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- EMDB-63457: Cryo-EM structure of PI3Kalpha H1047R in complex with compound UC... -

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Basic information

Entry
Database: EMDB / ID: EMD-63457
TitleCryo-EM structure of PI3Kalpha H1047R in complex with compound UCL-TRO-1938
Map data
Sample
  • Complex: Human PI3Kalpha H1047R in complex with 1938
    • Protein or peptide: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
    • Protein or peptide: Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Ligand: water
KeywordsPhosphoinositide 3-kinase / drug target / activator / allosteric binding pocket / CYTOSOLIC PROTEIN
Function / homology
Function and homology information


perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / phosphatidylinositol kinase activity / regulation of actin filament organization / negative regulation of actin filament depolymerization / response to L-leucine / positive regulation of focal adhesion disassembly / response to butyrate / 1-phosphatidylinositol-3-kinase regulator activity ...perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / phosphatidylinositol kinase activity / regulation of actin filament organization / negative regulation of actin filament depolymerization / response to L-leucine / positive regulation of focal adhesion disassembly / response to butyrate / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / IRS-mediated signalling / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / T follicular helper cell differentiation / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / autosome genomic imprinting / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase regulatory subunit binding / myeloid leukocyte migration / regulation of cellular respiration / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / cis-Golgi network / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / transmembrane receptor protein tyrosine kinase adaptor activity / ErbB-3 class receptor binding / phosphatidylinositol 3-kinase complex, class IB / positive regulation of protein localization to membrane / vasculature development / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by cytosolic FGFR1 fusion mutants / Co-stimulation by ICOS / RHOD GTPase cycle / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / Nephrin family interactions / RHOF GTPase cycle / kinase activator activity / Signaling by LTK in cancer / anoikis / phosphatidylinositol-3-phosphate biosynthetic process / positive regulation of leukocyte migration / relaxation of cardiac muscle / Signaling by LTK / MET activates PI3K/AKT signaling / PI3K/AKT activation / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / negative regulation of stress fiber assembly / RND1 GTPase cycle / positive regulation of filopodium assembly / phosphatidylinositol-4,5-bisphosphate 3-kinase / RND2 GTPase cycle / vascular endothelial growth factor signaling pathway / RND3 GTPase cycle / phosphatidylinositol 3-kinase / growth hormone receptor signaling pathway / insulin binding / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / RHOB GTPase cycle / RHOV GTPase cycle / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / GP1b-IX-V activation signalling / natural killer cell mediated cytotoxicity / negative regulation of macroautophagy / PI-3K cascade:FGFR2 / response to dexamethasone / PI-3K cascade:FGFR4 / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / intracellular glucose homeostasis / negative regulation of osteoclast differentiation / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / RHOU GTPase cycle / CDC42 GTPase cycle / RET signaling / negative regulation of anoikis / PI3K events in ERBB2 signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / insulin receptor substrate binding / intercalated disc / T cell differentiation / RHOG GTPase cycle / extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of cell-matrix adhesion / regulation of multicellular organism growth / RHOA GTPase cycle / protein kinase activator activity / CD28 dependent PI3K/Akt signaling / Role of LAT2/NTAL/LAB on calcium mobilization / RAC2 GTPase cycle
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. / Rho GTPase activation protein / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / 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: 3.3 Å
AuthorsLiu X / Zhou Q
Funding support China, 5 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82273961 China
National Natural Science Foundation of China (NSFC)82073904 China
National Science Foundation (NSF, China)81872915 China
Other government2021ZD0203400
Other governmentZDKJ2021028
CitationJournal: Cell Discov / Year: 2025
Title: Molecular mechanisms of PI3Kα activation by small-molecule activator 1938 and cancer-specific mutation H1047R.
Authors: Xiao Liu / Qingtong Zhou / Yanyan Chen / Wei Han / Jie Li / Yiting Mai / Ming-Wei Wang /
History
DepositionFeb 16, 2025-
Header (metadata) releaseOct 1, 2025-
Map releaseOct 1, 2025-
UpdateOct 1, 2025-
Current statusOct 1, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63457.png

Downloads & links

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Map

FileDownload / File: emd_63457.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 274.176 Å		1.07 Å/pix.
x 256 pix.
= 274.176 Å		1.07 Å/pix.
x 256 pix.
= 274.176 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.071 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-1.6558502 - 2.4281585
Average (Standard dev.)-0.0007933335 (±0.03870363)
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: #1

Fileemd_63457_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_63457_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 H1047R in complex with 1938

EntireName: Human PI3Kalpha H1047R in complex with 1938
Components
  • Complex: Human PI3Kalpha H1047R in complex with 1938
    • Protein or peptide: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
    • Protein or peptide: Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Ligand: water

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Supramolecule #1: Human PI3Kalpha H1047R in complex with 1938

SupramoleculeName: Human PI3Kalpha H1047R in complex with 1938 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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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

UniProtKB: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

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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

UniProtKB: Phosphatidylinositol 3-kinase regulatory subunit alpha

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Macromolecule #3: water

MacromoleculeName: water / type: ligand / ID: 3 / Number of copies: 8 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

BufferpH: 7.6
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: OTHER
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 440046
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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