9QC6

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

This is a non-PDB format compatible entry.

Summary for 9QC6

• Entry DOI: 10.2210/pdb9qc6/pdb
• EMDB information: 53004
• Descriptor: Translation initiation factor eIF2B subunit alpha, Translation initiation factor eIF2B subunit beta, Translation initiation factor eIF-2B subunit gamma, ... (7 entities in total)
• Functional Keywords: integrated stress response, complex, translation initiation, guanine exchange factor, translation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 11
• Total formula weight: 556729.97

Authors

Shilliday, F.,Maia de Oliveira, T.,Gancedo-Rodrigo, M. (deposition date: 2025-03-04, release date: 2026-05-13)

Primary citation

Shilliday, F.,Gancedo-Rodrigo, M.,George, G.,Aibara, S.,Adhikari, S.,Ashraf, S.N.,Barrey, E.J.,Centrella, P.A.,Crowther, D.,Dickson, P.,Gikunju, D.,Guie, M.A.,Guilinger, J.P.,Gunnarsson, A.,Harding, H.P.,Hupp, C.D.,Jetson, R.,Keefe, A.D.,Kim, J.M.,Lewis, R.J.,Maia de Oliveira, T.,Le-Marshall, J.,Narayanan, U.,Nugai, K.A.,Petrovic, D.,Rivers, E.,Ron, D.,Stringfellow, D.,Syson, K.,Ward, L.,Yeoman, J.T.S.,Yu, Y.,Zhang, Y.,Zyryanova, A.,Baker, D.J.,Breccia, P.,Linley, J.E.
A molecular stabiliser of an inhibitory eIF2B-eIF2( alpha P) complex activates the Integrated Stress Response.
Nat Commun, 2026

PubMed 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 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.

PubMed: 42091608
DOI: 10.1038/s41467-026-72688-y

Experimental method

ELECTRON MICROSCOPY (2.83 Å)