IGBMC, Strasbourg
Mechanism of read-through enhancement by aminoglycosides and mefloquine
Proc Natl Acad Sci U S A. 2025 Apr 29;122(17):e2420261122. doi: 10.1073/pnas.2420261122. Epub 2025 Apr 24. PMID: 40273100; PMCID: PMC12054815.
Kolosova O, Zgadzay Y, Stetsenko A, Sukhinina AP, Atamas A, Validov S, Rogachev A, Usachev K, Jenner L, Dmitriev SE, Yusupova G, Guskov A, Yusupov M
Cv
Olga Kolosova is a 32-year-old structural biologist specializing in ribosome biology and drug–ribosome interactions. She studied Physics at Kazan Federal University (Russia), where she investigated antimicrobial proteins during her bachelor’s and master’s degrees. She then shifted to biochemistry for her PhD, defended in 2023, focusing on the ribosome of the pathogenic yeast Candida albicans at the interface of X-ray crystallography and cryo-EM. During her thesis, she developed a protocol that enabled high-resolution ribosome structures without heavy-atom treatment, which revealed novel drug-binding sites, including that of mefloquine (published in PNAS). She also contributed to projects targeting C. albicans ribosomes as potential antifungal drug candidates. Since 2023, she has been a postdoctoral researcher in the laboratory of Marat Yusupov and Gulnara Yusupova at IGBMC, pursuing the search for specific anti-Candida inhibitors using structural and functional approaches.
Contact
IGBMC
1 rue Laurent Fries
Strasbourg
This email address is being protected from spambots. You need JavaScript enabled to view it.
Summary of the article
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.
