We recently described (Imai, et al., Nature Structural & Molecular Biology 2016) a mechanism that explains how viral Internal Ribosome Entry Sites (IRESs) are structurally designed to exploit host translation factors. This study provided the first structure of an IRES domain that interacts with initiation factors to assemble ribosomes. Our study showed how a conserved stretch of adenines in the J-K region of Encephalomyocarditis virus folds into a pentaloop and acts as a dual-sided docking station for basepair receptors present in J and K stems. This “adjuster module” thus precisely defines the relative orientation of the subdomains, and allows the HEAT-1 domain of eukaryotic initiation factor 4G (eIF4G) to dock onto the pre-organized motifs, with very little reorganization of the RNA upon binding. Mutations to the adjuster module, which does not make any protein contacts, to subtly change the orientation of the domains, leads to a complete loss of protein binding. This study thus illustrated how a virus adapts its RNA structure to acquire an affinity for a target protein of the host cell.

In addition to viral IRESs, we are also interested in IRESs in eukaryotic systems.