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- PDB-9hve: Native human eIF2-eIF2B complex -

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Basic information

Entry
Database: PDB / ID: 9hve
TitleNative human eIF2-eIF2B complex
Components
  • (Eukaryotic translation initiation factor 2 subunit ...) x 3
  • (Translation initiation factor eIF-2B subunit ...) x 3
  • (Translation initiation factor eIF2B subunit ...) x 2
KeywordsTRANSLATION / Phosphorylation / Eukaryotic Initiation Factor-2B / Eukaryotic Initiation Factor-2 / Translation Complex Catalytic Native
Function / homology
Function and homology information


male germ cell proliferation / translation initiation ternary complex / regulation of translation in response to endoplasmic reticulum stress / glial limiting end-foot / HRI-mediated signaling / eukaryotic translation initiation factor 2B complex / response to manganese-induced endoplasmic reticulum stress / Cellular response to mitochondrial stress / positive regulation of type B pancreatic cell apoptotic process / Response of EIF2AK1 (HRI) to heme deficiency ...male germ cell proliferation / translation initiation ternary complex / regulation of translation in response to endoplasmic reticulum stress / glial limiting end-foot / HRI-mediated signaling / eukaryotic translation initiation factor 2B complex / response to manganese-induced endoplasmic reticulum stress / Cellular response to mitochondrial stress / positive regulation of type B pancreatic cell apoptotic process / Response of EIF2AK1 (HRI) to heme deficiency / Recycling of eIF2:GDP / methionyl-initiator methionine tRNA binding / negative regulation of translational initiation in response to stress / PERK-mediated unfolded protein response / PERK regulates gene expression / response to kainic acid / eukaryotic translation initiation factor 2 complex / cytoplasmic translational initiation / regulation of translational initiation in response to stress / translation factor activity, RNA binding / formation of translation preinitiation complex / astrocyte development / guanyl-nucleotide exchange factor complex / eukaryotic 48S preinitiation complex / astrocyte differentiation / oligodendrocyte development / protein-synthesizing GTPase / regulation of translational initiation / Formation of the ternary complex, and subsequently, the 43S complex / Ribosomal scanning and start codon recognition / Translation initiation complex formation / positive regulation of translational initiation / Response of EIF2AK4 (GCN2) to amino acid deficiency / GTP hydrolysis and joining of the 60S ribosomal subunit / response to glucose / L13a-mediated translational silencing of Ceruloplasmin expression / ovarian follicle development / mitophagy / myelination / translation initiation factor binding / translation initiation factor activity / stress granule assembly / cellular response to amino acid starvation / guanyl-nucleotide exchange factor activity / response to endoplasmic reticulum stress / central nervous system development / hippocampus development / translational initiation / response to peptide hormone / PKR-mediated signaling / ABC-family proteins mediated transport / male gonad development / cytoplasmic stress granule / cellular response to UV / T cell receptor signaling pathway / regulation of translation / cellular response to heat / ribosome binding / response to heat / cellular response to oxidative stress / in utero embryonic development / positive regulation of apoptotic process / cadherin binding / mRNA binding / GTPase activity / synapse / GTP binding / mitochondrion / RNA binding / extracellular exosome / zinc ion binding / ATP binding / identical protein binding / nucleus / membrane / 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 / : / : / : / EIF2B subunit epsilon LbH domain / Initiation factor 2B-related / Initiation factor 2B-like, C-terminal ...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 / : / : / : / EIF2B subunit epsilon LbH 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. / 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 / 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 / : / Nucleotidyl transferase domain / Nucleotidyl transferase / NagB/RpiA transferase-like / 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 / Nucleotide-diphospho-sugar transferases / Translational (tr)-type GTP-binding domain / Elongation factor Tu GTP binding domain / Translational (tr)-type guanine nucleotide-binding (G) domain profile. / S1 domain / Armadillo-type fold / Translation protein, beta-barrel domain superfamily / Nucleic acid-binding, OB-fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-TRIPHOSPHATE / 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: 2.7 Å
AuthorsDe Miguel, C. / Thorkelsson, S.R. / Wang, C. / Bertolotti, A.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_U105185860 United Kingdom
Wellcome Trust206367/Z/ 17/Z United Kingdom
CitationJournal: Science / Year: 2025
Title: Termination of the integrated stress response.
Authors: Claudia De Miguel / Sigurdur R Thorkelsson / Agnieszka Fatalska / George Hodgson / Chao Wang / Anne Bertolotti /
Abstract: Stress responses enable cells to detect, adapt to, and survive challenges. The benefit of these signaling pathways depends on their reversibility. The integrated stress response (ISR) is elicited by ...Stress responses enable cells to detect, adapt to, and survive challenges. The benefit of these signaling pathways depends on their reversibility. The integrated stress response (ISR) is elicited by phosphorylation of translation initiation factor eIF2, which traps and inhibits rate-limiting translation factor eIF2B thereby attenuating translation initiation. Termination of this pathway thus requires relieving eIF2B from P-eIF2 inhibition. Here, we found that eIF2 phosphatase subunits PPP1R15A and PPP1R15B (R15B) bound P-eIF2 in complex with eIF2B. Biochemical investigations guided by cryo-EM structures of native eIF2-eIF2B and P-eIF2-eIF2B complexes bound to R15B demonstrated that R15B enabled dephosphorylation of otherwise dephosphorylation-incompetent P-eIF2 on eIF2B. This sheds light on ISR termination, revealing that R15B rescues eIF2B from P-eIF2 inhibition, thereby safeguarding translation and cell fitness.
History
DepositionDec 27, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 19, 2025Provider: repository / Type: Initial release
Revision 1.1Nov 26, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
F: Translation initiation factor eIF-2B subunit gamma
E: Translation initiation factor eIF-2B subunit gamma
K: Eukaryotic translation initiation factor 2 subunit 1
I: Translation initiation factor eIF2B subunit epsilon
O: Eukaryotic translation initiation factor 2 subunit 3
D: Translation initiation factor eIF2B subunit beta
A: Translation initiation factor eIF-2B subunit alpha
H: Translation initiation factor eIF-2B subunit delta
M: Eukaryotic translation initiation factor 2 subunit 2
N: Eukaryotic translation initiation factor 2 subunit 2
L: Eukaryotic translation initiation factor 2 subunit 1
J: Translation initiation factor eIF2B subunit epsilon
P: Eukaryotic translation initiation factor 2 subunit 3
C: Translation initiation factor eIF2B subunit beta
B: Translation initiation factor eIF-2B subunit alpha
G: Translation initiation factor eIF-2B subunit delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)775,04418
Polymers773,99816
Non-polymers1,0462
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Translation initiation factor eIF-2B subunit ... , 3 types, 6 molecules FEABHG

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


Mass: 50304.230 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: Q9NR50
#6: Protein Translation initiation factor eIF-2B subunit alpha / eIF-2B GDP-GTP exchange factor subunit alpha


Mass: 33754.148 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: Q14232
#7: Protein Translation initiation factor eIF-2B subunit delta / eIF-2B GDP-GTP exchange factor subunit delta


Mass: 57640.168 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: Q9UI10

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Eukaryotic translation initiation factor 2 subunit ... , 3 types, 6 molecules KLOPMN

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


Mass: 36161.180 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: P05198
#4: Protein Eukaryotic translation initiation factor 2 subunit 3 / Eukaryotic translation initiation factor 2 subunit gamma X / eIF-2gX


Mass: 51178.406 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: P41091, protein-synthesizing GTPase
#8: Protein Eukaryotic translation initiation factor 2 subunit 2 / Eukaryotic translation initiation factor 2 subunit beta / eIF-2-beta


Mass: 38454.484 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: P20042

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Translation initiation factor eIF2B subunit ... , 2 types, 4 molecules IJDC

#3: Protein Translation initiation factor eIF2B subunit epsilon / eIF2B GDP-GTP exchange factor subunit epsilon


Mass: 80466.609 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: Q13144
#5: Protein Translation initiation factor eIF2B subunit beta / S20I15 / S20III15 / eIF2B GDP-GTP exchange factor subunit beta


Mass: 39039.547 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: P49770

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Non-polymers , 1 types, 2 molecules

#9: Chemical ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE


Mass: 523.180 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: GTP, energy-carrying molecule*YM

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Details

Has ligand of interestY
Has protein modificationN

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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

ComponentName: eIF2-eIF2B complex. / Type: COMPLEX / Details: eIF2Bg subunits are bound to GTP. / Entity ID: #1-#8 / Source: NATURAL
Molecular weightValue: 0.77 MDa / Experimental value: NO
Source (natural)Organism: Expi293 (human) / Cellular location: cytoplasm
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHEPES1
21 mMtris(2-carboxyethyl)phosphineTCEP1
3100 mMpotassium chlorideKCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 9971
EM imaging opticsEnergyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2EPUimage acquisition
4CTFFIND4CTF correction
7Cootmodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIX1.21.2_5419:model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 171151
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 256000 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingSource name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00344850
ELECTRON MICROSCOPYf_angle_d0.5760704
ELECTRON MICROSCOPYf_dihedral_angle_d6.3446154
ELECTRON MICROSCOPYf_chiral_restr0.0447054
ELECTRON MICROSCOPYf_plane_restr0.0047780

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