Structural Basis for Ribosomal Stereo-selectivity and Action of Ribosome-targeting Antibiotics

The ribosome is a molecular machine that synthesizes all cellular proteins in a template dependent manner, catalyzing the peptide bond formation reaction between L-amino acids. While many small molecules have been developed to inhibit protein translation, the translational machinery may also encounter non-productive substrates, D-amino acids, that need to be regularly weeded out. Remarkably, the ribosome has evolved a preference for L-amino acids, over D-amino acids and is stereo-selective. This work utilizes a structural approach to provide a fundamental understanding the response of the ribosome to atypical occupiers, antibiotics, that block translation, and D-amino acyl tRNAs, that are excluded from protein synthesis. More specifically, we discuss the molecular mechanism of action of derivatives from 2 popular classes of antibiotics, namely, tetracylines and amphenicols, sarecycline (targeting the 30S subunit), CAM-BER (targeting the 50S subunit), respectively. Moreover, this work also examines the molecular basis for ribosomal stereo-specificity. The mechanistic insights into the functioning of the ribosome when faced with ribosome targeting antibiotics, or D-amino acids which can help guide rational drug design and provide a fundamental understanding of how the ribosome distinguishes between D- and L- amino acids.