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- PDB-7d43: eIF2B-eIF2(aP), aPg complex -

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Basic information

Entry
Database: PDB / ID: 7d43
TitleeIF2B-eIF2(aP), aPg complex
Components
  • (Eukaryotic translation initiation factor 2 subunit ...) x 3
  • (Translation initiation factor eIF-2B subunit ...) x 5
KeywordsTRANSLATION / 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 / HRI-mediated signaling / response to kainic acid / 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 / HRI-mediated signaling / response to kainic acid / 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 / 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 / methionyl-initiator methionine tRNA binding / PERK regulates gene expression / regulation of translational initiation in response to stress / eukaryotic translation initiation factor 2 complex / cytoplasmic translational initiation / translation factor activity, RNA binding / protein-synthesizing GTPase / guanyl-nucleotide exchange factor complex / formation of translation preinitiation complex / oligodendrocyte development / 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 / ovarian follicle development / stress granule assembly / translation initiation factor binding / response to endoplasmic reticulum stress / myelination / translation initiation factor activity / cellular response to amino acid starvation / guanyl-nucleotide exchange factor activity / hippocampus development / central nervous system development / translational initiation / ABC-family proteins mediated transport / PKR-mediated signaling / 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 heat / cellular response to oxidative stress / 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 / cytosol / cytoplasm
Similarity search - Function
Translation initiation factor eIF-2B subunit alpha, N-terminal / : / : / Translation initiation factor eIF-2B subunit epsilon, N-terminal / Translation initiation factor eIF-2B subunit epsilon, W2 domain / : / : / Initiation factor 2B-related / Initiation factor 2B-like, C-terminal / Initiation factor 2 subunit family ...Translation initiation factor eIF-2B subunit alpha, N-terminal / : / : / Translation initiation factor eIF-2B subunit epsilon, N-terminal / Translation initiation factor eIF-2B subunit epsilon, W2 domain / : / : / Initiation factor 2B-related / Initiation factor 2B-like, C-terminal / Initiation factor 2 subunit family / Translation initiation factor IF2/IF5 domain / Translation initiation factor IF2/IF5, N-terminal / Translation initiation factor IF2/IF5, zinc-binding / Translation initiation factor IF2/IF5 / Domain found in IF2B/IF5 / domain present in translation initiation factor eIF2B and eIF5 / eIF4-gamma/eIF5/eIF2-epsilon / Domain at the C-termini of GCD6, eIF-2B epsilon, eIF-4 gamma and eIF-5 / W2 domain / W2 domain profile. / Translation initiation factor 2, alpha subunit / Translation initiation factor 2, alpha subunit, middle domain superfamily / Translation initiation factor 2, alpha subunit, C-terminal / IF2a, S1-like domain / Eukaryotic translation initiation factor 2 alpha subunit / Initiation factor eIF2 gamma, C-terminal / Initiation factor eIF2 gamma, domain 2 / Initiation factor eIF2 gamma, GTP-binding domain / Initiation factor eIF2 gamma, C terminal / : / Nucleotidyl transferase domain / Nucleotidyl transferase / NagB/RpiA transferase-like / Bacterial transferase hexapeptide (six repeats) / Translation elongation factor EF1A/initiation factor IF2gamma, C-terminal / Trimeric LpxA-like superfamily / S1 domain profile. / Translation elongation factor EFTu-like, domain 2 / Elongation factor Tu domain 2 / Ribosomal protein S1-like RNA-binding domain / S1 RNA binding domain / S1 domain / Translational (tr)-type GTP-binding domain / Elongation factor Tu GTP binding domain / Translational (tr)-type guanine nucleotide-binding (G) domain profile. / Nucleotide-diphospho-sugar transferases / Armadillo-type fold / Translation protein, beta-barrel domain superfamily / Nucleic acid-binding, OB-fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Eukaryotic translation initiation factor 2 subunit 1 / Eukaryotic translation initiation factor 2 subunit 2 / Eukaryotic translation initiation factor 2 subunit 3 / Translation initiation factor eIF2B subunit beta / Translation initiation factor eIF2B subunit epsilon / Translation initiation factor eIF2B subunit alpha / Translation initiation factor eIF2B subunit gamma / Translation initiation factor eIF2B subunit delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsKashiwagi, K. / Ito, T.
Funding support Japan, 2items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS) Japan
Japan Agency for Medical Research and Development (AMED) Japan
CitationJournal: 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
DepositionSep 22, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.year

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Structure visualization

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Assembly

Deposited unit
A: Translation initiation factor eIF-2B subunit alpha
B: Translation initiation factor eIF-2B subunit alpha
C: Translation initiation factor eIF-2B subunit beta
D: Translation initiation factor eIF-2B subunit beta
E: Translation initiation factor eIF-2B subunit gamma
F: Translation initiation factor eIF-2B subunit gamma
G: Translation initiation factor eIF-2B subunit delta
H: Translation initiation factor eIF-2B subunit delta
I: Translation initiation factor eIF-2B subunit epsilon
J: Translation initiation factor eIF-2B subunit epsilon
K: Eukaryotic translation initiation factor 2 subunit 1
L: Eukaryotic translation initiation factor 2 subunit 1
M: Eukaryotic translation initiation factor 2 subunit 2
P: Eukaryotic translation initiation factor 2 subunit 3


Theoretical massNumber of molelcules
Total (without water)684,52514
Polymers684,52514
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Translation initiation factor eIF-2B subunit ... , 5 types, 10 molecules ABCDEFGHIJ

#1: Protein Translation initiation factor eIF-2B subunit alpha / eIF2Balpha / eIF-2B GDP-GTP exchange factor subunit alpha


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 Translation initiation factor eIF-2B subunit beta / eIF2Bbeta / S20I15 / S20III15 / eIF-2B GDP-GTP exchange factor subunit beta


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 Translation initiation factor eIF-2B subunit gamma / eIF2Bgamma / eIF2Bg / eIF-2B GDP-GTP exchange factor subunit gamma


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 Translation initiation factor eIF-2B subunit delta / eIF2Bdelta / eIF-2B GDP-GTP exchange factor subunit delta


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 Translation initiation factor eIF-2B subunit epsilon / eIF2Bepsilon / eIF-2B GDP-GTP exchange factor subunit epsilon


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

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Eukaryotic translation initiation factor 2 subunit ... , 3 types, 4 molecules KLMP

#6: Protein Eukaryotic translation initiation factor 2 subunit 1 / P-eIF2alpha / Eukaryotic translation initiation factor 2 subunit alpha / eIF-2alpha


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 Eukaryotic translation initiation factor 2 subunit 2 / eIF2beta / Eukaryotic translation initiation factor 2 subunit beta / eIF-2-beta


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 Eukaryotic translation initiation factor 2 subunit 3 / eIF2gamma / Eukaryotic translation initiation factor 2 subunit gamma X / eIF-2gX


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

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Complex of eIF2B with eIF2(aP)COMPLEXall0MULTIPLE SOURCES
2eIF2BCOMPLEX#1-#51RECOMBINANT
3eIF2(aP)COMPLEX#6-#81RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Homo sapiens (human)9606
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 66721 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00631506
ELECTRON MICROSCOPYf_angle_d0.98542908
ELECTRON MICROSCOPYf_dihedral_angle_d18.60110857
ELECTRON MICROSCOPYf_chiral_restr0.0515136
ELECTRON MICROSCOPYf_plane_restr0.0055626

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