+Open data
-Basic information
Entry | Database: PDB / ID: 7d43 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | eIF2B-eIF2(aP), aPg complex | |||||||||
Components |
| |||||||||
Keywords | TRANSLATION / Complex / Translational control | |||||||||
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 | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å | |||||||||
Authors | Kashiwagi, K. / Ito, T. | |||||||||
Funding support | Japan, 2items
| |||||||||
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 |
|
-Structure visualization
Movie |
Movie viewer |
---|---|
Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7d43.cif.gz | 725 KB | Display | PDBx/mmCIF format |
---|---|---|---|---|
PDB format | pdb7d43.ent.gz | 581.7 KB | Display | PDB format |
PDBx/mmJSON format | 7d43.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7d43_validation.pdf.gz | 810.6 KB | Display | wwPDB validaton report |
---|---|---|---|---|
Full document | 7d43_full_validation.pdf.gz | 942.6 KB | Display | |
Data in XML | 7d43_validation.xml.gz | 120.7 KB | Display | |
Data in CIF | 7d43_validation.cif.gz | 189.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/d4/7d43 ftp://data.pdbj.org/pub/pdb/validation_reports/d4/7d43 | HTTPS FTP |
-Related structure data
Related structure data | 30568MC 7d44C 7d45C 7d46C M: map data used to model this data C: citing same article (ref.) |
---|---|
Similar structure data |
-Links
-Assembly
Deposited unit |
|
---|---|
1 |
|
-Components
-Translation initiation factor eIF-2B subunit ... , 5 types, 10 molecules ABCDEFGHIJ
#1: Protein | Mass: 33754.148 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B1, EIF2BA / Production host: Escherichia coli (E. coli) / References: UniProt: Q14232 #2: Protein | Mass: 39039.547 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B2, EIF2BB / Production host: Escherichia coli (E. coli) / References: UniProt: P49770 #3: Protein | Mass: 50304.230 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9NR50 #4: Protein | Mass: 57640.168 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B4, EIF2BD / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UI10 #5: Protein | Mass: 80466.609 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B5, EIF2BE / Production host: Escherichia coli (E. coli) / References: UniProt: Q13144 |
---|
-Eukaryotic translation initiation factor 2 subunit ... , 3 types, 4 molecules KLMP
#6: Protein | Mass: 36241.156 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2S1, EIF2A / Production host: Homo sapiens (human) / References: UniProt: P05198 #7: Protein | | Mass: 38454.484 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2S2, EIF2B / Production host: Homo sapiens (human) / References: UniProt: P20042 #8: Protein | | Mass: 51178.406 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2S3, EIF2G / Production host: Homo sapiens (human) / References: UniProt: P41091, protein-synthesizing GTPase |
---|
-Details
Has ligand of interest | N |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component |
| ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Source (natural) |
| ||||||||||||||||||||||||
Source (recombinant) |
| ||||||||||||||||||||||||
Buffer solution | pH: 7.5 | ||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TECNAI ARCTICA |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.17.1_3660: / Classification: refinement | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTF correction | Type: PHASE FLIPPING ONLY | ||||||||||||||||||||||||
3D reconstruction | Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 66721 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
|