Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics.
Amino Acid Motifs
Amino Acid Sequence
Anti-Bacterial Agents
/ chemistry
Bacillus subtilis
/ drug effects
Binding Sites
/ genetics
Cryoelectron Microscopy
Drug Resistance, Microbial
/ genetics
Erythromycin
/ chemistry
Genes, Bacterial
Ketolides
/ chemistry
Macrolides
/ chemistry
Methyltransferases
/ chemistry
Molecular Dynamics Simulation
Mutagenesis, Insertional
Protein Biosynthesis
/ drug effects
Protein Synthesis Inhibitors
/ chemistry
Ribosomes
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 07 2021
22 07 2021
Historique:
received:
26
05
2021
accepted:
30
06
2021
entrez:
23
7
2021
pubmed:
24
7
2021
medline:
4
8
2021
Statut:
epublish
Résumé
Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics.
Identifiants
pubmed: 34294725
doi: 10.1038/s41467-021-24674-9
pii: 10.1038/s41467-021-24674-9
pmc: PMC8298421
doi:
Substances chimiques
Anti-Bacterial Agents
0
Ketolides
0
Macrolides
0
Protein Synthesis Inhibitors
0
Erythromycin
63937KV33D
Methyltransferases
EC 2.1.1.-
rRNA (adenosine-O-2'-)methyltransferase
EC 2.1.1.230
telithromycin
KI8H7H19WL
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4466Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM127134
Pays : United States
Informations de copyright
© 2021. The Author(s).
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