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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月6日

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  • 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

摘要

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.