3K-alpha / lipid kinase / allosteric inhibition | ||||||
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 / phosphatidylinositol 3-kinase regulator activity / response to butyrate / autosome genomic imprinting ...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 / phosphatidylinositol 3-kinase regulator activity / response to butyrate / autosome genomic imprinting / positive regulation of focal adhesion disassembly / cellular response to hydrostatic pressure / IRS-mediated signalling / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / myeloid leukocyte migration / phosphatidylinositol 3-kinase regulatory subunit binding / 1-phosphatidylinositol-3-kinase regulator activity / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / positive regulation of protein localization to membrane / cis-Golgi network / Activated NTRK3 signals through PI3K / kinase activator activity / ErbB-3 class receptor binding / negative regulation of fibroblast apoptotic process / RHOF GTPase cycle / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / RHOD GTPase cycle / positive regulation of endoplasmic reticulum unfolded protein response / Signaling by cytosolic FGFR1 fusion mutants / regulation of cellular respiration / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex / anoikis / Nephrin family interactions / 1-phosphatidylinositol-4-phosphate 3-kinase activity / RND1 GTPase cycle / Costimulation by the CD28 family / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / vascular endothelial growth factor signaling pathway / RND2 GTPase cycle / PI3K/AKT activation / MET activates PI3K/AKT signaling / RND3 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / positive regulation of leukocyte migration / positive regulation of filopodium assembly / phosphatidylinositol 3-kinase / phosphatidylinositol 3-kinase complex, class IA / negative regulation of stress fiber assembly / relaxation of cardiac muscle / growth hormone receptor signaling pathway / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / RHOV GTPase cycle / negative regulation of macroautophagy / GP1b-IX-V activation signalling / RHOB GTPase cycle / Signaling by ALK / negative regulation of cell-matrix adhesion / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / protein kinase activator activity / response to dexamethasone / PI-3K cascade:FGFR2 / RHOJ GTPase cycle / PI-3K cascade:FGFR4 / RHOC GTPase cycle / PI-3K cascade:FGFR1 / negative regulation of osteoclast differentiation / intracellular glucose homeostasis / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol phosphate biosynthetic process / CDC42 GTPase cycle / RHOU GTPase cycle / PI3K events in ERBB2 signaling / Signaling by ALK fusions and activated point mutants / RHOG GTPase cycle / regulation of multicellular organism growth / negative regulation of anoikis / RET signaling / T cell differentiation / extrinsic apoptotic signaling pathway via death domain receptors / insulin receptor substrate binding / PI3K Cascade / Interleukin-3, Interleukin-5 and GM-CSF signaling / RHOA GTPase cycle / intercalated disc / positive regulation of TOR signaling / endothelial cell migration / RAC3 GTPase cycle / RAC2 GTPase cycle / Role of phospholipids in phagocytosis Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å | ||||||
Authors | Huang, X. / Ren, X. / Zhong, W. | ||||||
Funding support | 1items
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Citation | Journal: Structure / Year: 2024 Title: Cryo-EM structures reveal two allosteric inhibition modes of PI3Kα involving a re-shaping of the activation loop. Authors: Xiuliang Huang / Kailiang Wang / Jing Han / Xiumei Chen / Zhenglin Wang / Tianlun Wu / Bo Yu / Feng Zhao / Xinjuan Wang / Huijuan Li / Zhi Xie / Xiaotian Zhu / Wenge Zhong / Xiaoming Ren / Abstract: PI3Kα is a lipid kinase that phosphorylates PIP2 and generates PIP3. The hyperactive PI3Kα mutation, H1047R, accounts for about 14% of breast cancer, making it a highly attractive target for drug ...PI3Kα is a lipid kinase that phosphorylates PIP2 and generates PIP3. The hyperactive PI3Kα mutation, H1047R, accounts for about 14% of breast cancer, making it a highly attractive target for drug discovery. Here, we report the cryo-EM structures of PI3Kα bound to two different allosteric inhibitors QR-7909 and QR-8557 at a global resolution of 2.7 Å and 3.0 Å, respectively. The structures reveal two distinct binding pockets on the opposite sides of the activation loop. Structural and MD simulation analyses show that the allosteric binding of QR-7909 and QR-8557 inhibit PI3Kα hyper-activity by reducing the fluctuation and mobility of the activation loop. Our work provides a strong rational basis for a further optimization and development of highly selective drug candidates to treat PI3Kα-driven cancers. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8w9a.cif.gz | 248.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8w9a.ent.gz | 189.7 KB | Display | PDB format |
PDBx/mmJSON format | 8w9a.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/w9/8w9a ftp://data.pdbj.org/pub/pdb/validation_reports/w9/8w9a | HTTPS FTP |
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-Related structure data
Related structure data | 37362MC 8w9bC 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: 124230.750 Da / Num. of mol.: 1 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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#2: Protein | Mass: 83710.281 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Production host: Escherichia coli (E. coli) / References: UniProt: P27986 |
#3: Chemical | ChemComp-UEX / Mass: 490.942 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H23ClN6O3 |
#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 PI3K-alpha (P85/P110-H1047R) with QR-7909 binding at an allosteric site Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli (E. coli) |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: DIFFRACTION / Nominal defocus max: 1300 nm / Nominal defocus min: 900 nm |
Image recording | Electron dose: 54.2 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
-Processing
EM software | Name: PHENIX / Version: 1.13_2998: / Category: model refinement |
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CTF correction | Type: NONE |
3D reconstruction | Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 420630 / Symmetry type: POINT |