[English] 日本語
Yorodumi
- EMDB-37363: CryoEM structure of human PI3K-alpha (P85/P110-H1047R) with QR-85... -

+
Open data


ID or keywords:

Loading...

-
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 / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / 1-phosphatidylinositol-3-kinase regulator activity / T follicular helper cell differentiation / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol kinase activity / regulation of actin filament organization / negative regulation of actin filament depolymerization / phosphatidylinositol 3-kinase activator activity ...perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / response to muscle inactivity / 1-phosphatidylinositol-3-kinase regulator activity / T follicular helper cell differentiation / positive regulation of endoplasmic reticulum unfolded protein response / phosphatidylinositol kinase activity / regulation of actin filament organization / negative regulation of actin filament depolymerization / phosphatidylinositol 3-kinase activator activity / phosphatidylinositol 3-kinase regulator activity / response to butyrate / IRS-mediated signalling / interleukin-18-mediated signaling pathway / phosphatidylinositol 3-kinase regulatory subunit binding / PI3K events in ERBB4 signaling / neurotrophin TRKA receptor binding / response to L-leucine / positive regulation of focal adhesion disassembly / cellular response to hydrostatic pressure / Activated NTRK2 signals through PI3K / cis-Golgi network / ErbB-3 class receptor binding / transmembrane receptor protein tyrosine kinase adaptor activity / negative regulation of stress fiber assembly / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex, class IB / phosphatidylinositol 3-kinase complex / TORC2 signaling / Co-stimulation by ICOS / RHOD GTPase cycle / positive regulation of protein localization to membrane / Signaling by cytosolic FGFR1 fusion mutants / vasculature development / Nephrin family interactions / positive regulation of filopodium assembly / anoikis / kinase activator activity / Signaling by LTK in cancer / RHOF GTPase cycle / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by LTK / RND1 GTPase cycle / phosphatidylinositol 3-kinase complex, class IA / RND2 GTPase cycle / MET activates PI3K/AKT signaling / PI3K/AKT activation / RND3 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / natural killer cell mediated cytotoxicity / growth hormone receptor signaling pathway / relaxation of cardiac muscle / insulin binding / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by ALK / cardiac muscle cell contraction / RHOV GTPase cycle / RHOB GTPase cycle / vascular endothelial growth factor signaling pathway / GP1b-IX-V activation signalling / 1-phosphatidylinositol-3-kinase activity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR3 / response to dexamethasone / negative regulation of macroautophagy / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / positive regulation of protein kinase activity / RHOU GTPase cycle / response to muscle stretch / phosphatidylinositol-mediated signaling / CDC42 GTPase cycle / RET signaling / negative regulation of anoikis / T cell differentiation / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K events in ERBB2 signaling / RHOG GTPase cycle / insulin receptor substrate binding / PI3K Cascade / Role of LAT2/NTAL/LAB on calcium mobilization / RAC3 GTPase cycle / RHOA GTPase cycle / CD28 dependent PI3K/Akt signaling / intercalated disc / RAC2 GTPase cycle / Interleukin receptor SHC signaling / positive regulation of TOR signaling / Role of phospholipids in phagocytosis / GAB1 signalosome / endothelial cell migration / enzyme-substrate adaptor activity / substrate adhesion-dependent cell spreading
Similarity search - Function
Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3Kalpha, catalytic 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 ...Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3Kalpha, catalytic 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: 3.0 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

-
Structure visualization

Supplemental images

emd_37363.png

Downloads & links

-
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 °

-
Supplemental data

-
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)

-
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)

-
Sample components

-
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

-
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)

-
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

-
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

-
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

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

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

-
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

+
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)

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more