Journal Article

A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response

Maia de Oliveira, Taiana, Stringfellow, Daisy, Ron, David, Dickson, Paige, Gancedo-Rodrigo, Miguel, Le-Marshall, Jennifer, Yeoman, John T. S., Petrović, Dušan, Shilliday, Fiona, Syson, Karl, Narayanan, Usha, Gunnarsson, Anders, Gikunju, Diana, Nugai, Katherine A., Ward, Lewis, Ashraf, Syedah Neha, Jetson, Rachael, George, Ginto, Barrey, Evelyne J., Baker, David J., Crowther, Damian, Rivers, Emma, Breccia, Perla, Linley, John E., Aibara, Shintaro, Centrella, Paolo A., Kim, JeeSoo Monica, Lewis, Richard J., Adhikari, Santosh, Keefe, Anthony D., Guilinger, John P., Guié, Marie-Aude, Hupp, Christopher D., Zhang, Ying, Yu, Yan, Zyryanova, Alisa, Harding, Heather P.

2026

Overview

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. Protein synthesis is tightly regulated by the integrated stress response, but therapeutic activation remains challenging. Here, the authors identify a drug‑like allosteric inhibitor, an ISRAC, that stabilises inactive eIF2B, mimicking stress‑induced eIF2α phosphorylation to activate the ISR, establishing eIF2B as a tractable target for ISR modulation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 13/31 / 45/91 / 49/98 / 631/337/574 / 631/45/173 / 631/535/1258/1259 / 631/92/613 / 82/1 / 82/80 / 82/83 / Acetamides / Allosteric properties / Allosteric Regulation - drug effects / Animals / Cryoelectron Microscopy / Cyclohexylamines / Eukaryotic Initiation Factor-2 - chemistry / Eukaryotic Initiation Factor-2 - genetics / Eukaryotic Initiation Factor-2 - metabolism / Eukaryotic Initiation Factor-2B - antagonists & inhibitors / Eukaryotic Initiation Factor-2B - chemistry / Eukaryotic Initiation Factor-2B - genetics / Eukaryotic Initiation Factor-2B - metabolism / Guanine nucleotide exchange factor / Humanities and Social Sciences / Humans / Inhibitors / Initiation factor eIF-2 / Integrated Stress Response - drug effects / Kinases / multidisciplinary / Mutation / Nucleotides / Phosphorylation / Phosphorylation - drug effects / Protein Binding / Protein biosynthesis / Protein synthesis / Proteins / Science / Science (multidisciplinary) / Small Molecule Libraries - chemistry / Small Molecule Libraries - pharmacology