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- PDB-9y5r: Eukaryotic translation initiation factor 2-B (eIF2B) bound to pho... -

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Basic information

Entry
Database: PDB / ID: 9y5r
TitleEukaryotic translation initiation factor 2-B (eIF2B) bound to phosphorylated eIF2alpha (NTD)
Components
  • (Translation initiation factor eIF-2B subunit ...) x 5
  • Eukaryotic translation initiation factor 2 subunit 1
KeywordsTRANSLATION / Guanine nucleotide exchange factor / GEF / initiation
Function / homology
Function and homology information


translation initiation ternary complex / cap-dependent translation initiation factor activity / IRES-mediated translation initiation factor activity / regulation of translation in response to endoplasmic reticulum stress / glial limiting end-foot / response to manganese-induced endoplasmic reticulum stress / Cellular response to mitochondrial stress / positive regulation of type B pancreatic cell apoptotic process / eukaryotic translation initiation factor 2B complex / HRI-mediated signaling ...translation initiation ternary complex / cap-dependent translation initiation factor activity / IRES-mediated translation initiation factor activity / regulation of translation in response to endoplasmic reticulum stress / glial limiting end-foot / response to manganese-induced endoplasmic reticulum stress / Cellular response to mitochondrial stress / positive regulation of type B pancreatic cell apoptotic process / eukaryotic translation initiation factor 2B complex / HRI-mediated signaling / Response of EIF2AK1 (HRI) to heme deficiency / negative regulation of translational initiation in response to stress / PERK-mediated unfolded protein response / Recycling of eIF2:GDP / astrocyte development / PERK regulates gene expression / response to kainic acid / eukaryotic translation initiation factor 2 complex / astrocyte differentiation / eukaryotic 48S preinitiation complex / oligodendrocyte development / regulation of translational initiation / cytoplasmic translational initiation / ovarian follicle development / Formation of the ternary complex, and subsequently, the 43S complex / Ribosomal scanning and start codon recognition / Translation initiation complex formation / response to glucose / positive regulation of translational initiation / 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 / myelination / translation initiation factor activity / translation initiation factor binding / guanyl-nucleotide exchange factor activity / response to endoplasmic reticulum stress / hippocampus development / cellular response to amino acid starvation / stress granule assembly / central nervous system development / translational initiation / PKR-mediated signaling / response to peptide hormone / ABC-family protein mediated transport / T cell receptor signaling pathway / cytoplasmic stress granule / cellular response to UV / regulation of translation / cellular response to heat / response to heat / ribosome binding / cellular response to oxidative stress / positive regulation of apoptotic process / synapse / GTP binding / mitochondrion / RNA binding / extracellular exosome / ATP binding / membrane / identical protein binding / nucleus / 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 ...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 / Nucleotide-diphospho-sugar transferases / S1 RNA binding domain / 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: 3.01 Å
AuthorsDalwadi, U. / Croll, T. / Subramanian, A. / Lee, D.J. / Arthur, C. / Walter, P. / Frost, A.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Nat Chem Biol / Year: 2026
Title: Allosteric disordering of eIF2B regulates the integrated stress response.
Authors: Udit Dalwadi / Advait Subramanian / Aniliese Deal / Julia E Conrad / Tamara Nadjsombati / Meera Venkatesh / Morgane Boone / Pascal F Egea / Lingjie He / Nimit Jain / D John Lee / Yuwei Liu / ...Authors: Udit Dalwadi / Advait Subramanian / Aniliese Deal / Julia E Conrad / Tamara Nadjsombati / Meera Venkatesh / Morgane Boone / Pascal F Egea / Lingjie He / Nimit Jain / D John Lee / Yuwei Liu / Lucas C Reineke / Kazuki Saito / Nathaniel Talledge / Hannah Toutkoushian / Maxence Le Vasseur / Francesca Zappa / Raoul J de Groot / Diego Acosta-Alvear / Christopher P Arthur / Jodi Nunnari / Susan Marqusee / Rosalie E Lawrence / Mauro Costa-Mattioli / James J Crawford / Frank J M van Kuppeveld / Tristan I Croll / Peter Walter / Adam Frost /
Abstract: The ternary complex, composed of eIF2, GTP and initiator methionyl-tRNA, delivers the first amino acid to the ribosome to initiate protein synthesis. Eukaryotic initiation factor 2B (eIF2B) catalyzes ...The ternary complex, composed of eIF2, GTP and initiator methionyl-tRNA, delivers the first amino acid to the ribosome to initiate protein synthesis. Eukaryotic initiation factor 2B (eIF2B) catalyzes GDP to GTP exchange on eIF2, thereby setting the ternary complex level. Stress-induced phosphorylation converts eIF2 from the substrate of eIF2B into an inhibitor (eIF2-P). This conversion reduces ternary complex levels and induces the integrated stress response (ISR). Here we chart an allosteric axis running through eIF2B, revealing the importance of an α-helix in its β-subunit, the 'latch-helix', that hooks onto the α-subunit to induce eIF2B activity. eIF2-P binding promotes latch-helix unhooking, opening eIF2B, which inhibits its activity. Convergently evolved viral proteins stabilize this latch-helix-binding active state of eIF2B. Using these insights, we generated ISR-activating compounds that stabilize eIF2B in its inhibited, unlatched state. Our study thus highlights how long-range eIF2B allostery can be pharmacologically manipulated to sustain or attenuate the ISR.
History
DepositionSep 5, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 8, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 8, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 8, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 8, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 8, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 8, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 8, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jul 8, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 15, 2026Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.1Jul 15, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin / Data content type: EM metadata / EM metadata / EM metadata
Item: _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
A: Translation initiation factor eIF-2B subunit epsilon
C: Translation initiation factor eIF-2B subunit beta
E: Translation initiation factor eIF-2B subunit delta
G: Translation initiation factor eIF-2B subunit alpha
I: Translation initiation factor eIF-2B subunit gamma
B: Translation initiation factor eIF-2B subunit epsilon
D: Translation initiation factor eIF-2B subunit beta
F: Translation initiation factor eIF-2B subunit delta
H: Translation initiation factor eIF-2B subunit alpha
J: Translation initiation factor eIF-2B subunit gamma
L: Eukaryotic translation initiation factor 2 subunit 1
M: Eukaryotic translation initiation factor 2 subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)577,81516
Polymers577,61412
Non-polymers2024
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 ... , 5 types, 10 molecules ABCDEFGHIJ

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


Mass: 80452.586 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
#2: Protein Translation initiation factor eIF-2B subunit beta / S20I15 / S20III15 / eIF-2B GDP-GTP exchange factor subunit beta


Mass: 41008.578 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 delta / 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
#4: 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 genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B1, EIF2BA / Production host: Escherichia coli (E. coli) / References: UniProt: Q14232
#5: 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 genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9NR50

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Protein , 1 types, 2 molecules LM

#6: 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: 25647.111 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2S1, EIF2A / Production host: Escherichia coli (E. coli) / References: UniProt: P05198

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Non-polymers , 2 types, 4 molecules

#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#8: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn

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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: eIF2B bound to phospho-eIF2alpha(S51P) / Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Molecular weightValue: 577213.2 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
Details: 40 mM HEPES KOH pH 7.4, 150 mM KCl, 2 mM MgCl2, 1 mM TCEP
Buffer component
IDConc.NameFormulaBuffer-ID
140 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHEPES1
2150 mMPotassium chlorideKCl1
32 mMMagnesium ChlorideMgCl21
41 mMtris(2-carboxyethyl)phosphineTCEP1
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 16000 nm / Nominal defocus min: 6000 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 16195
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV
Image scansWidth: 4096 / Height: 4096

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.2.1particle selection
2EPUimage acquisition
4cryoSPARC4.2.1CTF correction
7UCSF ChimeraXmodel fitting
9cryoSPARC4.2.1initial Euler assignment
10cryoSPARC4.2.1final Euler assignment
11cryoSPARC4.2.1classification
12cryoSPARC4.2.13D reconstruction
13ISOLDEmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 221364
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 130953 / Num. of class averages: 5 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 6o9z

6o9z


Accession code: 6o9z / Source name: PDB / Type: experimental model
RefinementResolution: 3.01→3.01 Å / Num. reflection obs: 3921563 / Average fsc work: 0.7403
Displacement parametersBiso mean: 102.52 Å2
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
ELECTRON MICROSCOPYs_bond_nonh_d0.0079321560.0119
ELECTRON MICROSCOPYs_angle_nonh_deg1.6375435441.8265
ELECTRON MICROSCOPYs_dihedral_angle_1_deg7.476140105
ELECTRON MICROSCOPYs_dihedral_angle_2_deg4.087710125
ELECTRON MICROSCOPYs_dihedral_angle_3_deg11.1953867810
ELECTRON MICROSCOPYs_dihedral_angle_6_deg14.3204160810
ELECTRON MICROSCOPYs_chiral_restr0.065450640.1311
ELECTRON MICROSCOPYs_planes0.0051446960.02
ELECTRON MICROSCOPYs_nbd0.2105431300.2
ELECTRON MICROSCOPYs_nbtor0.2242574660.2
ELECTRON MICROSCOPYs_hbond_nbd0.10476580.2
ELECTRON MICROSCOPYs_metal_ion0.208220.2

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