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Title | Structures of the Staphylococcus aureus ribosome inhibited by fusidic acid and fusidic acid cyclopentane. |
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Journal, issue, pages | Sci Rep, Vol. 14, Issue 1, Page 14253, Year 2024 |
Publish date | Jun 20, 2024 |
![]() | Adrián González-López / Daniel S D Larsson / Ravi Kiran Koripella / Brett N Cain / Martin Garcia Chavez / Paul J Hergenrother / Suparna Sanyal / Maria Selmer / ![]() ![]() |
PubMed Abstract | 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 ...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. |
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Methods | EM (single particle) |
Resolution | 2.02 - 2.49 Å |
Structure data | EMDB-17363, PDB-8p2f: EMDB-17364: Staphylococcus aureus 70S ribosome with elongation factor G locked with fusidic acid cyclopentane with a tRNA in pe/E chimeric hybrid state EMDB-17365, PDB-8p2h: |
Chemicals | ![]() ChemComp-ZN: ![]() ChemComp-MG: ![]() ChemComp-SPD: ![]() ChemComp-PUT: ![]() ChemComp-GDP: ![]()
ChemComp-WUX: ![]() ChemComp-K: ![]() ChemComp-HOH: ![]() ChemComp-FUA: |
Source |
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![]() | RIBOSOME / fusidic acid / EF-G / antibiotic |