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Title | Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 29, Issue 2, Page 162-171, Year 2022 |
Publish date | Feb 14, 2022 |
Authors | Kaitlyn Tsai / Vanja Stojković / D John Lee / Iris D Young / Teresa Szal / Dorota Klepacki / Nora Vázquez-Laslop / Alexander S Mankin / James S Fraser / Danica Galonić Fujimori / |
PubMed Abstract | The antibiotic linezolid, the first clinically approved member of the oxazolidinone class, inhibits translation of bacterial ribosomes by binding to the peptidyl transferase center. Recent work has ...The antibiotic linezolid, the first clinically approved member of the oxazolidinone class, inhibits translation of bacterial ribosomes by binding to the peptidyl transferase center. Recent work has demonstrated that linezolid does not inhibit peptide bond formation at all sequences but rather acts in a context-specific manner, namely when alanine occupies the penultimate position of the nascent chain. However, the molecular basis for context-specificity has not been elucidated. Here we show that the second-generation oxazolidinone radezolid also induces stalling with a penultimate alanine, and we determine high-resolution cryo-EM structures of linezolid- and radezolid-stalled ribosome complexes to explain their mechanism of action. These structures reveal that the alanine side chain fits within a small hydrophobic crevice created by oxazolidinone, resulting in improved ribosome binding. Modification of the ribosome by the antibiotic resistance enzyme Cfr disrupts stalling due to repositioning of the modified nucleotide. Together, our findings provide molecular understanding for the context-specificity of oxazolidinones. |
External links | Nat Struct Mol Biol / PubMed:35165456 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.35 - 2.48 Å |
Structure data | EMDB-24800, PDB-7s1g: EMDB-24801, PDB-7s1h: EMDB-24802, PDB-7s1i: EMDB-24803, PDB-7s1j: EMDB-24804, PDB-7s1k: |
Chemicals | ChemComp-MG: ChemComp-ZLD: ChemComp-ZN: ChemComp-HOH: ChemComp-RD8: |
Source |
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Keywords | RIBOSOME/ANTIBIOTIC / Escherichia coli stalled ribosome / oxazolidinone / linezolid / RIBOSOME-ANTIBIOTIC complex / Escherichia coli ribosome / RIBOSOME / stalled ribosome / radezolid / Cfr-modified |