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- EMDB-37362: CryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-79... -
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Open data
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Basic information
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Title | CryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-7909 binding at an allosteric site | |||||||||
![]() | CryoEM density map of human PI3K-alpha (P85/P110-H1047R) with Cpd1 binding at the allosteric site | |||||||||
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![]() | PI3K-alpha / lipid kinase / allosteric inhibition / ONCOPROTEIN | |||||||||
Function / homology | ![]() 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 / positive regulation of focal adhesion disassembly ...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 / positive regulation of focal adhesion disassembly / autosome genomic imprinting / IRS-mediated signalling / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase activator activity / 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 / cis-Golgi network / ErbB-3 class receptor binding / negative regulation of fibroblast apoptotic process / cardiac muscle cell contraction / RHOF GTPase cycle / kinase activator activity / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / RHOD GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / regulation of cellular respiration / positive regulation of endoplasmic reticulum unfolded protein response / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex, class IA / anoikis / phosphatidylinositol 3-kinase complex / Nephrin family interactions / RND1 GTPase cycle / Costimulation by the CD28 family / relaxation of cardiac muscle / positive regulation of leukocyte migration / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / MET activates PI3K/AKT signaling / RND2 GTPase cycle / PI3K/AKT activation / positive regulation of filopodium assembly / RND3 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / negative regulation of stress fiber assembly / growth hormone receptor signaling pathway / phosphatidylinositol 3-kinase / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / RHOV GTPase cycle / 1-phosphatidylinositol-3-kinase activity / negative regulation of cell-matrix adhesion / Signaling by ALK / RHOB GTPase cycle / negative regulation of macroautophagy / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR2 / response to dexamethasone / RHOJ GTPase cycle / PI-3K cascade:FGFR4 / protein kinase activator activity / 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-mediated signaling / phosphatidylinositol phosphate biosynthetic process / CDC42 GTPase cycle / RHOU GTPase cycle / PI3K events in ERBB2 signaling / negative regulation of anoikis / T cell differentiation / RET signaling / intercalated disc / regulation of multicellular organism growth / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / RHOG GTPase cycle / extrinsic apoptotic signaling pathway via death domain receptors / PI3K Cascade / RHOA GTPase cycle / positive regulation of TOR signaling / endothelial cell migration / RAC2 GTPase cycle / RAC3 GTPase cycle / Role of phospholipids in phagocytosis Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.7 Å | |||||||||
![]() | Huang X / Ren X / Zhong W | |||||||||
Funding support | 1 items
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![]() | ![]() 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 | ![]() | 59.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 17.5 KB 17.5 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 10.3 KB | Display | ![]() |
Images | ![]() | 43.2 KB | ||
Filedesc metadata | ![]() | 6.7 KB | ||
Others | ![]() ![]() | 49.6 MB 49.6 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 869.9 KB | Display | ![]() |
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Full document | ![]() | 869.5 KB | Display | |
Data in XML | ![]() | 16 KB | Display | |
Data in CIF | ![]() | 21.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8w9aMC ![]() 8w9bC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
File | ![]() | ||||||||||||||||||||
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Annotation | CryoEM density map of human PI3K-alpha (P85/P110-H1047R) with Cpd1 binding at the allosteric site | ||||||||||||||||||||
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 Cpd1-bound human PI3K-alpha (P85/P110-H1047R)
File | emd_37362_half_map_1.map | ||||||||||||
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Annotation | Half map 1 of Cpd1-bound human PI3K-alpha (P85/P110-H1047R) | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map 2 of Cpd1-bound human PI3K-alpha (P85/P110-H1047R)
File | emd_37362_half_map_2.map | ||||||||||||
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Annotation | Half map 2 of Cpd1-bound human PI3K-alpha (P85/P110-H1047R) | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : human PI3K-alpha (P85/P110-H1047R) with QR-7909 binding at an all...
Entire | Name: human PI3K-alpha (P85/P110-H1047R) with QR-7909 binding at an allosteric site |
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Components |
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-Supramolecule #1: human PI3K-alpha (P85/P110-H1047R) with QR-7909 binding at an all...
Supramolecule | Name: human PI3K-alpha (P85/P110-H1047R) with QR-7909 binding at an allosteric site type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: ![]() |
-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: ![]() |
Molecular weight | Theoretical: 124.23075 KDa |
Recombinant expression | Organism: ![]() |
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: ![]() |
Molecular weight | Theoretical: 83.710281 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MSAEGYQYRA LYDYKKEREE DIDLHLGDIL TVNKGSLVAL GFSDGQEARP EEIGWLNGYN ETTGERGDFP GTYVEYIGRK KISPPTPKP RPPRPLPVAP GSSKTEADVE QQALTLPDLA EQFAPPDIAP PLLIKLVEAI EKKGLECSTL YRTQSSSNLA E LRQLLDCD ...String: MSAEGYQYRA LYDYKKEREE DIDLHLGDIL TVNKGSLVAL GFSDGQEARP EEIGWLNGYN ETTGERGDFP GTYVEYIGRK KISPPTPKP RPPRPLPVAP GSSKTEADVE QQALTLPDLA EQFAPPDIAP PLLIKLVEAI EKKGLECSTL YRTQSSSNLA E LRQLLDCD TPSVDLEMID VHVLADAFKR YLLDLPNPVI PAAVYSEMIS LAPEVQSSEE YIQLLKKLIR SPSIPHQYWL TL QYLLKHF FKLSQTSSKN LLNARVLSEI FSPMLFRFSA ASSDNTENLI KVIEILISTE WNERQPAPAL PPKPPKPTTV ANN GMNNNM SLQDAEWYWG DISREEVNEK LRDTADGTFL VRDASTKMHG DYTLTLRKGG NNKLIKIFHR DGKYGFSDPL TFSS VVELI NHYRNESLAQ YNPKLDVKLL YPVSKYQQDQ VVKEDNIEAV GKKLHEYNTQ FQEKSREYDR LYEEYTRTSQ EIQMK RTAI EAFNETIKIF EEQCQTQERY SKEYIEKFKR EGNEKEIQRI MHNYDKLKSR ISEIIDSRRR LEEDLKKQAA EYREID KRM NSIKPDLIQL RKTRDQYLMW LTQKGVRQKK LNEWLGNENT EDQYSLVEDD EDLPHHDEKT WNVGSSNRNK AENLLRG KR DGTFLVRESS KQGCYACSVV VDGEVKHCVI NKTATGYGFA EPYNLYSSLK ELVLHYQHTS LVQHNDSLNV TLAYPVYA Q QRR UniProtKB: Phosphatidylinositol 3-kinase regulatory subunit alpha |
-Macromolecule #3: 6-chloranyl-3-[[(1R)-1-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)...
Macromolecule | Name: 6-chloranyl-3-[[(1R)-1-[2-(1,3-dihydropyrrolo[3,4-c]pyridin-2-yl)-3,6-dimethyl-4-oxidanylidene-quinazolin-8-yl]ethyl]amino]pyridine-2-carboxylic acid type: ligand / ID: 3 / Number of copies: 1 / Formula: UEX |
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Molecular weight | Theoretical: 490.942 Da |
-Macromolecule #4: water
Macromolecule | Name: water / type: ligand / ID: 4 / Number of copies: 2 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 8 |
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Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 54.2 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 1.3 µm / Nominal defocus min: 0.9 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |