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Non-apoptotic regulated cell death is not fully characterized, particularly for ferroptosis, the iron- and ROS-dependent form of regulated cell death. A systematic approach using modulatory profiling and cell line sensitivity analysis has unraveled the association of lipid metabolism with ferroptosis and enabled the discovery of a novel specific ferroptosis inducer.
Two independent high-throughput zebrafish behavioral screens of tens of thousands of compounds identify the 'finazines', a novel group of antipsychotics, and their endogenous genetic target, the σ1 receptor.
A phenotypic cell-based screen identifies an inhibitor of BET bromodomain transcriptional activity via inhibition of the alternative bromodomain-containing protein TAF1.
A small molecule has been identified that can mitigate the progression of an inherited form of deafness in transgenic mice by stabilizing mutant clarin-1, an essential component of a multimolecular complex of the mechanotransduction apparatus of hair cells in the inner ear.
Phosphoglycerate dehydrogenase (PHGDH) is an enzyme of serine biosynthesis overexpressed in various types of cancer. A new series of PHGDH inhibitors selectively block proliferation of PHGDH-dependent cancer cells and reveal an unexpected role of serine biosynthesis in coordinating one-carbon metabolism.
Iron–sulfur metalloproteins are critical for electron transfer in bacterial metabolism, but most crystal structures are insufficient for their in-depth study. Now, acquisition of an iron–sulfur protein structure at ultra-high resolution enables detailed visualization of its electron distribution.
The hydroxyl radical is the reactive oxygen species most cytotoxic to cells. A bioplastic-based hydroxyl radical scavenger that is more efficient than glutathione and vitamin C has been found to be produced by bacteria, adding an interesting twist to the story of oxidative stress defense by intracellular pathogens.
A highly selective JAK3 inhibitor with subnanomolar potency has been used to identify two waves of STAT5 phosphorylation in response to IL-2. This reveals a biphasic role for JAK3 catalytic activity in IL-2-mediated signaling that has therapeutic implications.
Cdk1 links mitotic entry to faithful chromosome segregation by activating the acetyltransferase TIP60. Acetylation of Aurora B kinase by TIP60 protects Aurora B's activation loop from dephosphorylation by the PP2A phosphatase to ensure robust Aurora B activation.
Histone 3 lysine 9 acetylation (H3K9ac) levels were modulated by photoresponsive histone deacetylase (HDAC) inhibitors to perturb the transcription of genes involved in cell cycle regulation and mitochondrial function.
Kinesin is a motor protein that drives intracellular transport by stepping along microtubules in a hand-over-hand manner. Advanced dark-field microscopy has made it possible to capture the gait of this motor with unprecedented resolution.
Bacterial pathogen–secreted proteases may have a key role in inhibiting a potentially widespread host-pathogen interaction. Activity-based protein profiling enabled the identification of a major Vibrio cholerae serine protease that limits the ability of a host-derived intestinal lectin to bind to the bacterial pathogen in vivo.
The arrest peptides that function with the macrolide antibiotic erythromycin stall translating ribosomes in the presence of the antibiotic, leading to remodeling of the downstream mRNA and enhancement of the translation of resistance genes. Current work suggests that small changes in the nascent peptide dictate the ability of ribosomes to respond to this and other small molecules.
The versatility of RNA is achieved in part through its ability to adopt various shapes of structures. A new technology called X-ray scattering interferometry enables the detection of 'invisible' states by lighting up gold pairs tagged to RNA molecules.
A sensor of membrane depolarization controls the activity of a bound enzyme through a novel mechanism involving two sequential voltage-dependent transitions allosterically coupled to changes in the substrate specificity of the catalytic domain.
Since the 1980s, scientists have worked on designing genetic codes to reinforce containment and control of genetically engineered microbes. New mechanistic studies of “deadman” and “passcode” gene circuits provide a flexible platform to build new safety switches.
Protein aggregation is associated with more than 50 human pathologies, including prevalent conditions such as Alzheimer's and Parkinson's diseases. A phenotypic screen in Escherichia coli associating antibiotic resistance with the inhibition of protein aggregation now allows screening for chemical inhibitors of protein aggregation in a simple, fast and inexpensive manner.
A small molecule's biological activity in a cell depends on the actions of many gene products. Correlations between basal gene expression and compound sensitivity across hundreds of human cell lines reveal a broad view of cellular mechanisms of action.
