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TitleA molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response.
Journal, issue, pagesNat Commun, Year 2026
Publish dateMay 6, 2026
AuthorsFiona 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 /
PubMed AbstractEukaryotic 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.
External linksNat Commun / PubMed:42091608
MethodsEM (single particle)
Resolution2.83 Å
Structure data

53004

9qc6

EMDB-53004, PDB-9qc6:
Structure of eIF2B decamer bound to (P)eIF2 alpha and Compound A-(S)
Method: EM (single particle) / Resolution: 2.83 Å

Chemicals

PDB-1i5o:
CRYSTAL STRUCTURE OF MUTANT R105A OF E. COLI ASPARTATE TRANSCARBAMOYLASE

Source
  • homo sapiens (human)
KeywordsTRANSLATION / integrated stress response / complex / translation initiation / guanine exchange factor

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