Mechanism of read-through enhancement by aminoglycosides and mefloquine
Nonsense mutations are associated with numerous and diverse pathologies, yet effective treatment strategies remain elusive. A promising approach to combat these conditions involves the use of aminoglycosides, particularly in combination with stop-codon read-through enhancers, for developing drugs that can rescue the production of full-length proteins. Using X-ray crystallography and single-particle cryo-EM, we obtained structures of the eukaryotic ribosome in complexes with several aminoglycosides (geneticin G418, paromomycin, and hygromycin B) and the antimalarial drug mefloquine (MFQ), which has also been identified as a read-through enhancer. Our study reveals a binding site of MFQ, which holds significant promise for the development of therapies targeting premature termination codon-related genetic and oncological diseases. The results underscore the crucial role of the bridge B7b/c in mediating the effects of MFQ on subunit rotation dynamics. Through a comprehensive analysis of the interactions between the drugs and the eukaryotic ribosome, we propose a unifying hypothesis for read-through enhancement by small molecules, highlighting the role of decoding center rearrangements and intersubunit rotation dynamics.
Authors
- Anastasiia Atamas (ORCID: https://orcid.org/0000-0002-7884-7653)
- L. Jenner (ORCID: https://orcid.org/0000-0003-3917-8853)
- Yury Zgadzay (ORCID: https://orcid.org/0000-0002-0801-4656)
- O A Kolosova (ORCID: https://orcid.org/0000-0003-1348-2152)
- Sergey E. Dmitriev (ORCID: https://orcid.org/0000-0002-1774-8475)
- Andrey Rogachev (ORCID: https://orcid.org/0000-0003-2872-7976)
- Albert Guskov (ORCID: https://orcid.org/0000-0003-2340-2216)
- G. Yusupova (ORCID: https://orcid.org/0000-0002-9119-9136)
- Shamil Validov (ORCID: https://orcid.org/0000-0002-9441-409X)
- Artem Stetsenko (ORCID: https://orcid.org/0000-0003-3032-3794)
- Konstantin S. Usachev (ORCID: https://orcid.org/0000-0002-6331-7764)
- Anastasia P. Sukhinina
- Marat Yusupov (ORCID: https://orcid.org/0000-0001-5544-0597)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Biotechnology Institute (US)
- University of Groningen (NL)
- Lomonosov Moscow State University (RU)
- Kazan Federal University (RU)
- Joint Institute for Nuclear Research (RU)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Centre of Advanced Studies (RU)
- Moscow State University (TJ)
- Université de Strasbourg (FR)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-04-24
- DOI
- https://doi.org/10.1073/pnas.2420261122
- Citations
- 7
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Fondation pour la Recherche Médicale
- Russian Science Foundation