Ribosome–mRNA complex at premature termination codons (PTC-ribosome complex)

The ribosome–mRNA complex at premature termination codons (PTCs) is a specialized assembly of the protein synthesis machinery that occurs when a nonsense mutation introduces a stop signal earlier than intended in the genetic sequence. In a healthy cell, the ribosome reaches a natural stop codon and recruits release factors to terminate translation; however, at a PTC, this process leads to the production of truncated, often non-functional proteins and triggers nonsense-mediated mRNA decay (NMD), which reduces the availability of the mRNA template (Kuzmiak & Maquat, 2006, J Biol Chem). This complex is a primary therapeutic target for nonsense suppression therapy, where small molecules interact with the ribosome to decrease the stringency of codon recognition. By allowing the incorporation of a near-cognate amino acid at the PTC, these drugs enable the ribosome to continue translation to the original stop codon, restoring the production of full-length, functional proteins (Keeling et al., 2014, Crit Rev Biochem Mol Biol). This strategy is currently being utilized and investigated for a variety of genetic disorders, including Duchenne muscular dystrophy and cystic fibrosis, where nonsense mutations are a common underlying cause (Welch et al., 2007, Nature).

Other names

Premature termination codonNonsense mutation siteStalled ribosome at PTCRibosomal decoding center at nonsense mutations

Drugs bind to the ribosomal decoding center to induce translational read-through by promoting the insertion of a near-cognate tRNA at the premature stop codon, thereby bypassing the mutation and producing a full-length protein.