Figure 2.

eIF2(αP) and ISRIB Associate with Different Conformations of eIF2B

(A) Overlay of the eIF2B apo structure (gray) and eIF2B in complex with two eIF2(αP) trimers (the α^Pγ complex; color-coded as in the adjacent cartoon). The blue spheres show the position of the C^α atoms of eIF2Bδ^E310 and δ^L314.

(B) Different arrangements of the eIF2B pocket that accommodates the eIF2α-NTD: unphosphorylated in the catalytically productive conformation, and phosphorylated in complexes containing one (α^P1) or two (α^Pγ) bound eIF2(αP) trimers. Upper panels: an overlay of the productive eIF2B⋅ISRIB⋅eIF2 complex (cyan, PDB: 6O81), the eIF2B apo structure (gray), and the α^Pγ complex (magenta). For clarity, only the unphosphorylated eIF2α-NTD of the eIF2B⋅ISRIB⋅eIF2 complex is shown. Lower panels: similar alignment of the apo structure, the α^Pγ structure, and the α^P1 structure (green). Right panels: close-up views showing the displacements of helix δ-α3 between the different complexes.

(C) Deformation of the ISRIB-binding pocket in eIF2B with two bound eIF2(αP) trimers (the α^Pγ complex). The eIF2B⋅ISRIB complex structure (PDB: 6CAJ) is shown in gray and the α^Pγ complex in color-coded representation (as in the adjacent cartoon). Key residues known to affect the binding or action of ISRIB are highlighted as spheres.

Structures are aligned by the four C-terminal domains of the β- and δ-subunits of eIF2B for (A) and (B), and by the C^α atoms surrounding (within 10 Å) the ISRIB molecule in the eIF2B⋅ISRIB structure for (C).

See also Figures S1 and S2.