Selective Protein Synthesis by Ribosomes with a Drug-Obstructed Exit Tunnel

The polypeptide exit tunnel is an important functional compartment of the ribosome where the newly synthesized proteins are surveyed. The tunnel is the target of clinically important macrolide antibiotics. Macrolides plug the tunnel and are believed to stop production of all proteins. Contrary to this view, we show that drug-bound ribosomes can synthesize a distinct subset of cellular polypeptides. The structure of a protein defines its ability to thread through the antibiotic-obstructed tunnel. Synthesis of certain polypeptides that initially bypass translational arrest can be stopped at later stages of elongation while translation of some proteins goes to completion. Our findings reveal that small-molecule effectors can accentuate the discriminatory properties of the ribosomal exit tunnel and that macrolide antibiotics reshape the cellular proteome rather than block global protein synthesis. º Cells treated with macrolide antibiotics can synthesize a subset of proteins º The nascent peptide sequence determines its ability to bypass the antibiotic block º Some proteins can be arrested by macrolides at the late elongation stage º Binding of small molecules renders ribosomal exit tunnel highly selective A subset of bacterial proteins evades macrolide antibiotic-induced translational arrest. The small molecules shape the proteome by only allowing proteins with characteristic N-terminal sequences to be fully synthesized.