+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-30568 | |||||||||
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Title | eIF2B-eIF2(aP), aPg complex | |||||||||
Map data | ||||||||||
Sample |
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Function / homology | Function and homology information male germ cell proliferation / regulation of translation in response to endoplasmic reticulum stress / translation initiation ternary complex / glial limiting end-foot / response to kainic acid / HRI-mediated signaling / Cellular response to mitochondrial stress / eukaryotic translation initiation factor 2B complex / response to manganese-induced endoplasmic reticulum stress / positive regulation of type B pancreatic cell apoptotic process ...male germ cell proliferation / regulation of translation in response to endoplasmic reticulum stress / translation initiation ternary complex / glial limiting end-foot / response to kainic acid / HRI-mediated signaling / Cellular response to mitochondrial stress / eukaryotic translation initiation factor 2B complex / response to manganese-induced endoplasmic reticulum stress / positive regulation of type B pancreatic cell apoptotic process / methionyl-initiator methionine tRNA binding / negative regulation of translational initiation in response to stress / Response of EIF2AK1 (HRI) to heme deficiency / Recycling of eIF2:GDP / PERK-mediated unfolded protein response / PERK regulates gene expression / eukaryotic translation initiation factor 2 complex / regulation of translational initiation in response to stress / protein-synthesizing GTPase / cytoplasmic translational initiation / translation factor activity, RNA binding / formation of translation preinitiation complex / oligodendrocyte development / guanyl-nucleotide exchange factor complex / astrocyte development / eukaryotic 48S preinitiation complex / astrocyte differentiation / regulation of translational initiation / Formation of the ternary complex, and subsequently, the 43S complex / Ribosomal scanning and start codon recognition / Translation initiation complex formation / Response of EIF2AK4 (GCN2) to amino acid deficiency / mitophagy / GTP hydrolysis and joining of the 60S ribosomal subunit / L13a-mediated translational silencing of Ceruloplasmin expression / positive regulation of translational initiation / response to glucose / stress granule assembly / ovarian follicle development / translation initiation factor binding / myelination / translation initiation factor activity / cellular response to amino acid starvation / response to endoplasmic reticulum stress / guanyl-nucleotide exchange factor activity / central nervous system development / translational initiation / hippocampus development / PKR-mediated signaling / ABC-family proteins mediated transport / response to peptide hormone / cytoplasmic stress granule / male gonad development / cellular response to UV / ribosome binding / regulation of translation / T cell receptor signaling pathway / cellular response to oxidative stress / cellular response to heat / response to heat / in utero embryonic development / cadherin binding / positive regulation of apoptotic process / GTPase activity / mRNA binding / synapse / GTP binding / mitochondrion / RNA binding / extracellular exosome / ATP binding / identical protein binding / membrane / nucleus / metal ion binding / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.3 Å | |||||||||
Authors | Kashiwagi K / Ito T | |||||||||
Funding support | Japan, 2 items
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Citation | Journal: Mol Cell / Year: 2021 Title: ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Authors: Alisa F Zyryanova / Kazuhiro Kashiwagi / Claudia Rato / Heather P Harding / Ana Crespillo-Casado / Luke A Perera / Ayako Sakamoto / Madoka Nishimoto / Mayumi Yonemochi / Mikako Shirouzu / ...Authors: Alisa F Zyryanova / Kazuhiro Kashiwagi / Claudia Rato / Heather P Harding / Ana Crespillo-Casado / Luke A Perera / Ayako Sakamoto / Madoka Nishimoto / Mayumi Yonemochi / Mikako Shirouzu / Takuhiro Ito / David Ron / Abstract: The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in ...The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(αP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_30568.map.gz | 7.1 MB | EMDB map data format | |
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Header (meta data) | emd-30568-v30.xml emd-30568.xml | 21.4 KB 21.4 KB | Display Display | EMDB header |
Images | emd_30568.png | 54.7 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-30568 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-30568 | HTTPS FTP |
-Validation report
Summary document | emd_30568_validation.pdf.gz | 328.5 KB | Display | EMDB validaton report |
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Full document | emd_30568_full_validation.pdf.gz | 328.1 KB | Display | |
Data in XML | emd_30568_validation.xml.gz | 6.4 KB | Display | |
Data in CIF | emd_30568_validation.cif.gz | 7.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-30568 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-30568 | HTTPS FTP |
-Related structure data
Related structure data | 7d43MC 7d44C 7d45C 7d46C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_30568.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 1.47 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
+Entire : Complex of eIF2B with eIF2(aP)
+Supramolecule #1: Complex of eIF2B with eIF2(aP)
+Supramolecule #2: eIF2B
+Supramolecule #3: eIF2(aP)
+Macromolecule #1: Translation initiation factor eIF-2B subunit alpha
+Macromolecule #2: Translation initiation factor eIF-2B subunit beta
+Macromolecule #3: Translation initiation factor eIF-2B subunit gamma
+Macromolecule #4: Translation initiation factor eIF-2B subunit delta
+Macromolecule #5: Translation initiation factor eIF-2B subunit epsilon
+Macromolecule #6: Eukaryotic translation initiation factor 2 subunit 1
+Macromolecule #7: Eukaryotic translation initiation factor 2 subunit 2
+Macromolecule #8: Eukaryotic translation initiation factor 2 subunit 3
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TECNAI ARCTICA |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 66721 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |