Articles

Park et al. redesigned the abscisic acid-induced dimerization module to respond to diverse ligands and function orthogonally to the natural modules, enabling synthetic biological circuit design in plants and yeast.

A controllable protease-based protein secretion platform was developed for the rapid delivery of user-defined therapeutic protein secretion in response to FDA-approved drugs, tumor antigen and light, enabling cell-based precision therapies.

A lipid-like small molecule, MAO-N₃, was developed to assemble inner mitochondrial membrane-specific probes for confocal and various super-resolution microscopy techniques, with significantly improved time-lapse capability and minimal toxicity.

Almost all terpenoids discovered so far have backbones made up of multiples of five carbon atoms. Here, the authors combine gene mining with biochemical characterization and chemical structure analysis to unveil an extensive class of terpenoids with 16 carbon atoms in bacteria.

A cell-based phenotypic screen led to the discovery of compounds called NVS-STGs, which bind to the N-terminal domain of STING and act as a molecular glue to induce higher-order oligomerization and activation.

Determining which covalent binding events impact protein function is challenging. Now, a strategy has been reported that integrates base editing and chemical proteomics to infer the functionality of ligandable cysteines in cancer dependency proteins by quantifying the impact of their missense mutation on cancer cell proliferation.

The flavoenzyme nicotine oxidoreductase degrades nicotine in the bloodstream. Now, genetic selection in bacteria has been used to improve the catalytic performance of nicotine oxidoreductase, isolating variants with increased O₂ reactivity that were more effective at degrading nicotine in the blood of rats.

Nou et al. engineered Bacillus subtilis cells into a living sentinel system, which can take up environmental DNA and fluoresce when a matching sequence is detected. This system enables recording of SNPs for facial features and has broad applications spanning forensics to agriculture.

Condensates have been proposed to create a distinct chemical solvating environment. In vitro condensate screens suggest that condensate chemical environments influence the intracellular distribution of small molecules.

This study reveals β-arrestin-independent GPCR signaling via the cAMP pathway from endosomes, and it delineates a discrete function of β-arrestin in temporally resolving the endosomal signaling phase as a separate peak of cytoplasmic cAMP.

Through directed evolution, the PAM compatibility of the compact Cas9 variant CjCas9 was increased. Evolved CjCas9 shows higher nuclease activity at canonical and non-canonical sites and enables robust in vivo gene editing from single AAV vectors.

Nitric oxide (NO) is a potent vascular signaling agent, but its bioavailability is limited through rapid scavenging reactions. DeMartino et al. characterize the formation and bioactivity of NO-ferroheme, a stable NO analog that forms readily, bypasses scavenging reactions and mediates NO signaling.

Questions remain on the nature of the bioactivity of nitric oxide (NO) synthase signaling despite its wide appreciation. Here the authors describe NO-ferroheme as a vascular signaling species, whose biological activity is unrelated to the release of free nitric oxide, but allows it to travel protected to its main target guanylyl cyclase.

Most miniature Cas12f nucleases have T-rich PAM specificity, restricting their targeting scopes. The cryo-EM structure of the Clostridium novyi Cas12f1 reveals the molecular basis for rare C-rich PAM recognition and enables optimization of sgRNA scaffold to improve CnCas12f1 activity.

Detailed analysis of the structure–activity relationship for cyclin K degraders reveals diverse compounds that acquire glue activity through simultaneous binding to the CDK12 kinase pocket and engagement of several key DDB1 interfacial residues.

Peptide phage display reveals a non-catalytic binding site on the intervening domain of O-GlcNAc transferase. Its roles in substrate recognition, posttranslational modification (PTM) crosstalk and nutrient response provide insight into the function of this cryptic domain.

By solving the cryogenic electron microscopy structures of bacterial calcium-activated potassium channels, Fan et al. report a pathway for blockers to enter the closed pore of the channels through membrane portals rather than through the canonical ion entryway, opening new avenues for drug-targeting this class of channels.

Henneberg et al. developed conformation-specific antibodies enabling probing NEDD8-activated cullin–RING ubiquitin E3 ligase networks in response to extracellular stimuli, metabolic signals and degrader drugs.

Tryptophan hydroxylases have only been known from eukaryotes and are involved in the biosynthesis of serotonin or melatonin. Here, the authors characterize a family of bacterial tryptophan hydroxylases that differ markedly from their eukaryotic counterpart in cofactor and catalytic mechanism.

Homologous to E6AP C-terminus (HECT) E3s forge polyubiquitin chains through multiple reaction steps. A HECT polyubiquitylation cascade was visualized step-by-step, through use of chemical tools and cryo‐EM, and revealed how K48 linkage-specificity is attained by oligomeric UBR5.