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Molecular basis for erythromycin-dependent ribosome stalling during translation of the ErmBL leader peptide

2014; Nature Portfolio; Volume: 5; Issue: 1 Linguagem: Inglês

10.1038/ncomms4501

2041-1723

Stefan Arenz, Haripriya Ramu, Pulkit Gupta, Otto Berninghausen, Roland Beckmann, Nora Vázquez‐Laslop, Alexander S. Mankin, Daniel N. Wilson,

RNA modifications and cancer

In bacteria, ribosome stalling during translation of ErmBL leader peptide occurs in the presence of the antibiotic erythromycin and leads to induction of expression of the downstream macrolide resistance methyltransferase ErmB. The lack of structures of drug-dependent stalled ribosome complexes (SRCs) has limited our mechanistic understanding of this regulatory process. Here we present a cryo-electron microscopy structure of the erythromycin-dependent ErmBL-SRC. The structure reveals that the antibiotic does not interact directly with ErmBL, but rather redirects the path of the peptide within the tunnel. Furthermore, we identify a key peptide–ribosome interaction that defines an important relay pathway from the ribosomal tunnel to the peptidyltransferase centre (PTC). The PTC of the ErmBL-SRC appears to adopt an uninduced state that prevents accommodation of Lys-tRNA at the A-site, thus providing structural basis for understanding how the drug and the nascent peptide cooperate to inhibit peptide bond formation and induce translation arrest. In bacteria, the ribosomal stalling during translation of leader peptides is a mechanism of antibiotic resistance that has not been well understood. Here, the structure of a drug-dependent stalled ribosome complex has allowed the authors to propose a detailed mechanism for this translational arrest.