Macrolide antibiotics allosterically predispose the ribosome for translation arrest

Shanmugapriya Sothiselvam, Bo Liu, Wei Han, Haripriya Ramu, Dorota Klepacki, Gemma Catherine Atkinson, Age Brauer, Maido Remm, Tanel Tenson, Klaus Schulten, Nora Vaźquez-Laslop, Alexander S. Mankin

Research output: Contribution to journalArticlepeer-review


Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome.

Original languageEnglish (US)
Pages (from-to)9804-9809
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number27
StatePublished - Jul 8 2014
Externally publishedYes


  • Azithromycin
  • Ketolides
  • Solithromycin

ASJC Scopus subject areas

  • General


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