Mechanism of read-through enhancement by aminoglycosides and mefloquine
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (13)
Olga Kolosova
Department of Integrated Structural Biology, Institute of Genetics and Molecular and Cellular Biology, University of Strasbourg
Yury Zgadzay
Department of Integrated Structural Biology, Institute of Genetics and Molecular and Cellular Biology, University of Strasbourg
Artem Stetsenko
Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen
Anastasia P. Sukhinina
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University
Anastasia Atamas
Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen
Shamil Validov
Laboratory of Structural Biology, Institute of Fundamental Medicine and Biology, Kazan Federal University
Andrey Rogachev
Moscow Centre for Advanced Studies
Konstantin Usachev
Laboratory of Structural Biology, Institute of Fundamental Medicine and Biology, Kazan Federal University
Lasse Jenner
Department of Integrated Structural Biology, Institute of Genetics and Molecular and Cellular Biology, University of Strasbourg
Sergey E. Dmitriev
Gulnara Yusupova
Department of Integrated Structural Biology, Institute of Genetics and Molecular and Cellular Biology, University of Strasbourg
Albert Guskov
Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen
Marat Yusupov
Department of Integrated Structural Biology, Institute of Genetics and Molecular and Cellular Biology, University of Strasbourg