Eukaryotic translation initiation factor 2␣ (eIF2␣) is a member of the eIF2 heterotrimeric complex that binds and delivers Met-tRNA i Met to the 40 S ribosomal subunit in a GTP-dependent manner. Phosphorylation/dephosphorylation of eIF2␣ at Ser-51 is the major regulator of protein synthesis in eukaryotic cells. Here, we report the first structural analysis on eIF2, the three-dimensional structure of a 22-kDa N-terminal portion of human eIF2␣ by x-ray diffraction at 1.9 Å resolution. This

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... re contains two major domains. The N terminus is a ␤-barrel with five antiparallel ␤-strands in an oligonucleotide binding domain (OB domain) fold. The phosphorylation site (Ser-51) is on the loop connecting ␤3 and ␤4 in the OB domain. A helical domain follows the OB domain, and the first helix has extensive interactions, including a disulfide bridge, to fix its orientation with respect to the OB domain. The two domains meet along a negatively charged groove with highly conserved residues, indicating a likely site for protein-protein interaction. factor 2␣; MAD, multiple anomalous dispersion; SeMet, selenomethionine; OB fold, oligonucleotide-binding fold.