Bacterial 23S ribosomal RNA (23S rRNA) cryptic site (23S rRNA)

The Bacterial 50S ribosomal subunit – 23S rRNA cryptic site refers to a specialized binding region within the 23S ribosomal RNA (rRNA) that is not constitutively open but becomes accessible through conformational changes upon ligand binding [1, 2]. Located primarily within the peptidyl transferase center (PTC) and the nascent peptide exit tunnel (NPET), this site is essential for the catalytic formation of peptide bonds and the subsequent passage of the growing protein chain [1, 3]. It is the primary target for several important classes of antibiotics, including oxazolidinones (e.g., linezolid) and pleuromutilins (e.g., lefamulin), which exploit the flexibility of the rRNA to exert their inhibitory effects [2, 3, 5]. By occupying this cryptic pocket, these drugs interfere with the positioning of aminoacyl-tRNA or physically obstruct the exit tunnel, effectively halting bacterial protein synthesis [1, 2]. While highly selective for bacterial ribosomes, the structural similarity between the 23S rRNA and human mitochondrial rRNA can lead to off-target effects and clinical safety concerns such as myelosuppression [1, 4]. Understanding the dynamics of this cryptic site is crucial for overcoming antibiotic resistance, which often arises from mutations in the rRNA or enzymatic modifications that prevent drug access to the pocket [4, 5].

Other names

23S ribosomal RNAPeptidyl transferase center (PTC)Nascent peptide exit tunnel (NPET)50S ribosomal subunit A-siteRibosomal RNA cryptic pocket

Inhibition of bacterial protein synthesis by binding to the 23S rRNA at the peptidyl transferase center (PTC) or the nascent peptide exit tunnel (NPET), which prevents the proper positioning of tRNA or blocks the progression of the growing peptide chain [1, 2, 3].