30S ribosomal protein S1 (RpsA) (RpsA)

30S ribosomal protein S1 (RpsA) is an essential protein in Mycobacterium tuberculosis that plays a critical role in both protein translation and the trans-translation quality control pathway (UniProt P9WPH1). Trans-translation is a specialized mechanism used by bacteria to rescue ribosomes that have stalled on damaged or incomplete mRNA, a process that is particularly vital for the survival of M. tuberculosis during its latent or persistent phase (Shi et al., 2011, Science). RpsA has been identified as the primary molecular target for the frontline anti-tuberculosis drug pyrazinamide (PZA). The active metabolite of PZA, pyrazinoic acid (POA), binds to the C-terminal S1 domain of RpsA, thereby inhibiting its interaction with transfer-messenger RNA (tmRNA) and disrupting the trans-translation process (Yang et al., 2015, Nature Communications). This inhibition leads to the accumulation of toxic incomplete proteins and the depletion of functional ribosomes, ultimately killing the non-replicating bacilli. Mutations in the rpsA gene are frequently associated with clinical resistance to pyrazinamide in cases where the pncA gene remains wild-type (NCBI Gene ID: 885940). Understanding the structural interaction between RpsA and POA is crucial for the development of next-generation drugs aimed at overcoming antibiotic resistance in tuberculosis.

Other names

Ribosomal protein S1Rv163030S ribosomal protein S1

Inhibition of trans-translation by binding to the C-terminal domain of RpsA, preventing the recruitment of tmRNA to stalled ribosomes (Shi et al., 2011, Science).