title: Macrolide antibiotics allosterically predispose the ribosome for translation arrest.
abstract: 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.
authors: Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607;
authors: Shanmugapriya
authors: S
authors: Sothiselvam
authors: Beckman Institute and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors: Bo
authors: B
authors: Liu
authors: Beckman Institute and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors: Wei
authors: W
authors: Han
authors: Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607;
authors: Haripriya
authors: H
authors: Ramu
authors: Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607;
authors: Dorota
authors: D
authors: Klepacki
authors: Institute of Technology, University of Tartu, 50411 Tartu, Estonia;Department of Molecular Biology andLaboratory for Molecular Infection Medicine Sweden, Umeå University, Umeå 90187, Sweden; and.
authors: Gemma Catherine
authors: GC
authors: Atkinson
authors: Institute of Molecular and Cell Biology, University of Tartu, 50411 Tartu, Estonia.
authors: Age
authors: A
authors: Brauer
authors: Institute of Molecular and Cell Biology, University of Tartu, 50411 Tartu, Estonia.
authors: Maido
authors: M
authors: Remm
authors: Institute of Technology, University of Tartu, 50411 Tartu, Estonia;
authors: Tanel
authors: T
authors: Tenson
authors: Beckman Institute and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors: Klaus
authors: K
authors: Schulten
authors: Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607; shura@uic.edu nvazquez@uic.edu.
authors: Nora
authors: N
authors: Vázquez-Laslop
authors: Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607; shura@uic.edu nvazquez@uic.edu.
authors: Alexander S
authors: AS
authors: Mankin
mesh_terms: D000494:Allosteric Regulation; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002474:Cell-Free System; D018942:Macrolides / Q000494:pharmacology*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D014176:Protein Biosynthesis / Q000187:drug effects*; D012270:Ribosomes / Q000187:drug effects* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides
keywords: azithromycin; ketolides; solithromycin