Mechanism of read-through enhancement by aminoglycosides and mefloquine

• 成果类型: Article
• 署名作者: Kolosova, Olga; Zgadzay, Yury; Stetsenko, Artem; Sukhinina, Anastasia P.; Atamas, Anastasia; Validov, Shamil; Rogachev, Andrey; Usachev, Konstantin; Jenner, Lasse; Dmitriev, Sergey E.; Yusupova, Gulnara; Guskov, Albert; Yusupov, Marat
• 署名单位: Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Institut National de la Sante et de la Recherche Medicale (Inserm); University of Groningen; Lomonosov Moscow State University; Lomonosov Moscow State University; Kazan Federal University; Joint Institute for Nuclear Research - Russia
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12464
• DOI: 10.1073/pnas.2420261122
• 发表日期: 2025-04-29
• 关键词: termination codon readthrough; structural basis; hygromycin-b; stop-codon; rna; inhibition; ribosomes; antibiotics; translocation; specificity

摘要

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 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.