9Y3Q
Eukaryotic translation initiation factor 2-B in its apo form (inactive-state)
Summary for 9Y3Q
| Entry DOI | 10.2210/pdb9y3q/pdb |
| EMDB information | 72462 72463 |
| Descriptor | Translation initiation factor eIF-2B subunit epsilon, Translation initiation factor eIF-2B subunit beta, Translation initiation factor eIF-2B subunit delta, ... (7 entities in total) |
| Functional Keywords | guanine nucleotide exchange factor, gef, translation, initiation |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 10 |
| Total formula weight | 526627.50 |
| Authors | Dalwadi, U.,Croll, T.,Subramanian, A.,Lee, D.J.,Arthur, C.,Walter, P.,Frost, A. (deposition date: 2025-09-02, release date: 2026-06-24, Last modification date: 2026-07-15) |
| Primary citation | Dalwadi, U.,Subramanian, A.,Deal, A.,Conrad, J.E.,Nadjsombati, T.,Venkatesh, M.,Boone, M.,Egea, P.F.,He, L.,Jain, N.,Lee, D.J.,Liu, Y.,Reineke, L.C.,Saito, K.,Talledge, N.,Toutkoushian, H.,Le Vasseur, M.,Zappa, F.,de Groot, R.J.,Acosta-Alvear, D.,Arthur, C.P.,Nunnari, J.,Marqusee, S.,Lawrence, R.E.,Costa-Mattioli, M.,Crawford, J.J.,van Kuppeveld, F.J.M.,Croll, T.I.,Walter, P.,Frost, A. Allosteric disordering of eIF2B regulates the integrated stress response. Nat.Chem.Biol., 2026 Cited by PubMed Abstract: 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. PubMed: 42373951DOI: 10.1038/s41589-026-02256-4 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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