7s1k
Cfr-modified Escherichia coli stalled ribosome with antibiotic radezolid
Structural highlights
FunctionRS19_ECOLI In the E.coli 70S ribosome in the initiation state (PubMed:12809609) it has been modeled to contact the 23S rRNA of the 50S subunit forming part of bridge B1a; this bridge is broken in the model with bound EF-G. The 23S rRNA contact site in bridge B1a is modeled to differ in different ribosomal states (PubMed:12859903), contacting alternately S13 or S19. In the 3.5 angstroms resolved ribosome structures (PubMed:16272117) the contacts between L5, S13 and S19 bridge B1b are different, confirming the dynamic nature of this interaction. Bridge B1a is not visible in the crystallized ribosomes due to 23S rRNA disorder.[HAMAP-Rule:MF_00531] Protein S19 forms a complex with S13 that binds strongly to the 16S ribosomal RNA. Contacts the A site tRNA.[HAMAP-Rule:MF_00531] Publication Abstract from PubMedThe 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. Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics.,Tsai K, Stojkovic V, Lee DJ, Young ID, Szal T, Klepacki D, Vazquez-Laslop N, Mankin AS, Fraser JS, Fujimori DG Nat Struct Mol Biol. 2022 Feb;29(2):162-171. doi: 10.1038/s41594-022-00723-9. , Epub 2022 Feb 14. PMID:35165456[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
