{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Tsai K"],"funding":["Howard Hughes Medical Institute","NIAID NIH HHS","NIGMS NIH HHS","NIH HHS"],"pagination":["162-171"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8906282"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["29(2)"],"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 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."],"journal":["Nature structural & molecular biology"],"pubmed_title":["Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics."],"pmcid":["PMC8906282"],"funding_grant_id":["R01 AI125518","U24 GM129541","S10 OD020054","R01 AI137270","F32 GM133129","U24 GM129539","R35 GM124724","F32 AI148120","R35 GM127134","S10 OD021741"],"pubmed_authors":["Szal T","Young ID","Vazquez-Laslop N","Lee DJ","Fraser JS","Mankin AS","Tsai K","Stojkovic V","Klepacki D","Fujimori DG"],"additional_accession":[]},"is_claimable":false,"name":"Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Feb","modification":"2026-06-02T16:19:19.094Z","creation":"2025-02-19T01:53:13.37Z"},"accession":"S-EPMC8906282","cross_references":{"pubmed":["35165456"],"doi":["10.1038/s41594-022-00723-9"]}}