Volume 19 Issue 9, September 2023

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.

A study of drug-resistant lymphomas with hypermorphic mutations in PRC2 has identified a ‘methylation index’ by which cancer cells maintain optimal H3K27me3 levels for survival, emphasizing the importance of understanding how tumors adapt to changes in chromatin and to drug-resistance mutations.

The development of biosensors has been slowed by the optimization required for each new iteration. Now, the ChemoX platform facilitates the expansion of sensor design, resulting in unique Förster resonance energy transfer pairings with versatile applications and optimized readouts.

Protein stability is important for biological function, but little is known about in-cell stability. In the New Delhi metallo-β-lactamase NDM-1, enhancement of zinc binding or amino acid substitutions at the C terminus increase in-cell kinetic stability and prevent proteolysis. These findings link NDM-1-mediated resistance with its in-cell stability and physiology.

Synthetic cells are modular gene-expressing compartments with promising applications in biology and medicine. However, a more diverse toolkit is needed to enhance their capabilities, particularly in terms of controlling their gene expression and employing novel synthetic cell–to–living cell signaling pathways. In this work, photocaged promoters and cell-free synthesis of the acyl homoserine lactone synthase BjaI were used to achieve light-activated communication between synthetic cells and living cells.

A selective inhibitor of Sec61 blocks protein entry into the secretory pathway and has therapeutic efficacy in rheumatoid arthritis. A cryo-EM structure of the inhibited Sec61 provides a model for client-selective protein translocation inhibition.

Itskanov and Wang et al. determined high-resolution structures of the human Sec61 channel inhibited by several structurally distinct small molecules and revealed the common inhibitor-binding site in Sec61 and molecular interactions in atomic detail.

Koller et al. determined structures of the O-glycosylated antimicrobial peptide drosocin from Drosophila melanogaster in complex with the bacterial ribosome, revealing the mechanism by which drosocin inhibits the termination phase of protein synthesis.

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.

Biochemical and structural analyses reveal how tetracenomycin X inhibits bacterial translation in a context-dependent manner that relies primarily on the presence of Gln-Lys motifs in the nascent polypeptide chain.

Zhu et al. show how the growth-rate-dependent gene expression reshapes the landscape of cell-fate determination and highlight that expression capacities of genes have unbalanced response to growth variations.

Profiling the resistance landscape to PRC2 inhibitors in EZH2-mutant lymphoma with CRISPR-suppressor scanning reveals drug addiction mutations and a repressive methylation ceiling. Surpassing the ceiling with SETD2 inhibition halts lymphoma growth.

Identification of the molecular features that define the kinetic stability of the clinically relevant NDM-1 metallo-β-lactamase in the bacterial periplasm links the cellular metabolism of this protein with its natural evolution.

De novo designed interleukin-4 mimetics were engineered that induce biased signaling activation and exhibit high thermal stability. These mimetics offer insight into cytokine signaling and can be directly incorporated into 3D-printed biomaterials

Synthetic cells, modular gene-expressing compartments, have shown promising applications in biology and medicine; however, more diverse tools are required for their control and communication. Now, photocaged promoters and cell-free synthesis of an acyl homoserine lactone have been used to demonstrate light-activated communication between synthetic cells and living cells.

Fluorescent proteins and HaloTag allow the flexible design of FRET-based biosensors with adjustable color using different fluorescent proteins or fluorophores and readout can be modified to fluorescence intensity, lifetime or bioluminescence.

The secreted aminopeptidase Pseudomonas aeruginosa aminopeptidase (PaAP) is required for nutrient recycling in biofilms. Using the information from protein structure and kinetics, a potent cyclic peptide inhibitor for PaAP was designed that killed cells in late-stage biofilms.