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CAG triple-nucleotide repeats in multiple genes have been linked to various human diseases. A recent study unveils the effects of CAG repeat RNA gelation on protein translation, thereby expanding our knowledge of CAG-elicited toxicities.
A universally effective method has been developed to enable cryo-electron microscopy structural determination of G protein–coupled receptors in various states. This method will accelerate structure-based drug discovery and enhance understanding of the activation mechanism for these receptors.
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.
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.
Modular polyketide synthases are multidomain megasynthases catalyzing polyketide chain elongation, modification and release. New work reveals a full ~360-kDa modular polyketide synthases with just one active domain, ketosynthase, catalyzing an amidation that releases the completed product (a reaction type typically catalyzed by dedicated thioesterases).
A study has now shown that copper ions can drive inflammation via a mitochondrial signaling pathway that regulates epigenetic states of immune cells. This pathway could offer a new route for treating inflammatory diseases.
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.
Brassinosteroid (BR) hormones promote root growth by controlling meristem size and cell elongation, but the mechanism of BR transport remains elusive. A new study shows that BR precursors move via intercellular pores called plasmodesmata to modulate BR cellular levels and their signaling functions.
Medicinal drugs can cross-react with gut bacterial proteins, but the identification of these off-target interactions is difficult. Multi-omic approaches enabled the discovery of a bacterial peptidase that is inhibited by diabetic drugs and unexpectedly influences bacterial fitness within complex microbial communities via a non-proteolytic mechanism.
We designed FAK-SPARK, a fluorescent reporter of focal adhesion kinase (FAK) activity based on phase separation. FAK-SPARK revealed polarized FAK activity within single focal adhesions in the leading edges of migrating cells. By combining FAK-SPARK with DNA tension probes, we showed that FAK activity is proportional to the tension strength.
New biochemical and structural studies into the capsule biosynthesis pathway of Haemophilus influenzae serotype b (Hib) provide invaluable insights into a unique, basket-shaped multi-modular enzymatic machinery, allowing accelerated development of fermentation-free production methods for Hib glycoconjugate vaccine.
Lysosomal hyperacidification is regarded as a hallmark of autophagy. A new pH nanosensor that detects shifts in near-infrared emission bands is used to quantify cellular and intratumoral lysosomal pH.
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.
Sodium bisulfite is widely used in methylation sequencing, yet it degrades DNA, and on its own, it does not discriminate methylated cytosine from its oxidized derivative, 5-hydroxymethylcytosine. A new bisulfite-free technique uses enzymatic modification of DNA for direct and accurate methylation mapping.
We identified a comprehensive targetome for glycolytic metabolites in cancer cells using a novel target discovery approach — target responsive accessibility profiling (TRAP). The targetome revealed diverse regulatory modalities for glycolytic metabolites that include engaging with metabolic enzymes, influencing transcriptional outputs and modulating post-translational modification levels, thereby elucidating how glycolytic metabolites function as signaling molecules.
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.
A new platform for screening nucleophilic-fragment-based covalent ligands enables the identification and targeting of ligandable sulfenic acid sites, setting the stage for exploration of nucleophile-directed probe and drug development.
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.
Tricyclic peptides have reduced conformational flexibility, making them well suited for ligand development. Researchers have now generated large combinatorial libraries of tricyclic peptides using a disulfide-directing motif. Screening these libraries discovered binders to challenging protein targets.
