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Terminal triple bonds feature in natural products, but their biosynthesis is little known. Now a terminal acetylenase has been characterized for substrate specificity for the first time, and an application to 'bio-click' chemistry has been shown by incorporation of the moiety into natural product scaffolds.
Hydrogen peroxide regulates cell signaling pathways through oxidation of specific thiol proteins. A new study describes a relay system involving peroxiredoxin 2 as a peroxide sensor that oxidizes the mammalian transcription factor STAT3 via a mixed disulfide intermediate.
The small molecule inflachromene was discovered as a microglia-selective inhibitor of the central nervous system proinflammatory response and found to target HMGB2 and HMGB1 to impair proinflammatory signaling in microglia, resulting in neuroprotection.
The dynamic interplay between p53 and Mdm2 triggers cell cycle arrest after DNA damage. A new study reveals that disorder in the transactivation domain of p53 is important for tuning this negative feedback system to ensure normal cellular signaling responses.
AAA+ proteases are quality control machineries consisting of substrate-binding ATPase modules for protein unfolding and a proteolytic chamber. New research now shows a redox switch in the Escherichia coli Lon protease that controls this process, widening the exit pore and activating proteolysis during transition from anaerobic to aerobic environments.
In the assembly of metalloenzymes, the matching of metals and proteins must occur with absolute precision. When zinc-starved, Chlamydomonas maintains its balance of metals by sequestering copper in electron-dense traps for metals, thus preventing mishaps in protein metallation.
A recent study reveals a new cellular pathway that clears the endoplasmic reticulum of misfolded, GPI-anchored proteins at the onset of endoplasmic reticulum (ER) stress. This mechanism, termed rapid ER stress–induced export, represents a nontranscriptional response to mitigate acute ER stress.
Understanding the mechanisms that determine cell fate under endoplasmic reticulum (ER) stress had been hampered by the lack of models to study unfolded protein response (UPR) adaptive phases. The development of an engineered protein to conditionally induce its misfolding allowed the establishment of a resolvable ER stress condition.
Two studies demonstrate that natural killer T-cell adjuvants, covalently attached to either carbohydrate or peptide epitopes, yield effective vaccines.
Biosynthetic gene clusters encode the enzymatic pathways to make secondary metabolites, molecules of great interest for the pharmaceutical and biotechnology industries. Access to an increasing number of microbial genomes, coupled with efficient bioinformatic tools, is creating new momentum in secondary metabolite research.
A newly discovered small molecule with broad reactivity against diverse HIV-1 strains prevents the surface envelope glycoprotein from fusing with host cells and offers a potential new anti–HIV-1 target.
A new family of radical halogenases has been discovered that regio- and stereoselectively chlorinates the unactivated carbon center of indolemonoterpenoid substrates without the prerequisite for the substrate to be bound to a protein carrier.
Development of highly specific kinase inhibitors has been a long-standing challenge in chemical biology. The structural and mechanistic characterization of an Erk1/2 kinase inhibitor provides new strategies to develop specific kinase inhibitors by targeting a binding pocket adjacent to the ATP binding site.
Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory neurotransmission, which is crucial for memory and learning. New cryo-electron microscopy structures of these receptors trapped in distinct functional states provide remarkable insight into conformational changes triggered by agonist binding.
The application of macrocycles to previously undruggable targets has aroused a great deal of interest in this structural class. Recent studies advance our understanding of the way macrocycles bind protein targets and provide new strategies and tools to generate peptide-based macrocycles.
Conventional allosteric modulators of G protein–coupled receptors (GPCRs) bind their target from the extracellular site. A new study shows that a GPCR's intracellular face can likewise be exploited. In particular, they sensitize a class B GPCR for activation by a hardly active peptide-hormone metabolite.
The gene cluster that produces the sponge-derived cytotoxin calyculin A has been located in an uncultivated bacterial symbiont. Biochemical analyses reveal a pyrophosphorylated protoxin as the true biosynthetic product and suggest that calyculins result from activated chemical defense.
Comprehensive selectivity profiling is key for the development of safe drugs. Few current methods are capable of profiling large compound sets against entire target classes. The new EnPlex method expands the existing toolbox, allowing for the surveying of the serine hydrolase enzyme family.
Therapeutic drug monitoring is vital for maintaining drug concentrations within the body in real time, maximizing therapeutic effects while minimizing the risk of harmful overdosing or wasteful underdosing. Semisynthetic fusion proteins now provide a straightforward strategy for drug monitoring by simply taking a picture of glowing paper.
