8TQO
Eukaryotic translation initiation factor 2B tetramer
Summary for 8TQO
| Entry DOI | 10.2210/pdb8tqo/pdb |
| EMDB information | 41510 |
| Descriptor | Translation initiation factor eIF-2B subunit epsilon, Translation initiation factor eIF-2B subunit gamma, Translation initiation factor eIF-2B subunit beta, ... (4 entities in total) |
| Functional Keywords | protein translation, eif2b, integrated stress response, translation |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 229405.56 |
| Authors | Wang, L.,Lawrence, R.,Sangwan, S.,Anand, A.,Shoemaker, S.,Deal, A.,Marqusee, S.,Watler, P. (deposition date: 2023-08-08, release date: 2023-12-06, Last modification date: 2024-04-10) |
| Primary citation | Lawrence, R.E.,Shoemaker, S.R.,Deal, A.,Sangwan, S.,Anand, A.A.,Wang, L.,Marqusee, S.,Walter, P. A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling. Nat.Chem.Biol., 20:422-431, 2024 Cited by PubMed Abstract: The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling downregulates translation and activates expression of stress-responsive factors that promote return to homeostasis and is initiated by inhibition of the decameric guanine nucleotide exchange factor eIF2B. Conformational and assembly transitions regulate eIF2B activity, but the allosteric mechanisms controlling these dynamic transitions and mediating the therapeutic effects of the small-molecule ISR inhibitor ISRIB are unknown. Using hydrogen-deuterium exchange-mass spectrometry and cryo-electron microscopy, we identified a central α-helix whose orientation allosterically coordinates eIF2B conformation and assembly. Biochemical and cellular signaling assays show that this 'switch-helix' controls eIF2B activity and signaling. In sum, the switch-helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. This work uncovers a conserved allosteric mechanism and unlocks new therapeutic possibilities for ISR-linked diseases. PubMed: 37945896DOI: 10.1038/s41589-023-01453-9 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.1 Å) |
Structure validation
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