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- PDB-9qc6: Structure of eIF2B decamer bound to (P)eIF2 alpha and Compound A-(S) -

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Basic information

Entry
Database: PDB / ID: 9qc6
TitleStructure of eIF2B decamer bound to (P)eIF2 alpha and Compound A-(S)
Components
  • (Translation initiation factor eIF-2B subunit ...) x 2
  • (Translation initiation factor eIF2B subunit ...) x 3
  • Eukaryotic translation initiation factor 2 subunit 1
KeywordsTRANSLATION / integrated stress response / complex / translation initiation / guanine exchange factor
Function / homology
Function and homology information


translation initiation ternary complex / 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 / eukaryotic translation initiation factor 2B complex / positive regulation of type B pancreatic cell apoptotic process / HRI-mediated signaling / Response of EIF2AK1 (HRI) to heme deficiency / negative regulation of translational initiation in response to stress ...translation initiation ternary complex / 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 / eukaryotic translation initiation factor 2B complex / positive regulation of type B pancreatic cell apoptotic process / 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 / PERK regulates gene expression / response to kainic acid / eukaryotic translation initiation factor 2 complex / regulation of translational initiation in response to stress / astrocyte development / eukaryotic 48S preinitiation complex / astrocyte differentiation / oligodendrocyte development / regulation of translational initiation / cytoplasmic 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 / response to glucose / GTP hydrolysis and joining of the 60S ribosomal subunit / L13a-mediated translational silencing of Ceruloplasmin expression / ovarian follicle development / mitophagy / myelination / translation initiation factor activity / translation initiation factor binding / guanyl-nucleotide exchange factor activity / response to endoplasmic reticulum stress / cellular response to amino acid starvation / stress granule assembly / central nervous system development / hippocampus development / translational initiation / PKR-mediated signaling / response to peptide hormone / ABC-family protein mediated transport / cytoplasmic stress granule / cellular response to UV / regulation of translation / T cell receptor signaling pathway / 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 / cytoplasm / cytosol
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 / 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: 2.83 Å
AuthorsShilliday, F. / Maia de Oliveira, T. / Gancedo-Rodrigo, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2026
Title: A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response.
Authors: Fiona Shilliday / Miguel Gancedo-Rodrigo / Ginto George / Shintaro Aibara / Santosh Adhikari / Syedah Neha Ashraf / Evelyne J Barrey / Paolo A Centrella / Damian Crowther / Paige Dickson / ...Authors: Fiona Shilliday / Miguel Gancedo-Rodrigo / Ginto George / Shintaro Aibara / Santosh Adhikari / Syedah Neha Ashraf / Evelyne J Barrey / Paolo A Centrella / Damian Crowther / Paige Dickson / Diana Gikunju / Marie-Aude Guié / John P Guilinger / Anders Gunnarsson / Heather P Harding / Christopher D Hupp / Rachael Jetson / Anthony D Keefe / JeeSoo Monica Kim / Richard J Lewis / Taiana Maia de Oliveira / Jennifer Le-Marshall / Usha Narayanan / Katherine A Nugai / Dušan Petrović / Emma Rivers / David Ron / Daisy Stringfellow / Karl Syson / Lewis Ward / John T S Yeoman / Yan Yu / Ying Zhang / Alisa Zyryanova / David J Baker / Perla Breccia / John E Linley /
Abstract: Eukaryotic initiation factor 2B (eIF2B), a guanine nucleotide exchange factor (GEF), promotes protein synthesis by charging translation initiation factor 2 (eIF2) with GTP. Stress-induced ...Eukaryotic initiation factor 2B (eIF2B), a guanine nucleotide exchange factor (GEF), promotes protein synthesis by charging translation initiation factor 2 (eIF2) with GTP. Stress-induced phosphorylation of eIF2 on its α-subunit [eIF2(αP)] inhibits this reaction triggering a protective Integrated Stress Response (ISR). A DNA-encoded chemical library (DEL) screen for modulators of eIF2B, led to the identification of a chemical series that stabilises the inactive state of eIF2B, stimulating the ISR. Cryo-EM of compound-bound eIF2B reveals a conformational switch to the inactive state engaged by eIF2(αP). In cells, compound activity is sensitive to eIF2's phosphorylation state and to a competing eIF2B ligand (ISRIB) that activates the GEF allosterically. These findings establish the feasibility of targeting eIF2B with a drug-like allosteric inhibitor, that serves as an ISR activator (ISRAC), paving the way to explore the therapeutic potential of eIF2B-directed ISR activation.
History
DepositionMar 4, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 13, 2026Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Translation initiation factor eIF2B subunit alpha
B: Translation initiation factor eIF2B subunit alpha
C: Translation initiation factor eIF2B subunit beta
D: Translation initiation factor eIF2B 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 eIF2B subunit epsilon
J: Translation initiation factor eIF2B subunit epsilon
K: Eukaryotic translation initiation factor 2 subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)556,73012
Polymers556,16611
Non-polymers5641
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 eIF2B subunit ... , 3 types, 6 molecules ABCDIJ

#1: Protein Translation initiation factor eIF2B subunit alpha / eIF2B GDP-GTP exchange factor subunit alpha


Mass: 36060.656 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 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 genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B2, EIF2BB / Production host: Escherichia coli (E. coli) / References: UniProt: P49770
#5: Protein Translation initiation factor eIF2B subunit epsilon / eIF2B GDP-GTP exchange factor subunit epsilon


Mass: 82773.133 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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Translation initiation factor eIF-2B subunit ... , 2 types, 4 molecules EFGH

#3: 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
#4: 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

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Protein / Non-polymers , 2 types, 2 molecules K

#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: 24530.879 Da / Num. of mol.: 1
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
#7: Chemical ChemComp-A1I5O / ~{N}-[(1~{S})-7-[3-[[ethanoyl(methyl)amino]methyl]phenyl]-5-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-2-[[(3~{R},4~{S})-3-fluoranylpiperidin-4-yl]methoxy]-~{N}-methyl-ethanamide


Mass: 563.627 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H37F4N3O3 / Feature type: SUBJECT OF INVESTIGATION

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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: Complex of eIF2B decamer bound to (P)eIF2 alpha and Compound A-(S)
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
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: 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 defocus max: 3000 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21rc1_5084model refinement
12RELIONclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.83 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 18192 / Symmetry type: POINT
RefinementHighest resolution: 2.83 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00324829
ELECTRON MICROSCOPYf_angle_d0.56133898
ELECTRON MICROSCOPYf_dihedral_angle_d4.1093636
ELECTRON MICROSCOPYf_chiral_restr0.0444184
ELECTRON MICROSCOPYf_plane_restr0.0044321

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