9qc6

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

spinqualitylabelsall models 9qc6, resolution 2.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9qc6 is a 11 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.83Å Ligands: A1I5O, SEP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease EI2BA_HUMAN Cree leukoencephalopathy;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry. Function EI2BA_HUMAN Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. Publication Abstract from PubMed 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 alpha-subunit [eIF2(alphaP)] 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(alphaP). 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. A molecular stabiliser of an inhibitory eIF2B-eIF2(alphaP) complex activates the Integrated Stress Response.,Shilliday F, Gancedo-Rodrigo M, George G, Aibara S, Adhikari S, Ashraf SN, Barrey EJ, Centrella PA, Crowther D, Dickson P, Gikunju D, Guie MA, Guilinger JP, Gunnarsson A, Harding HP, Hupp CD, Jetson R, Keefe AD, Kim JM, Lewis RJ, Maia de Oliveira T, Le-Marshall J, Narayanan U, Nugai KA, Petrovic D, Rivers E, Ron D, Stringfellow D, Syson K, Ward L, Yeoman JTS, Yu Y, Zhang Y, Zyryanova A, Baker DJ, Breccia P, Linley JE Nat Commun. 2026 May 6. doi: 10.1038/s41467-026-72688-y. PMID:42091608 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA