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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2021,1,12]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Nonsense mutations giving rise to premature stop codons (PSCs) cause many diseases, creating the need to develop safe and effective translational read-through\u2013inducing drugs (TRIDs). The current best-characterized TRIDs are ataluren and aminoglycosides. Only ataluren has been approved for clinical use, albeit in a limited context. Here, we provide rate measurements of elementary steps in a single eukaryotic translation elongation cycle, allowing us to demonstrate that ataluren and the aminoglycoside G418 employ orthogonal mechanisms in stimulating PSC read-through: ataluren by inhibiting release factor-dependent termination of protein synthesis and G418 by increasing functional near-cognate transfer RNA mispairing, which permits continuation of synthesis. 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