Nature chemical biology · 2026
Allosteric disordering of eIF2B regulates the integrated stress response.
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Dalwadi Udit, Subramanian Advait, Deal Aniliese, Conrad Julia E, Nadjsombati Tamara, Venkatesh Meera, Boone Morgane, Egea Pascal F, He Lingjie, Jain Nimit, Lee D John, Liu Yuwei, Reineke Lucas C, Saito Kazuki, Talledge Nathaniel, Toutkoushian Hannah, Le Vasseur Maxence, Zappa Francesca, de Groot Raoul J, Acosta-Alvear Diego, Arthur Christopher P, Nunnari Jodi, Marqusee Susan, Lawrence Rosalie E, Costa-Mattioli Mauro, Crawford James J, van Kuppeveld Frank J M, Croll Tristan I, Walter Peter, Frost Adam
Аннотация
The ternary complex, composed of eIF2, GTP and initiator methionyl-tRNA, delivers the first amino acid to the ribosome to initiate protein synthesis. Eukaryotic initiation factor 2B (eIF2B) catalyzes GDP to GTP exchange on eIF2, thereby setting the ternary complex level. Stress-induced phosphorylation converts eIF2 from the substrate of eIF2B into an inhibitor (eIF2-P). This conversion reduces ternary complex levels and induces the integrated stress response (ISR). Here we chart an allosteric axis running through eIF2B, revealing the importance of an α-helix in its β-subunit, the 'latch-helix', that hooks onto the α-subunit to induce eIF2B activity. eIF2-P binding promotes latch-helix unhooking, opening eIF2B, which inhibits its activity. Convergently evolved viral proteins stabilize this latch-helix-binding active state of eIF2B. Using these insights, we generated ISR-activating compounds that stabilize eIF2B in its inhibited, unlatched state. Our study thus highlights how long-range eIF2B allostery can be pharmacologically manipulated to sustain or attenuate the ISR.