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- EMDB-49119: PROTAC-induced IRE1 ternary complex -

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Basic information

Entry
Database: EMDB / ID: EMD-49119
TitlePROTAC-induced IRE1 ternary complex
Map data
Sample
  • Complex: IRE1:G6374:VHL:Eloc:Elob
    • Protein or peptide: Serine/threonine-protein kinase/endoribonuclease IRE1
    • Protein or peptide: von Hippel-Lindau disease tumor suppressor
    • Protein or peptide: Elongin-C
  • Protein or peptide: Elongin-B peptide
  • Ligand: 3-methyl-N-(5-{4-[(1r,4S)-4-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}cyclohexyl]piperazin-1-yl}pentanoyl)-L-valyl-(4R)-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-L-prolinamide
  • Ligand: water
KeywordsComplex / degrader / TRANSFERASE
Function / homology
Function and homology information


peptidyl-serine trans-autophosphorylation / mRNA splicing, via endonucleolytic cleavage and ligation / AIP1-IRE1 complex / Ire1 complex / IRE1alpha activates chaperones / IRE1-TRAF2-ASK1 complex / insulin metabolic process / positive regulation of endoplasmic reticulum unfolded protein response / regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle ...peptidyl-serine trans-autophosphorylation / mRNA splicing, via endonucleolytic cleavage and ligation / AIP1-IRE1 complex / Ire1 complex / IRE1alpha activates chaperones / IRE1-TRAF2-ASK1 complex / insulin metabolic process / positive regulation of endoplasmic reticulum unfolded protein response / regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / target-directed miRNA degradation / elongin complex / IRE1-RACK1-PP2A complex / platelet-derived growth factor receptor binding / nuclear inner membrane / endothelial cell proliferation / Hydrolases; Acting on ester bonds; Endoribonucleases producing 5'-phosphomonoesters / Replication of the SARS-CoV-1 genome / VCB complex / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / intracellular membraneless organelle / IRE1-mediated unfolded protein response / SUMOylation of ubiquitinylation proteins / mRNA catabolic process / positive regulation of JUN kinase activity / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / negative regulation of transcription elongation by RNA polymerase II / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to vascular endothelial growth factor stimulus / cellular response to unfolded protein / regulation of macroautophagy / negative regulation of signal transduction / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / ubiquitin-like ligase-substrate adaptor activity / Formation of HIV elongation complex in the absence of HIV Tat / positive regulation of vascular associated smooth muscle cell proliferation / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / negative regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / Hsp70 protein binding / RNA endonuclease activity / protein serine/threonine kinase binding / negative regulation of autophagy / response to endoplasmic reticulum stress / positive regulation of RNA splicing / transcription corepressor binding / positive regulation of cell differentiation / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / cellular response to glucose stimulus / transcription elongation by RNA polymerase II / Hsp90 protein binding / Vif-mediated degradation of APOBEC3G / Inactivation of CSF3 (G-CSF) signaling / ADP binding / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Evasion by RSV of host interferon responses / Regulation of expression of SLITs and ROBOs / cellular response to hydrogen peroxide / cell morphogenesis / ubiquitin-protein transferase activity / transcription corepressor activity / unfolded protein binding / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / microtubule cytoskeleton / regulation of gene expression / protein-containing complex assembly / Replication of the SARS-CoV-2 genome / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / cellular response to hypoxia / DNA-binding transcription factor binding / molecular adaptor activity / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / protein phosphorylation / non-specific serine/threonine protein kinase / protein stabilization / protein ubiquitination / cilium / negative regulation of cell population proliferation / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / endoplasmic reticulum membrane / negative regulation of apoptotic process / positive regulation of DNA-templated transcription
Similarity search - Function
Serine/threonine-protein kinase/endoribonuclease IRE1/2-like / KEN domain / KEN domain superfamily / Ribonuclease 2-5A / KEN domain profile. / domain in protein kinases, N-glycanases and other nuclear proteins / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily ...Serine/threonine-protein kinase/endoribonuclease IRE1/2-like / KEN domain / KEN domain superfamily / Ribonuclease 2-5A / KEN domain profile. / domain in protein kinases, N-glycanases and other nuclear proteins / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Pyrrolo-quinoline quinone beta-propeller repeat / beta-propeller repeat / Elongin-C / Elongin B / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / Quinoprotein alcohol dehydrogenase-like superfamily / SKP1/BTB/POZ domain superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Serine/threonine-protein kinase/endoribonuclease IRE1 / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsDu J / Johnson M / Azumaya C / Rohou A / Hsu PL / Ashkenazi A
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
CitationJournal: To Be Published
Title: PROTAC-induced IRE1 ternary complex
Authors: Du J / Johnson M / Azumaya C / Rohou A / Hsu PL / Ashkenazi A
History
DepositionFeb 7, 2025-
Header (metadata) releaseNov 5, 2025-
Map releaseNov 5, 2025-
UpdateNov 5, 2025-
Current statusNov 5, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49119.png

Downloads & links

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Map

FileDownload / File: emd_49119.map.gz / Format: CCP4 / Size: 259.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 408 pix.
= 298.248 Å		0.73 Å/pix.
x 408 pix.
= 298.248 Å		0.73 Å/pix.
x 408 pix.
= 298.248 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.731 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.0645948 - 0.1749696
Average (Standard dev.)-0.00004245554 (±0.0029520201)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions408408408
Spacing408408408
CellA=B=C: 298.24802 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_49119_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_49119_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : IRE1:G6374:VHL:Eloc:Elob

EntireName: IRE1:G6374:VHL:Eloc:Elob
Components
  • Complex: IRE1:G6374:VHL:Eloc:Elob
    • Protein or peptide: Serine/threonine-protein kinase/endoribonuclease IRE1
    • Protein or peptide: von Hippel-Lindau disease tumor suppressor
    • Protein or peptide: Elongin-C
  • Protein or peptide: Elongin-B peptide
  • Ligand: 3-methyl-N-(5-{4-[(1r,4S)-4-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}cyclohexyl]piperazin-1-yl}pentanoyl)-L-valyl-(4R)-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-L-prolinamide
  • Ligand: water

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Supramolecule #1: IRE1:G6374:VHL:Eloc:Elob

SupramoleculeName: IRE1:G6374:VHL:Eloc:Elob / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: G6374 is the PROTAC that recruits VHL to IRE1. IRE1 is recombinantly expressed and purified from Sf9 cells, VHL is co-expressed and co-purified with Eloc and Elob in BL21 cells. The complex ...Details: G6374 is the PROTAC that recruits VHL to IRE1. IRE1 is recombinantly expressed and purified from Sf9 cells, VHL is co-expressed and co-purified with Eloc and Elob in BL21 cells. The complex was formed by adding each component in vitro. Because the EloB density had insufficient quality for de novo modeling, we built only residues 68 to 73 into the structure.
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Serine/threonine-protein kinase/endoribonuclease IRE1

MacromoleculeName: Serine/threonine-protein kinase/endoribonuclease IRE1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.329266 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: VVIVGKISFC PKDVLGHGAE GTIVYRGMFD NRDVAVKRIL PECFSFADRE VQLLRESDEH PNVIRYFCTE KDRQFQYIAI ELCAATLQE YVEQKDFAHL GLEPITLLQQ TTSGLAHLHS LNIVHRDLKP HNILISMPNA HGKIKAMISD FGLCKKLAVG R HSFSRRSG ...String:
VVIVGKISFC PKDVLGHGAE GTIVYRGMFD NRDVAVKRIL PECFSFADRE VQLLRESDEH PNVIRYFCTE KDRQFQYIAI ELCAATLQE YVEQKDFAHL GLEPITLLQQ TTSGLAHLHS LNIVHRDLKP HNILISMPNA HGKIKAMISD FGLCKKLAVG R HSFSRRSG VPGTEGWIAP EMLSEDCKEN PTYTVDIFSA GCVFYYVISE GSHPFGKSLQ RQANILLGAC SLDCLHPEKH ED VIARELI EKMIAMDPQK RPSAKHVLKH PFFWSLEKQL QFFQDVSDRI EKESLDGPIV KQLERGGRAV VKMDWRENIT VPL QTDLRK FRTYKGGSVR DLLRAMRNKK HHYRELPAEV RETLGSLPDD FVCYFTSRFP HLLAHTYRAM ELCSHERLFQ PYYF HE

UniProtKB: Serine/threonine-protein kinase/endoribonuclease IRE1

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Macromolecule #2: von Hippel-Lindau disease tumor suppressor

MacromoleculeName: von Hippel-Lindau disease tumor suppressor / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.031412 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
PVLRSVNSRE PSQVIFCNRS PRVVLPVWLN FDGEPQPYPT LPPGTGRRIH SYRGHLWLFR DAGTHDGLLV NQTELFVPSL NVDGQPIFA NITLPVYTLK ERCLQVVRSL VKPENYRRLD IVRSLYEDLE DHPNVQKDLE RLTQERIA

UniProtKB: von Hippel-Lindau disease tumor suppressor

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Macromolecule #3: Elongin-C

MacromoleculeName: Elongin-C / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.62519 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MYVKLISSDG HEFIVKREHA LTSGTIKAML SGPGQFAENE TNEVNFREIP SHVLSKVCMY FTYKVRYTNS STEIPEFPIA PEIALELLM AANFL

UniProtKB: Elongin-C

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Macromolecule #4: Elongin-B peptide

MacromoleculeName: Elongin-B peptide / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 639.723 Da
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
RPQAPA

UniProtKB: Elongin-B

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Macromolecule #5: 3-methyl-N-(5-{4-[(1r,4S)-4-{[7-oxo-8-(propan-2-yl)-7,8-dihydropy...

MacromoleculeName: 3-methyl-N-(5-{4-[(1r,4S)-4-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}cyclohexyl]piperazin-1-yl}pentanoyl)-L-valyl-(4R)-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl) ...Name: 3-methyl-N-(5-{4-[(1r,4S)-4-{[7-oxo-8-(propan-2-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}cyclohexyl]piperazin-1-yl}pentanoyl)-L-valyl-(4R)-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-L-prolinamide
type: ligand / ID: 5 / Number of copies: 2 / Formula: A1BWF
Molecular weightTheoretical: 883.156 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 6 / 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

Concentration0.15 mg/mL
BufferpH: 7.2
Component:
ConcentrationFormulaName
20.0 mMHEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
150.0 mMNaClsodium chloride
1.0 mMTCEPtris(2-carboxyethyl)phosphine
0.005 %CTABcetrimonium bromide

Details: I used 0.5 mM BS3 for crosslinking the protein complex, then diluted it to 0.05 mM for grid preparation.
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 2.5
Details: The grid was coated with a hydrophilic self-assembled PEG monolayer to improve particle distribution.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV / Details: 7 force; 2 s blot time..
DetailsGot monodispersed particles on the grid.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number real images: 12400 / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.5 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 5101645
CTF correctionSoftware - Name: cryoSPARC (ver. 4.6) / Type: PHASE FLIPPING ONLY
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6w3b


Details: I have used 2 PDB entries to build the model: 6W3B 5T35
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6) / Number images used: 400055
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: cryoSPARC (ver. 4.6)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6)
FSC plot (resolution estimation)

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