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- PDB-9hvd: Native human P-eIF2-eIF2B complex -

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Basic information

Entry
Database: PDB / ID: 9hvd
TitleNative human P-eIF2-eIF2B complex
Components
  • (Translation initiation factor eIF-2B subunit ...) x 3
  • (Translation initiation factor eIF2B subunit ...) x 2
  • Eukaryotic translation initiation factor 2 subunit 1
KeywordsTRANSLATION / phosphorylation / Eukaryotic Initiation Factor-2B / Eukaryotic Initiation Factor-2
Function / homology
Function and homology information


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 ...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 / 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 / astrocyte development / guanyl-nucleotide exchange factor complex / eukaryotic 48S preinitiation complex / astrocyte differentiation / oligodendrocyte development / 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 / 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 / positive regulation of apoptotic process / synapse / GTP binding / mitochondrion / RNA binding / extracellular exosome / 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 / 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 / Nucleotidyl transferase domain / Nucleotidyl transferase / NagB/RpiA transferase-like / Trimeric LpxA-like superfamily / S1 domain profile. / Ribosomal protein S1-like RNA-binding domain / S1 RNA binding domain / Nucleotide-diphospho-sugar transferases / S1 domain / Armadillo-type fold / Nucleic acid-binding, OB-fold
Similarity search - Domain/homology
Eukaryotic translation initiation factor 2 subunit 1 / 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: 3.04 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
K: Eukaryotic translation initiation factor 2 subunit 1
J: Translation initiation factor eIF2B subunit epsilon
D: Translation initiation factor eIF2B subunit beta
B: Translation initiation factor eIF-2B subunit alpha
G: Translation initiation factor eIF-2B subunit delta
E: Translation initiation factor eIF-2B subunit gamma
I: Translation initiation factor eIF2B subunit epsilon
C: Translation initiation factor eIF2B subunit beta
A: Translation initiation factor eIF-2B subunit alpha
H: Translation initiation factor eIF-2B subunit delta
L: Eukaryotic translation initiation factor 2 subunit 1


Theoretical massNumber of molelcules
Total (without water)594,89212
Polymers594,89212
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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

#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
#5: 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
#6: 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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Protein , 1 types, 2 molecules KL

#2: Protein Eukaryotic translation initiation factor 2 subunit 1 / Eukaryotic translation initiation factor 2 subunit alpha / eIF-2-alpha / eIF-2A / eIF-2alpha / eIF2-alpha


Mass: 36241.156 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: P05198

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

#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
#4: 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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Details

Has ligand of interestY
Has protein modificationY

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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: P-eIF2-eIF2B complex / Type: COMPLEX / Entity ID: all / Source: NATURAL
Molecular weightValue: 0.78 MDa / Experimental value: NO
Source (natural)Organism: Expi293 cells (human) / Cellular location: cytoplasm
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mM2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acidHEPES1
2150 mMpotassium chlorideKCl1
31 mMtris(2-carboxyethyl)phosphineTCEP1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: 15mA / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil 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: 75000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of real images: 9438

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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: 1184000
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.04 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 326401 / Num. of class averages: 200 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00331860
ELECTRON MICROSCOPYf_angle_d0.57643132
ELECTRON MICROSCOPYf_dihedral_angle_d4.7294354
ELECTRON MICROSCOPYf_chiral_restr0.0445023
ELECTRON MICROSCOPYf_plane_restr0.0045520

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