Figure 7. A model for initiation of translation by type IV IRESs.
Starting from the bottom left, type IV IRESs are able to establish a stable binary interaction with the 40S through the IRES elements SL-IV and V. This interaction restricts the flexibility of the 40S-head in a conformation that both allows decoding of PKI and recruitment of the 60S subunit. Top: once the 60S subunit is recruited, the binary CrPV-IRES/80S complex oscillates between canonical and rotated states mimicking the hybrid states of tRNAs (Fernández et al., 2014; Koh et al., 2014). Right: eEF2 in its GTP form binds to the rotated state and induces an extra ~3 degree of rotation of the 40S. This extra rotation results in the IRES interacting with the L1 stalk of the 60S in a wider conformation. Domain IV of eEF2 contacts PKI of the IRES and stabilizes it in an intermediate ap/P-like state. Bottom, post-translocated state (Muhs et al., 2015): GTP hydrolysis results in conformational changes in eEF2 and the ribosome, the translocation of PKI in the P site, breaking of the original contacts of the IRES elements SL-IV and V with the 40S, and release of eEF2. In order for the IRES to adopt such a conformation, a rotation along its longitudinal axes is necessary.