A model for how ribosomal release factors induce peptidyl-tRNA cleavage in termination of protein synthesis.

A major unresolved question in messenger RNA translation is how ribosomal release factors terminate protein synthesis. Class 1 release factors decode stop codons and trigger hydrolysis of the bond between the nascent polypeptide and tRNA some 75 A away from the decoding site. While the gross features of the release factor-ribosome interaction have been revealed by low-resolution crystal structures, there is no information on the atomic level at either the decoding or peptidyl transfer center. We used extensive computer simulations, constrained by experimental data, to predict how bacterial release factors induce peptide dissociation from the ribosome. A distinct structural solution is presented for how the methylated Gln residue of the universally conserved GGQ release factor motif inserts into the ribosomal A site and promotes rapid reaction with the peptidyl-tRNA substrate. This model explains key mutation experiments and shows that the ribosomal peptidyl transfer center catalyzes its two chemical reactions by a common mechanism.