Interplay between the ribosomal tunnel, nascent chain, and macrolides influences drug inhibition.
Accumulating evidence suggests that, during translation, nascent chains can form specific interactions with ribosomal exit tunnel to regulate translation and promote initial folding events. The clinically important macrolide antibiotics bind within the exit tunnel and inhibit translation by preventing progression of the nascent chain and inducing peptidyl-tRNA drop-off. Here, we have synthesized amino acid- and peptide-containing macrolides, which are used to demonstrate that distinct amino acids and peptides can establish interaction with components of the ribosomal tunnel and enhance the ribosome-binding and inhibitory properties of the macrolide drugs, consistent with the concept that the exit tunnel is not simply a Teflon-like channel. Surprisingly, we find that macrolide antibiotics do not inhibit translation of all nascent chains similarly, but rather exhibit polypeptide-specific inhibitory effects, providing a change to our general mechanistic understanding of macrolide inhibition.
Gene Center and Department of Biochemistry, University of Munich, LMU, Munich D-81377, Germany.
Agata L
AL
Starosta
Viktoriya V
VV
Karpenko
Anna V
AV
Shishkina
Aleksandra
A
Mikolajka
Natalia V
NV
Sumbatyan
Frank
F
Schluenzen
Galina A
GA
Korshunova
Alexey A
AA
Bogdanov
Daniel N
DN
Wilson
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011500:Protein Synthesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D012346:RNA, Transfer, Amino Acyl / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry* / Q000378:metabolism; D015645:Tylosin / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D018942:Macrolides; D010455:Peptides; D011500:Protein Synthesis Inhibitors; D012346:RNA, Transfer, Amino Acyl; C019037:tRNA, peptidyl-; D015645:Tylosin