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Structural basis for differential inhibition of eukaryotic ribosomes by tigecycline

Author

Listed:
  • 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)

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.

Suggested Citation

  • Xiang Li & Mengjiao Wang & Timo Denk & Robert Buschauer & Yi Li & Roland Beckmann & Jingdong Cheng, 2024. "Structural basis for differential inhibition of eukaryotic ribosomes by tigecycline," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49797-7
    DOI: 10.1038/s41467-024-49797-7
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    1. Hua Su & Fei Yang & Rao Fu & Brittney Trinh & Nina Sun & Junlai Liu & Avi Kumar & Jacopo Baglieri & Jeremy Siruno & Michelle Le & Yuhan Li & Stephen Dozier & Ajay Nair & Aveline Filliol & Nachanok Sin, 2022. "Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome," Nature, Nature, vol. 610(7931), pages 366-372, October.
    2. Momoko Narita & Timo Denk & Yoshitaka Matsuo & Takato Sugiyama & Chisato Kikuguchi & Sota Ito & Nichika Sato & Toru Suzuki & Satoshi Hashimoto & Iva Machová & Petr Tesina & Roland Beckmann & Toshifumi, 2022. "A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Heeseon An & Alban Ordureau & Maria Körner & Joao A. Paulo & J. Wade Harper, 2020. "Systematic quantitative analysis of ribosome inventory during nutrient stress," Nature, Nature, vol. 583(7815), pages 303-309, July.
    4. T. Martin Schmeing & Kevin S. Huang & Scott A. Strobel & Thomas A. Steitz, 2005. "An induced-fit mechanism to promote peptide bond formation and exclude hydrolysis of peptidyl-tRNA," Nature, Nature, vol. 438(7067), pages 520-524, November.
    5. Jingdong Cheng & Otto Berninghausen & Roland Beckmann, 2021. "A distinct assembly pathway of the human 39S late pre-mitoribosome," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
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