Structures of the Staphylococcus aureus ribosome inhibited by fusidic acid and fusidic acid cyclopentane.
Cryo-EM
EF-G
Elongation factor G
Fusidic acid
Ribosome
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
20 06 2024
20 06 2024
Historique:
received:
23
01
2024
accepted:
13
06
2024
medline:
21
6
2024
pubmed:
21
6
2024
entrez:
20
6
2024
Statut:
epublish
Résumé
The antibiotic fusidic acid (FA) is used to treat Staphylococcus aureus infections. It inhibits protein synthesis by binding to elongation factor G (EF-G) and preventing its release from the ribosome after translocation. While FA, due to permeability issues, is only effective against gram-positive bacteria, the available structures of FA-inhibited complexes are from gram-negative model organisms. To fill this knowledge gap, we solved cryo-EM structures of the S. aureus ribosome in complex with mRNA, tRNA, EF-G and FA to 2.5 Å resolution and the corresponding complex structures with the recently developed FA derivative FA-cyclopentane (FA-CP) to 2.0 Å resolution. With both FA variants, the majority of the ribosomal particles are observed in chimeric state and only a minor population in post-translocational state. As expected, FA binds in a pocket between domains I, II and III of EF-G and the sarcin-ricin loop of 23S rRNA. FA-CP binds in an identical position, but its cyclopentane moiety provides additional contacts to EF-G and 23S rRNA, suggesting that its improved resistance profile towards mutations in EF-G is due to higher-affinity binding. These high-resolution structures reveal new details about the S. aureus ribosome, including confirmation of many rRNA modifications, and provide an optimal starting point for future structure-based drug discovery on an important clinical drug target.
Identifiants
pubmed: 38902339
doi: 10.1038/s41598-024-64868-x
pii: 10.1038/s41598-024-64868-x
doi:
Substances chimiques
Fusidic Acid
59XE10C19C
Cyclopentanes
0
Peptide Elongation Factor G
0
Anti-Bacterial Agents
0
RNA, Transfer
9014-25-9
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
14253Subventions
Organisme : Vetenskapsrådet
ID : 2018-05946
Organisme : Vetenskapsrådet
ID : 2017-03827
Organisme : Knut och Alice Wallenbergs Stiftelse
ID : KAW 2017.0055
Informations de copyright
© 2024. The Author(s).
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