9CN3

Human 39S mitoribosome in complex with antibiotic Linezolid

This is a non-PDB format compatible entry.

Summary for 9CN3

• Entry DOI: 10.2210/pdb9cn3/pdb
• EMDB information: 45757
• Descriptor: 39S ribosomal protein L32, mitochondrial, 39S ribosomal protein L41, mitochondrial, 16S rRNA, ... (58 entities in total)
• Functional Keywords: mitochondrial ribosome, oxazolidinone, antibiotics, ribosome-antibiotic complex, ribosome/antibiotic
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 56
• Total formula weight: 1861058.19

Authors

Raskar, T.,Bibel, B.,Galonic Fujimori, D.,Fraser, J. (deposition date: 2024-07-15, release date: 2025-04-23, Last modification date: 2025-05-21)

Primary citation

Bibel, B.,Raskar, T.,Couvillion, M.,Lee, M.,Kleinman, J.I.,Takeuchi-Tomita, N.,Churchman, L.S.,Fraser, J.S.,Fujimori, D.G.
Context-specific inhibition of mitochondrial ribosomes by phenicol and oxazolidinone antibiotics.
Nucleic Acids Res., 53:-, 2025

PubMed Abstract: The antibiotics chloramphenicol (CHL) and oxazolidinones, including linezolid (LZD), are known to inhibit mitochondrial translation. This can result in serious, potentially deadly, side effects when used therapeutically. Although the mechanism by which CHL and LZD inhibit bacterial ribosomes has been elucidated in detail, their mechanism of action against mitochondrial ribosomes has yet to be explored. CHL and oxazolidinones bind to the ribosomal peptidyl transfer center (PTC) of the bacterial ribosome and prevent incorporation of incoming amino acids under specific sequence contexts, causing ribosomes to stall only at certain sequences. Through mitoribosome profiling, we show that inhibition of mitochondrial ribosomes is similarly context-specific-CHL and LZD lead to mitoribosome stalling primarily when there is an alanine, serine, or threonine in the penultimate position of the nascent peptide chain. We further validate context-specific stalling through in vitro translation assays. A high-resolution cryo-electron microscopy structure of LZD bound to the PTC of the human mitoribosome shows extensive similarity to the mode of bacterial inhibition and also suggests potential avenues for altering selectivity. Our findings could help inform the rational development of future, less mitotoxic, antibiotics, which are critically needed in the current era of increasing antimicrobial resistance.

PubMed: 39907106
DOI: 10.1093/nar/gkaf046

Experimental method

ELECTRON MICROSCOPY (2.62 Å)