Structural basis for differential inhibition of eukaryotic ribosomes by tigecycline

Xiang Li, Mengjiao Wang, Timo Denk, Robert Buschauer, Yi Li, Roland Beckmann () and Jingdong Cheng ()
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Xiang Li: Fudan University
Mengjiao Wang: Fudan University
Timo Denk: Ludwig-Maximilians-Universität München
Robert Buschauer: Ludwig-Maximilians-Universität München
Yi Li: Fudan University
Roland Beckmann: Ludwig-Maximilians-Universität München
Jingdong Cheng: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49797-7

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