Nascent peptide assists the ribosome in recognizing chemically distinct small molecules

Regulation of gene expression in response to the changing environment is critical for cell survival. For instance, binding of macrolide antibiotics to the ribosome promote the translation arrest at the leader ORFs ermCL and ermBL necessary for inducing antibiotic resistance genes ermC and ermB. Cladinose-containing macrolides, like erythromycin (ERY), but not ketolides e.g., telithromycin (TEL), arrest translation of ermCL, while either ERY or TEL stall ermBL translation. How the ribosome distinguishes between chemically similar small molecules is unknown. We show that single amino acid changes in the leader peptide switch the specificity of recognition of distinct molecules, triggering gene activation in response to only ERY, only TEL, to both antibiotics, or preventing stalling altogether. Thus, the ribosomal response to chemical signals can be modulated by minute changes in the nascent peptide, suggesting that protein sequences could have been optimized for rendering translation sensitive to environmental cues.