Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G

eIF4E is critical for protein synthesis and becomes hyperactive in cancer cells. Small-molecule inhibitors of the eIF4E/eIF4G initiation factor complex have recently been found to exhibit antitumor activity in vitro and in vivo. However, their mode of action at the atomic level has remained elusive. Here, we report high-resolution crystal structures of complexes of 4EGI-1 analogue inhibitors with eIF4E. We find that inhibition of eIF4G binding must be allosteric, because the 4EGI-1 and eIF4G bind at distant epitopes on eIF4E. Compound binding induces extension of an α-helix that stretches between the two binding sites. Indeed, mutations increasing helix propensity in this region reduce eIF4G affinity in the absence of the inhibitor, which is consistent with the proposed allosteric model.