Ribosome translating mRNA with premature termination codons (PTC-ribosome) (PTC-ribosome)

The ribosome translating mRNA with premature termination codons (PTCs) is a specialized ribonucleoprotein complex that serves as the primary target for nonsense suppression therapy (Welch et al., 2007, Nature). In genetic diseases caused by nonsense mutations, a premature stop codon (UAA, UAG, or UGA) is introduced into the protein-coding sequence, leading to the production of truncated, non-functional proteins and the degradation of mRNA via nonsense-mediated decay (NMD) (Keeling et al., 2014, Crit Rev Biochem Mol Biol). Small molecule read-through agents, such as ataluren and certain aminoglycosides, interact with the ribosomal decoding center when it encounters a PTC (Lynch and Puglisi, 2001, J Mol Biol). These drugs decrease the accuracy of codon-anticodon recognition, favoring the recruitment of a near-cognate aminoacyl-tRNA over release factors. This allows the ribosome to continue translation through the PTC to the natural stop codon, restoring the synthesis of full-length, functional protein (Nagel-Wolfrum et al., 2016, Gene Ther). This target is central to treating thousands of rare genetic disorders where a single point mutation results in a complete loss of protein function. Restoring even small amounts of functional protein can significantly alter disease progression in conditions like cystic fibrosis or Duchenne muscular dystrophy.

Other names

Premature termination codon-stalled ribosomeNonsense-mutated mRNA-ribosome complexPTC-containing ribonucleoprotein complexRibosome-PTC complex

Induction of translational read-through by binding to the ribosomal decoding center and promoting the insertion of near-cognate aminoacyl-tRNAs at premature stop codons, thereby bypassing the mutation and producing full-length protein.