The ribosome is a major target for clinically used antibiotics, but multidrug resistant pathogenic bacteria are making our current arsenal of antimicrobials obsolete. Here we present cryo-electron-microscopy structures of 17 distinct compounds from six different antibiotic classes bound to the bacterial ribosome at resolutions ranging from 1.6 to 2.2 Å. The improved resolution enables a precise description of antibiotic-ribosome interactions, encompassing solvent networks that mediate multiple additional interactions between the drugs and their target. Our results reveal a high structural conservation in the binding mode between antibiotics with the same scaffold, including ordered water molecules. Water molecules are visualized within the antibiotic binding sites that are preordered, become ordered in the presence of the drug and that are physically displaced on drug binding. Insight into RNA-ligand interactions will facilitate development of new antimicrobial agents, as well as other RNA-targeting therapies.

• MeSH
• antibakteriální látky * farmakologie   chemie   MeSH
• Bacteria metabolismus   MeSH
• ribozomy * metabolismus   MeSH
• RNA metabolismus   MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Ribosomes synthesizing proteins containing consecutive proline residues become stalled and require rescue via the action of uniquely modified translation elongation factors, EF-P in bacteria, or archaeal/eukaryotic a/eIF5A. To date, no structures exist of EF-P or eIF5A in complex with translating ribosomes stalled at polyproline stretches, and thus structural insight into how EF-P/eIF5A rescue these arrested ribosomes has been lacking. Here we present cryo-EM structures of ribosomes stalled on proline stretches, without and with modified EF-P. The structures suggest that the favored conformation of the polyproline-containing nascent chain is incompatible with the peptide exit tunnel of the ribosome and leads to destabilization of the peptidyl-tRNA. Binding of EF-P stabilizes the P-site tRNA, particularly via interactions between its modification and the CCA end, thereby enforcing an alternative conformation of the polyproline-containing nascent chain, which allows a favorable substrate geometry for peptide bond formation.

• MeSH
• elektronová kryomikroskopie MeSH
• elongační faktory chemie   genetika   metabolismus   ultrastruktura   MeSH
• Escherichia coli genetika   metabolismus   MeSH
• iniciační faktory chemie   metabolismus   MeSH
• konformace nukleové kyseliny MeSH
• konformace proteinů MeSH
• messenger RNA chemie   genetika   metabolismus   MeSH
• mutace MeSH
• peptidy chemie   metabolismus   MeSH
• proteiny vázající RNA chemie   metabolismus   MeSH
• proteiny z Escherichia coli chemie   genetika   metabolismus   ultrastruktura   MeSH
• proteosyntéza MeSH
• ribozomy chemie   metabolismus   ultrastruktura   MeSH
• RNA transferová chemie   genetika   metabolismus   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• otorinolaryngologie MeSH
• Publikační typ
• periodika MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• otorinolaryngologie