Role of antibiotic ligand in nascent peptide-dependent ribosome stalling

Role of antibiotic ligand in nascent peptide-dependent ribosome stalling.

Specific nascent peptides in the ribosome exit tunnel can elicit translation arrest. Such ribosome stalling is used for regulation of expression of some bacterial and eukaryotic genes. The stalling is sensitive to additional cellular cues, most commonly the binding of specific small-molecular-weight cofactors to the ribosome. The role of cofactors in programmed translation arrest is unknown. By...

Nascent peptide-mediated ribosome stalling promoted by antibiotics

Critical 23S rRNA interactions for macrolide-dependent ribosome stalling on the ErmCL nascent peptide chain

The nascent peptide exit tunnel has recently been identified as a functional region of ribosomes contributing to translation regulation and co-translational protein folding. Inducible expression of the erm resistance genes depends on ribosome stalling at specific codons of an upstream open reading frame in the presence of an exit tunnel-bound macrolide antibiotic. The molecular basis for this t...

Molecular basis for erythromycin-dependent ribosome stalling during translation of the ErmBL leader peptide.

In bacteria, ribosome stalling during translation of ErmBL leader peptide occurs in the presence of the antibiotic erythromycin and leads to induction of expression of the downstream macrolide resistance methyltransferase ErmB. The lack of structures of drug-dependent stalled ribosome complexes (SRCs) has limited our mechanistic understanding of this regulatory process. Here we present a cryo-e...

Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces pla...