8XT2

Cryo-EM structure of the human 55S mitoribosome with 10uM Tigecycline

This is a non-PDB format compatible entry.

Summary for 8XT2

• Entry DOI: 10.2210/pdb8xt2/pdb
• EMDB information: 38634
• Descriptor: 16s rRNA, Large ribosomal subunit protein uL14m, Large ribosomal subunit protein uL15m, ... (87 entities in total)
• Functional Keywords: ribosome, tigecycline, antibiotic
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 83
• Total formula weight: 2888610.55

Authors

Li, X.,Wang, M.,Cheng, J. (deposition date: 2024-01-10, release date: 2024-07-10, Last modification date: 2024-11-13)

Primary citation

Li, X.,Wang, M.,Denk, T.,Buschauer, R.,Li, Y.,Beckmann, R.,Cheng, J.
Structural basis for differential inhibition of eukaryotic ribosomes by tigecycline.
Nat Commun, 15:5481-5481, 2024

PubMed Abstract: Tigecycline is widely used for treating complicated bacterial infections for which there are no effective drugs. It inhibits bacterial protein translation by blocking the ribosomal A-site. However, even though it is also cytotoxic for human cells, the molecular mechanism of its inhibition remains unclear. Here, we present cryo-EM structures of tigecycline-bound human mitochondrial 55S, 39S, cytoplasmic 80S and yeast cytoplasmic 80S ribosomes. We find that at clinically relevant concentrations, tigecycline effectively targets human 55S mitoribosomes, potentially, by hindering A-site tRNA accommodation and by blocking the peptidyl transfer center. In contrast, tigecycline does not bind to human 80S ribosomes under physiological concentrations. However, at high tigecycline concentrations, in addition to blocking the A-site, both human and yeast 80S ribosomes bind tigecycline at another conserved binding site restricting the movement of the L1 stalk. In conclusion, the observed distinct binding properties of tigecycline may guide new pathways for drug design and therapy.

PubMed: 38942792
DOI: 10.1038/s41467-024-49797-7

Experimental method

ELECTRON MICROSCOPY (3.3 Å)