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- EMDB-37363: CryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-85... -

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Basic information

Entry
Database: EMDB / ID: EMD-37363
TitleCryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an allosteric site
Map dataCryoEM density map of human PI3K-alpha (P85/P110-H1047R) with Cpd2 binding at an unidentified allosteric site
Sample
  • Complex: human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an allosteric site
    • Protein or peptide: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
    • Protein or peptide: Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Ligand: 1-[(1S)-1-(5-fluoranyl-3-methyl-1-benzofuran-2-yl)-2-methyl-propyl]-3-(1-oxidanylidene-2,3-dihydroisoindol-5-yl)urea
KeywordsPI3K-alpha / lipid kinase / allosteric inhibition / ONCOPROTEIN
Function / homology
Function and homology information


perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / negative regulation of actin filament depolymerization / phosphatidylinositol kinase activity / response to L-leucine / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling ...perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / negative regulation of actin filament depolymerization / phosphatidylinositol kinase activity / response to L-leucine / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling / positive regulation of focal adhesion disassembly / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase activator activity / autosome genomic imprinting / 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 / negative regulation of fibroblast apoptotic process / cis-Golgi network / ErbB-3 class receptor binding / kinase activator activity / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / RHOF GTPase cycle / regulation of cellular respiration / Signaling by cytosolic FGFR1 fusion mutants / positive regulation of endoplasmic reticulum unfolded protein response / RHOD GTPase cycle / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / enzyme-substrate adaptor activity / Nephrin family interactions / anoikis / Signaling by LTK in cancer / Costimulation by the CD28 family / RND1 GTPase cycle / Signaling by LTK / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / relaxation of cardiac muscle / MET activates PI3K/AKT signaling / positive regulation of leukocyte migration / PI3K/AKT activation / RND2 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / positive regulation of filopodium assembly / RND3 GTPase cycle / growth hormone receptor signaling pathway / vascular endothelial growth factor signaling pathway / negative regulation of stress fiber assembly / phosphatidylinositol 3-kinase / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / natural killer cell mediated cytotoxicity / 1-phosphatidylinositol-3-kinase activity / RHOV GTPase cycle / negative regulation of cell-matrix adhesion / Signaling by ALK / negative regulation of macroautophagy / RHOB GTPase cycle / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR2 / protein kinase activator activity / PI-3K cascade:FGFR4 / response to dexamethasone / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / intracellular glucose homeostasis / negative regulation of osteoclast differentiation / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / CD28 dependent PI3K/Akt signaling / RHOU GTPase cycle / CDC42 GTPase cycle / PI3K events in ERBB2 signaling / negative regulation of anoikis / RET signaling / intercalated disc / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / T cell differentiation / RHOG GTPase cycle / PI3K Cascade / regulation of multicellular organism growth / extrinsic apoptotic signaling pathway via death domain receptors / endothelial cell migration / positive regulation of TOR signaling / RHOA 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. / 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 / Rho GTPase activation protein / 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: 3.0 Å
AuthorsHuang X / Ren X / Zhong W
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: 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
DepositionSep 5, 2023-
Header (metadata) releaseApr 17, 2024-
Map releaseApr 17, 2024-
UpdateJul 24, 2024-
Current statusJul 24, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_37363.png

Downloads & links

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Map

FileDownload / File: emd_37363.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM density map of human PI3K-alpha (P85/P110-H1047R) with Cpd2 binding at an unidentified allosteric site
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 256 pix.
= 189.44 Å		0.74 Å/pix.
x 256 pix.
= 189.44 Å		0.74 Å/pix.
x 256 pix.
= 189.44 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.74 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0101
Minimum - Maximum-0.04682459 - 0.0741632
Average (Standard dev.)-0.000042731906 (±0.002505825)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 189.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map 1 of Cpd2-bound human PI3K-alpha (P85/P110-H1047R)

Fileemd_37363_half_map_1.map
AnnotationHalf map 1 of Cpd2-bound human PI3K-alpha (P85/P110-H1047R)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2 of Cpd2-bound human PI3K-alpha (P85/P110-H1047R)

Fileemd_37363_half_map_2.map
AnnotationHalf map 2 of Cpd2-bound human PI3K-alpha (P85/P110-H1047R)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an all...

EntireName: human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an allosteric site
Components
  • Complex: human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an allosteric site
    • Protein or peptide: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
    • Protein or peptide: Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Ligand: 1-[(1S)-1-(5-fluoranyl-3-methyl-1-benzofuran-2-yl)-2-methyl-propyl]-3-(1-oxidanylidene-2,3-dihydroisoindol-5-yl)urea

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Supramolecule #1: human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an all...

SupramoleculeName: human PI3K-alpha (P85/P110-H1047R) with QR-8557 binding at an allosteric site
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: 124.23075 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: 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

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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: 33.666961 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: 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

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Macromolecule #3: 1-[(1S)-1-(5-fluoranyl-3-methyl-1-benzofuran-2-yl)-2-methyl-propy...

MacromoleculeName: 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
Molecular weightTheoretical: 395.427 Da

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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: 8
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 48.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 1.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

34272

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 326253
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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