Volume 19 Issue 10, October 2023

A drug-resistance mechanism emphasizes the dependence of epigenetic signaling on acetyl-CoA.

Cryo-EM structures of chemical-compound-bound α-synuclein amyloid fibrils shed light on the mechanism by which small molecules bind to cross-beta-sheet amyloid structures, opening the gateway to rational drug design for targeting pathological amyloid assemblies.

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.

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.

We used chemical proteomics to identify candidate protein targets of indole metabolites in mammalian cells. We discovered that microbiota-derived and synthetic aromatic monoamines can activate recruitment of β-arrestin to the orphan receptor GPRC5A. Specific microbiota species that express amino acid decarboxylases were found to produce aromatic monoamine agonists for GPRC5A.

Pseudouridine (Ψ) is an important modification in RNA biology and mRNA vaccine. A method called PRAISE was developed via selective labeling of Ψ by bisulfite to induce nucleotide deletion signature during reverse transcription, thus realizing quantitative assessment of the Ψ landscape in the human transcriptome.

By using a combined computational and experimental approach, peptide exchange of 12 abundant MHC-II allotypes is shown to maintain responsiveness to HLA-DM catalysis. HLA-DM susceptibility is postulated to contribute to disease association.

The use of chemical proteomics and cell-based assays enabled the discovery of gut microbiota-derived aromatic monoamines and synthetic agonists for an orphan G protein-coupled receptor GPRC5A that stimulated beta-arrestin recruitment.

A resistance mechanism for a class of drugs targeting histone acetyltransferase inhibitors was identified where metabolic rewiring creates high concentrations of acetyl-CoA that outcompete drug-target engagement.

Wang et al. discovered that many cancer-causing fusion proteins form abnormal condensates that affect gene expression and developed a kinetics-dependent screening method called DropScan to find drugs that can dissolve the abnormal condensates to restore normal gene expression.

Tao et al. reported a series of cryo-EM structures of α-synuclein fibrils in complex with amyloid dyes and imaging tracers, and identified druggable pockets in the fibrils of multiple system atrophy.

By developing a genetically encoded biosensor for enzymes that act on O-glycoproteins, Wardman et al. have provided a new method for rapid screening and analysis of these enzymes and performed the first O-glycopeptidase-directed evolution.

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 neuropeptides target G-protein-coupled receptors. Now, it has been shown that the tetrapeptide FMRFamide can directly bind and activate a type of ion channel called FMRFamide-activated sodium channels (FaNaCs). This study reports the structure of the FaNaC ion channel in the apo and FMRFamide-bound states and the substrate specificity and possible gating mechanism of FaNaCs.