[English] 日本語

- EMDB-34272: Cryo-EM structure of cancer-specific PI3Kalpha mutant H1047R in c... -
+
Open data
-
Basic information
Entry | ![]() | ||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of cancer-specific PI3Kalpha mutant H1047R in complex with BYL-719 | ||||||||||||||||||||||||||||||||||||||||||
![]() | |||||||||||||||||||||||||||||||||||||||||||
![]() |
| ||||||||||||||||||||||||||||||||||||||||||
Function / homology | ![]() response to muscle inactivity / negative regulation of actin filament depolymerization / positive regulation of gene expression via CpG island demethylation / insulin receptor signaling pathway via phosphatidylinositol 3-kinase / perinuclear endoplasmic reticulum membrane / regulation of actin filament organization / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||||||||||||||||||||||||||||||||||||||
Biological species | ![]() ![]() | ||||||||||||||||||||||||||||||||||||||||||
Method | ![]() ![]() | ||||||||||||||||||||||||||||||||||||||||||
![]() | Liu X / Zhou Q / Hart JR / Xu Y / Yang S / Yang D / Vogt PK / Wang M-W | ||||||||||||||||||||||||||||||||||||||||||
Funding support | ![]() ![]()
| ||||||||||||||||||||||||||||||||||||||||||
![]() | ![]() Title: Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3Kα. Authors: Xiao Liu / Qingtong Zhou / Jonathan R Hart / Yingna Xu / Su Yang / Dehua Yang / Peter K Vogt / Ming-Wei Wang / ![]() ![]() ![]() Abstract: Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that perform multiple and important cellular functions. The protein investigated here belongs to class IA of the PI3Ks; it is a dimer ...Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that perform multiple and important cellular functions. The protein investigated here belongs to class IA of the PI3Ks; it is a dimer consisting of a catalytic subunit, p110α, and a regulatory subunit, p85α, and is referred to as PI3Kα. The catalytic subunit p110α is frequently mutated in cancer. The mutations induce a gain of function and constitute a driving force in cancer development. About 80% of these mutations lead to single-amino-acid substitutions in one of three sites of p110α: two in the helical domain of the protein (E542K and E545K) and one at the C-terminus of the kinase domain (H1047R). Here, we report the cryo-electron microscopy structures of these mutants in complex with the p110α-specific inhibitor BYL-719. The H1047R mutant rotates its sidechain to a new position and weakens the kα11 activation loop interaction, thereby reducing the inhibitory effect of p85α on p110α. E542K and E545K completely abolish the tight interaction between the helical domain of p110α and the N-terminal SH2 domain of p85α and lead to the disruption of all p85α binding and a dramatic increase in flexibility of the adaptor-binding domain (ABD) in p110α. Yet, the dimerization of PI3Kα is preserved through the ABD-p85α interaction. The local and global structural features induced by these mutations provide molecular insights into the activation of PI3Kα, deepen our understanding of the oncogenic mechanism of this important signaling molecule, and may facilitate the development of mutant-specific inhibitors. | ||||||||||||||||||||||||||||||||||||||||||
History |
|
-
Structure visualization
Supplemental images |
---|
-
Downloads & links
-EMDB archive
Map data | ![]() | 59.6 MB | ![]() | |
---|---|---|---|---|
Header (meta data) | ![]() ![]() | 19.9 KB 19.9 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 9.1 KB | Display | ![]() |
Images | ![]() | 96.3 KB | ||
Others | ![]() ![]() | 59.4 MB 59.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 685.2 KB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 684.8 KB | Display | |
Data in XML | ![]() | 16.3 KB | Display | |
Data in CIF | ![]() | 21.5 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8gubMC ![]() 8guaC ![]() 8gudC M: atomic model generated by this map C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
EMDB pages | ![]() ![]() |
---|---|
Related items in Molecule of the Month |
-
Map
File | ![]() | ||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.071 Å | ||||||||||||||||||||||||||||||||||||
Density |
| ||||||||||||||||||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
|
-Supplemental data
-Half map: #2
File | emd_34272_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: #1
File | emd_34272_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-
Sample components
-Entire : Human PI3Kalpha mutant H1047R in complex with BYL-719
Entire | Name: Human PI3Kalpha mutant H1047R in complex with BYL-719 |
---|---|
Components |
|
-Supramolecule #1: Human PI3Kalpha mutant H1047R in complex with BYL-719
Supramolecule | Name: Human PI3Kalpha mutant H1047R in complex with BYL-719 / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
---|---|
Source (natural) | Organism: ![]() ![]() |
Recombinant expression | 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: ![]() |
---|---|
Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 127.841625 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MSYYHHHHHH DYDIPTTENL YFQGAMGSMP PRPSSGELWG IHLMPPRILV ECLLPNGMIV TLECLREATL ITIKHELFKE ARKYPLHQL LQDESSYIFV SVTQEAEREE FFDETRRLCD LRLFQPFLKV IEPVGNREEK ILNREIGFAI GMPVCEFDMV K DPEVQDFR ...String: MSYYHHHHHH DYDIPTTENL YFQGAMGSMP PRPSSGELWG IHLMPPRILV ECLLPNGMIV TLECLREATL ITIKHELFKE ARKYPLHQL LQDESSYIFV SVTQEAEREE FFDETRRLCD LRLFQPFLKV IEPVGNREEK ILNREIGFAI GMPVCEFDMV K DPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK IN HDCVPEQ VIAEAIRKKT RSMLLSSEQL KLCVLEYQGK YILKVCGCDE YFLEKYPLSQ YKYIRSCIML GRMPNLMLMA KES LYSQLP MDCFTMPSYS RRISTATPYM NGETSTKSLW VINSALRIKI LCATYVNVNI RDIDKIYVRT GIYHGGEPLC DNVN TQRVP CSNPRWNEWL NYDIYIPDLP RAARLCLSIC SVKGRKGAKE EHCPLAWGNI NLFDYTDTLV SGKMALNLWP VPHGL EDLL NPIGVTGSNP NKETPCLELE FDWFSSVVKF PDMSVIEEHA NWSVSREAGF SYSHAGLSNR LARDNELREN DKEQLK AIS TRDPLSEITE QEKDFLWSHR HYCVTIPEIL PKLLLSVKWN SRDEVAQMYC LVKDWPPIKP EQAMELLDCN YPDPMVR GF AVRCLEKYLT DDKLSQYLIQ LVQVLKYEQY LDNLLVRFLL KKALTNQRIG HFFFWHLKSE MHNKTVSQRF GLLLESYC R ACGMYLKHLN RQVEAMEKLI NLTDILKQEK KDETQKVQMK FLVEQMRRPD FMDALQGFLS PLNPAHQLGN LRLEECRIM SSAKRPLWLN WENPDIMSEL LFQNNEIIFK NGDDLRQDML TLQIIRIMEN IWQNQGLDLR MLPYGCLSIG DCVGLIEVVR NSHTIMQIQ CKGGLKGALQ FNSHTLHQWL KDKNKGEIYD AAIDLFTRSC AGYCVATFIL GIGDRHNSNI MVKDDGQLFH I DFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PE LQSFDDI AYIRKTLALD KTEQEALEYF MKQMNDARHG GWTTKMDWIF HTIKQHALN |
-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 |
---|---|
Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 83.623203 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MAEGYQYRAL YDYKKEREED IDLHLGDILT VNKGSLVALG FSDGQEARPE EIGWLNGYNE TTGERGDFPG TYVEYIGRKK ISPPTPKPR PPRPLPVAPG SSKTEADVEQ QALTLPDLAE QFAPPDIAPP LLIKLVEAIE KKGLECSTLY RTQSSSNLAE L RQLLDCDT ...String: MAEGYQYRAL YDYKKEREED IDLHLGDILT VNKGSLVALG FSDGQEARPE EIGWLNGYNE TTGERGDFPG TYVEYIGRKK ISPPTPKPR PPRPLPVAPG SSKTEADVEQ QALTLPDLAE QFAPPDIAPP LLIKLVEAIE KKGLECSTLY RTQSSSNLAE L RQLLDCDT PSVDLEMIDV HVLADAFKRY LLDLPNPVIP AAVYSEMISL APEVQSSEEY IQLLKKLIRS PSIPHQYWLT LQ YLLKHFF KLSQTSSKNL LNARVLSEIF SPMLFRFSAA SSDNTENLIK VIEILISTEW NERQPAPALP PKPPKPTTVA NNG MNNNMS LQDAEWYWGD ISREEVNEKL RDTADGTFLV RDASTKMHGD YTLTLRKGGN NKLIKIFHRD GKYGFSDPLT FSSV VELIN HYRNESLAQY NPKLDVKLLY PVSKYQQDQV VKEDNIEAVG KKLHEYNTQF QEKSREYDRL YEEYTRTSQE IQMKR TAIE AFNETIKIFE EQCQTQERYS KEYIEKFKRE GNEKEIQRIM HNYDKLKSRI SEIIDSRRRL EEDLKKQAAE YREIDK RMN SIKPDLIQLR KTRDQYLMWL TQKGVRQKKL NEWLGNENTE DQYSLVEDDE DLPHHDEKTW NVGSSNRNKA ENLLRGK RD GTFLVRESSK QGCYACSVVV DGEVKHCVIN KTATGYGFAE PYNLYSSLKE LVLHYQHTSL VQHNDSLNVT LAYPVYAQ Q RR |
-Macromolecule #3: (2S)-N~1~-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyr...
Macromolecule | Name: (2S)-N~1~-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl}pyrrolidine-1,2-dicarboxamide type: ligand / ID: 3 / Number of copies: 1 / Formula: 1LT |
---|---|
Molecular weight | Theoretical: 441.47 Da |
Chemical component information | ![]() ChemComp-1LT: |
-Experimental details
-Structure determination
Method | ![]() |
---|---|
![]() | ![]() |
Aggregation state | particle |
-
Sample preparation
Concentration | 1.0 mg/mL |
---|---|
Buffer | pH: 7.6 |
Vitrification | Cryogen name: ETHANE |
-
Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Electron beam | Acceleration voltage: 300 kV / Electron source: OTHER |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number real images: 5881 / Average electron dose: 70.0 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |