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- EMDB-34272: Cryo-EM structure of cancer-specific PI3Kalpha mutant H1047R in c... -

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Basic information

Entry
Database: EMDB / ID: EMD-34272
TitleCryo-EM structure of cancer-specific PI3Kalpha mutant H1047R in complex with BYL-719
Map data
Sample
  • Complex: Human PI3Kalpha mutant H1047R in complex with BYL-719
    • Protein or peptide: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
    • Protein or peptide: Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Ligand: (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
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
PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain ...PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / PI3-kinase family, Ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain / PI3-kinase family, ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain profile. / Phosphoinositide 3-kinase C2 / Phosphoinositide 3-kinase, region postulated to contain C2 domain / C2 phosphatidylinositol 3-kinase-type domain / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Rho GTPase activation protein / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / C2 domain superfamily / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Phosphatidylinositol 3-kinase regulatory subunit alpha / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.73 Å
AuthorsLiu X / Zhou Q / Hart JR / Xu Y / Yang S / Yang D / Vogt PK / Wang M-W
Funding support China, United States, 13 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81872915 China
National Natural Science Foundation of China (NSFC)82073904 China
National Natural Science Foundation of China (NSFC)82121005 China
National Natural Science Foundation of China (NSFC)81973373 China
National Natural Science Foundation of China (NSFC)21704064 China
Other government2018ZX09735-001
Other government2018ZX09711002-002-005
Other government2021ZD0203400
Other government2018YFA0507000
Other governmentZDKJ2021028
Other privateNNCAS-2017-1-CC
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 CA197582 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R50 CA243899 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
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
DepositionSep 11, 2022-
Header (metadata) releaseNov 23, 2022-
Map releaseNov 23, 2022-
UpdateNov 23, 2022-
Current statusNov 23, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34272.png

Downloads & links

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Map

FileDownload / File: emd_34272.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.071 Å
Density
Contour LevelBy AUTHOR: 0.136
Minimum - Maximum-1.922759 - 2.7782829
Average (Standard dev.)-0.00021614318 (±0.051497024)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 274.176 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_34272_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_34272_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Human PI3Kalpha mutant H1047R in complex with BYL-719

EntireName: Human PI3Kalpha mutant H1047R in complex with BYL-719
Components
  • Complex: Human PI3Kalpha mutant H1047R in complex with BYL-719
    • Protein or peptide: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
    • Protein or peptide: Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Ligand: (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

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Supramolecule #1: Human PI3Kalpha mutant H1047R in complex with BYL-719

SupramoleculeName: Human PI3Kalpha mutant H1047R in complex with BYL-719 / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper) / Recombinant strain: Sf-9

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Macromolecule #1: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit ...

MacromoleculeName: 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127.841625 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: 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

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Macromolecule #2: Phosphatidylinositol 3-kinase regulatory subunit alpha

MacromoleculeName: Phosphatidylinositol 3-kinase regulatory subunit alpha
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 83.623203 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: 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

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Macromolecule #3: (2S)-N~1~-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyr...

MacromoleculeName: (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 weightTheoretical: 441.47 Da
Chemical component information

ChemComp-1LT:
(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 / medication*YM / Alpelisib

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.0 mg/mL
BufferpH: 7.6
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: OTHER
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Image recordingFilm 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

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Image processing

Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.73 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 306201
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7myn

RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 89.2 / Target criteria: Correlation coefficient
Output model

PDB-8gub:
Cryo-EM structure of cancer-specific PI3Kalpha mutant H1047R in complex with BYL-719

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