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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.

Membrane-less organelles formed by liquid–liquid phase separation provide additional cellular compartmentalization for precise spatiotemporal regulation of biological processes. Ke Ruan, Yi Lin, Peiguo Yang and Wen Zhou report on the formation, regulation and function of biomolecular condensates, discussed at the 2023 Xiangshan Science Conference on Membrane-less Organelles.

The susceptibility of nitric oxide (NO) to scavenging and oxidation limits its bioavailability and signaling role. New studies indicate that a NO–ferroheme adduct is resistant to such constraints and may serve as an alternative NO-derived signaling molecule in vasculature.

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.

By investigating the structure–activity relationship of molecular glue degraders that target cyclin K, we discovered that a wide range of compounds, including known kinase inhibitors, possess this gain-of-function activity. These findings provide insights that might enable more rational design and optimization of molecular glue compounds.

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.

Newly developed synthetic antibodies offer the means to be used as high-affinity, conformation-specific probes to capture dynamic repertoires of neddylated cullin–RING E3 ligase complexes. This allows nonenzymatic profiling of the diverse signaling networks that are based on these active complexes.

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.