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Yorodumi- EMDB-37363: CryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-85... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-37363 | |||||||||
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Title | CryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an allosteric site | |||||||||
Map data | CryoEM density map of human PI3K-alpha (P85/P110-H1047R) with Cpd2 binding at an unidentified allosteric site | |||||||||
Sample |
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Keywords | PI3K-alpha / lipid kinase / allosteric inhibition / ONCOPROTEIN | |||||||||
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 | single particle reconstruction / cryo EM / Resolution: 3.0 Å | |||||||||
Authors | Huang X / Ren X / Zhong W | |||||||||
Funding support | 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_37363.map.gz | 59.9 MB | EMDB map data format | |
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Header (meta data) | emd-37363-v30.xml emd-37363.xml | 16.7 KB 16.7 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_37363_fsc.xml | 10.8 KB | Display | FSC data file |
Images | emd_37363.png | 45.4 KB | ||
Filedesc metadata | emd-37363.cif.gz | 6.3 KB | ||
Others | emd_37363_half_map_1.map.gz emd_37363_half_map_2.map.gz | 49.7 MB 49.8 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-37363 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-37363 | HTTPS FTP |
-Related structure data
Related structure data | 8w9bMC 8w9aC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_37363.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | CryoEM density map of human PI3K-alpha (P85/P110-H1047R) with Cpd2 binding at an unidentified allosteric site | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.74 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Half map 1 of Cpd2-bound human PI3K-alpha (P85/P110-H1047R)
File | emd_37363_half_map_1.map | ||||||||||||
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Annotation | Half map 1 of Cpd2-bound human PI3K-alpha (P85/P110-H1047R) | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map 2 of Cpd2-bound human PI3K-alpha (P85/P110-H1047R)
File | emd_37363_half_map_2.map | ||||||||||||
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Annotation | Half map 2 of Cpd2-bound human PI3K-alpha (P85/P110-H1047R) | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an all...
Entire | Name: human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an allosteric site |
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Components |
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-Supramolecule #1: human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an all...
Supramolecule | Name: human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an allosteric site type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit ...
Macromolecule | Name: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: phosphatidylinositol 3-kinase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 124.23075 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRL CDLRLFQPFL KVIEPVGNRE EKILNREIGF AIGMPVCEFD MVKDPEVQDF RRNILNVCKE AVDLRDLNSP H SRAMYVYP ...String: MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRL CDLRLFQPFL KVIEPVGNRE EKILNREIGF AIGMPVCEFD MVKDPEVQDF RRNILNVCKE AVDLRDLNSP H SRAMYVYP PNVESSPELP KHIYNKLDKG QIIVVIWVIV SPNNDKQKYT LKINHDCVPE QVIAEAIRKK TRSMLLSSEQ LK LCVLEYQ GKYILKVCGC DEYFLEKYPL SQYKYIRSCI MLGRMPNLML MAKESLYSQL PMDCFTMPSY SRRISTATPY MNG ETSTKS LWVINSALRI KILCATYVNV NIRDIDKIYV RTGIYHGGEP LCDNVNTQRV PCSNPRWNEW LNYDIYIPDL PRAA RLCLS ICSVKGRKGA KEEHCPLAWG NINLFDYTDT LVSGKMALNL WPVPHGLEDL LNPIGVTGSN PNKETPCLEL EFDWF SSVV KFPDMSVIEE HANWSVSREA GFSYSHAGLS NRLARDNELR ENDKEQLKAI STRDPLSEIT EQEKDFLWSH RHYCVT IPE ILPKLLLSVK WNSRDEVAQM YCLVKDWPPI KPEQAMELLD CNYPDPMVRG FAVRCLEKYL TDDKLSQYLI QLVQVLK YE QYLDNLLVRF LLKKALTNQR IGHFFFWHLK SEMHNKTVSQ RFGLLLESYC RACGMYLKHL NRQVEAMEKL INLTDILK Q EKKDETQKVQ MKFLVEQMRR PDFMDALQGF LSPLNPAHQL GNLRLEECRI MSSAKRPLWL NWENPDIMSE LLFQNNEII FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEI YDAAIDLFTR SCAGYCVATF ILGIGDRHNS NIMVKDDGQL FHIDFGHFLD HKKKKFGYKR ERVPFVLTQD F LIVISKGA QECTKTREFE RFQEMCYKAY LAIRQHANLF INLFSMMLGS GMPELQSFDD IAYIRKTLAL DKTEQEALEY FM KQMNDAR HGGWTTKMDA AAHTIKQHAL N UniProtKB: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform |
-Macromolecule #2: Phosphatidylinositol 3-kinase regulatory subunit alpha
Macromolecule | Name: Phosphatidylinositol 3-kinase regulatory subunit alpha type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 33.666961 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: MNNNMSLQDA EWYWGDISRE EVNEKLRDTA DGTFLVRDAS TKMHGDYTLT LRKGGNNKLI KIFHRDGKYG FSDPLTFSSV VELINHYRN ESLAQYNPKL DVKLLYPVSK YQQDQVVKED NIEAVGKKLH EYNTQFQEKS REYDRLYEEY TRTSQEIQMK R TAIEAFNE ...String: MNNNMSLQDA EWYWGDISRE EVNEKLRDTA DGTFLVRDAS TKMHGDYTLT LRKGGNNKLI KIFHRDGKYG FSDPLTFSSV VELINHYRN ESLAQYNPKL DVKLLYPVSK YQQDQVVKED NIEAVGKKLH EYNTQFQEKS REYDRLYEEY TRTSQEIQMK R TAIEAFNE TIKIFEEQCQ TQERYSKEYI EKFKREGNEK EIQRIMHNYD KLKSRISEII DSRRRLEEDL KKQAAEYREI DK RMNSIKP DLIQLRKTRD QYLMWLTQKG VRQKKLNEWL GN UniProtKB: Phosphatidylinositol 3-kinase regulatory subunit alpha |
-Macromolecule #3: 1-[(1S)-1-(5-fluoranyl-3-methyl-1-benzofuran-2-yl)-2-methyl-propy...
Macromolecule | Name: 1-[(1S)-1-(5-fluoranyl-3-methyl-1-benzofuran-2-yl)-2-methyl-propyl]-3-(1-oxidanylidene-2,3-dihydroisoindol-5-yl)urea type: ligand / ID: 3 / Number of copies: 1 / Formula: UJ3 |
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Molecular weight | Theoretical: 395.427 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
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Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 1.5 µm / Nominal defocus min: 1.0 µm |
Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 48.5 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |