Fiche publication
Date publication
avril 2025
Journal
Proceedings of the National Academy of Sciences of the United States of America
Auteurs
Membres identifiés du Cancéropôle Est :
Dr YUSUPOV Marat
,
Dr YUSUPOVA Gulnara
Tous les auteurs :
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
Lien Pubmed
Résumé
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.
Mots clés
aminoglycosides, mefloquine, read-through, ribosome
Référence
Proc Natl Acad Sci U S A. 2025 04 29;122(17):e2420261122
