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Chemical modification of mRNA nucleobases alters hydrogen bonding during translation. Here the authors show that the N1-methylpseudouridine (m1ψ), used in therapeutics, does not change translation rate but modestly modulates its fidelity in a codon-position and tRNA dependent manner.

Macrolide antibiotics halt protein synthesis in a sequence-dependent manner. Here, authors reveal a comprehensive molecular mechanism by which macrolides induce ribosome stalling selectively at Arg/Lys-X-Arg/Lys motifs in growing polypeptide chains.

Single-molecule FRET technologies reveal the mechanism of sequence-specific translational inhibition induced by two antibiotics, chloramphenicol and linezolid, where aminoacyl-tRNA was repeatedly rejected from the A-site and failed to form a peptide bond.

Antibiotic resistance can be addressed by reinventing classes of antibiotics through chemical synthesis. Here BT-33—a fully synthetic antibiotic—affords broad-spectrum activity against the bacterial ribosome. X-ray crystallography, theoretical calculations and structure–activity relationship studies reveal the structural features that contribute to the enhanced antibacterial activity and metabolic stability of BT-33.

High-resolution crystal structures of Thermus thermophilus ribosomes reveal previously unseen modifications of rRNA and their contacts with mRNA and tRNAs or the protein pY.

A new lasso peptide antibiotic exhibits broad-spectrum activity against Gram-negative and Gram-positive bacteria by interfering with bacterial protein synthesis, is unaffected by common resistance mechanisms and shows no toxicity towards human cells.

The authors discovered that hygromycin A not only enhances the cell-killing properties of macrolides but also renders them active against resistant bacteria. The provided structures of antibiotic pairs in complex with WT and macrolide-resistant ribosomes rationalize binding cooperativity of these drugs.

The antimicrobial peptide Drosocin encoded in the fruit fly genome inhibits bacterial translation by stalling the ribosomes at stop codons, sequestering class 1 release factors and inducing stop codon readthrough. Comprehensive mutational analysis reveals key activity determinants of Drosocin.

Hybrids of macrolides and quinolones, called macrolones, can overcome macrolide-induced resistance through new interactions between the quinolone moiety and the ribosome and can concurrently inhibit both ribosome and DNA gyrase targets.

Structure-guided design and component-based synthesis are used to produce iboxamycin, a novel ribosome-binding antibiotic with potent activity against Gram-positive and Gram-negative bacteria.

Synthesis of peptidyl-tRNAs is challenging because there are no enzymes that can directly attach the desired peptide to tRNA. Now it has been shown that a chemoenzymatic approach based on native chemical ligation can be used for the semi-synthesis of peptidyl-tRNAs for structural/biochemical studies of arrested and non-arrested ribosome complexes.

Structural analysis of the A2058-dimethylated and unmethylated 70S ribosome complex alone and in combination with macrolides reveals the role of the desosamine moiety of macrolides in drug binding and resistance.

The authors determined a set of structures of the methylase Cfr-methylated 70S ribosome with iboxamycin and tylosin, two antibiotics that evade Cfr-mediated drug resistance, and revealed two distinct mechanisms by which small molecules can maintain their ability to engage the Cfr-methylated ribosome.

The authors solve structures of the bacterial ribosome bound to the peptidyl transferase center targeting antibiotic chloramphenicol with adjacent growing peptide chains to explain the context-specificity of action of this antibiotic.

Cells can simultaneously produce structurally dissimilar ribosomes, suggesting functional specialization of distinct ribosome populations. Here, the authors show that distinct ribosomes cooperate rather than specialize in protein synthesis.

The authors report the identification of phazolicin (PHZ) - a prokaryotic translation inhibitory peptide - and its structure in complex with the E. coli ribosome, delineating PHZ’s mode of action and suggesting a basis for its bacterial species-specific activity.

Structural and biochemical analysis reveal that tetracenomycin X acts as an inhibitor of protein synthesis by binding within the exit tunnel in a large ribosomal unit to prevent the prolongation of the nascent polypeptide chain.

Antimicrobial peptide Api137 inhibits translation by trapping release factors 1 or 2 associated with ribosomes and arresting termination.

Initiation factor 2 (IF2) guides the ribosome to the elongation phase of protein synthesis. Here, Basu et al. provide structural insights into how compact IF2-GDP makes way for initiator tRNA accommodation into the peptidyl (P) site of the ribosome.

Identification of the antibiotic peptide KLB, from Klebsiella pneumoniae, which inhibits the growth of various Gram-negative bacteria by binding the nascent peptide exit tunnel on the large ribosomal subunit in a compact curled conformation, thereby stalling translation.

High-throughput analysis of translation arrest sites and structural studies reveal tetracenomycin X as a selective protein synthesis inhibitor, acting predominantly at distinct sequence motifs. The drug may be developed as an antibiotic or for treatments based on halting the expression of individual proteins.

High-resolution structures of the 70S ribosome from Thermus thermophilus reveal a network of ordered waters in the peptidyl transferase center that suggests a mechanism for proton movement and formation and breakdown of the tetrahedral intermediate.

Macrolide antibiotics inhibit bacterial translation in a context-specific manner, arresting ribosomes at defined sites within mRNAs and selectively inhibiting synthesis of only a subset of cellular proteins. Here the authors provide a structural basis for the context-specific activity of macrolides on the eukaryotic ribosome.

Ribosome engineering is an emerging powerful approach for synthetic protein synthesis. Here the authors invert the Ribo-T system, using the engineered ribosome to translate the proteome while the native ribosome translates specific mRNA.

The tethered ribosome system Ribo-T supports cell proliferation though at a reduced rate. Here the authors show this is due to slower ribosome assembly instead of reduced functionality.

Ribosomes of all organisms have retained 5S rRNA as an autonomous rRNA species. Here the authors engineer a bacterial strain with ribosomes that do not have free 5S rRNA, and carry structural analyses that suggest the evolutionary preservation of 5S rRNA as an independent molecule is based on its role in the dynamic process of ribosome biogenesis.

Bacterial MutS2, a paralogue of the DNA mismatch-repair protein MutS, is found to bind collided ribosomes and function in translational quality control.

This report describes an imaging and analysis platform enabling high-throughput single-molecule fluorescence investigations of fast, transient molecular recognition events.

A ribosome with tethered subunits, ‘Ribo-T’, is engineered by making a hybrid RNA composed of ribosomal RNA of large and small subunits; Ribo-T can support cell growth in vivo in the absence of wild-type ribosomes, and is used to establish a fully orthogonal ribosome–mRNA system.