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β2-adrenergic receptor–mediated cAMP signaling from internal compartments is more effective compared to the plasma membrane in regulating a distinct set of genes, demonstrating a functional significance for the spatial separation of cAMP signaling.
Biosynthesis of the strigolactones—important plant hormones—has been solved up to carlactone. Biochemical and genetic evidence now demonstrate that homologous enzymes perform two subsequent oxidations, setting the strigolactone scaffold in place.
A collection of chemical tools and spectroscopic techniques demonstrate that Zn availability influences Cu+ storage and localization in the green alga Chlamydomonas, with Zn limitation causing the accumulation of Cu+ in lysosome-related organelles.
A modification of the in silico screening tool, DOCK, allows for identification of compounds that covalently modify catalytic and noncatalytic protein nucleophiles to modulate the activities of bacterial β-lactamase and the kinases RSK2, MSK1 and JAK3.
By biochemical purification and functional validation using knockout animals, ENPP1 is now defined as a major hydrolase for 2′,3′-cGAMP, a cyclic dinucleotide generated during antiviral innate immunity. New nonhydrolyzable 2′,3′-cGAMP analogs are potent activators of this system.
A small-molecule inhibitor of the type III phosphatidylinositol 3-kinase, Vps34, binds the ATP binding pocket and prevents vesicle trafficking and autophagy.
The use of ATP competitive kinase inhibitors against the pseudokinase Her3 has been largely unsuccessful. Hydrophobic tagging of a covalent kinase inhibitor promotes Her3 degradation and prevents productive dimerization and signaling.
A new synthetic biology circuit using recombinases to control the timing of downstream steps allows 1,000-fold differences in signal between on and off states, facilitating cell identification and selective turn-on of cytotoxic agents.
A screen for inhibitors of microglial activation of neuroinflammation identified the compound ICM, which is anti-inflammatory and neuroprotective by targeting HMGB1 and HMGB2, implicating these proteins in a toxic microglial response.
Activity-based probes (ABPs) are widely used for system-wide profiling of enzymatic activity. Electrophilic ABPs applied to genomic RNA libraries led to the isolation of a 42-nt RNA motif that was adapted as an alkylation-based RNA labeling strategy.
A vaccine combining an allergen-specific CD8+ T-cell epitope with an invariant natural killer T (iNKT) cell agonist stimulates immune responses in an animal model of asthma. Rather than a typical pattern recognition receptor ligand as adjuvant, the iNKT agonist used was a glycolipid.
A semisynthetic carbohydrate-lipid vaccine that combines a known adjuvant that has been used in disease models with a lipid capable of activating iNKT cells protects against Streptococcus pneumoniae infection in mice.
A small-molecule activator of procaspase 3, 1541, forms chemical fibrils. shRNA screens, caspase proteomics and small-molecule profiling reveal that these fibrils enter cells through endocytosis and promote a distinctive form of cell death.
A global bioinformatic classification of >11,000 biosynthetic gene clusters from >800 bacterial genomes and cross-correlation with metabolomics data from nearly 200 strains sets the stage for targeted natural product discovery.
N6-methyladenosine (m6A) is an abundant eukaryotic RNA modification that regulates mRNA stability. Biochemical analysis and crystallographic visualization of m6A-YTHDC1 interactions establish this YTH family member as an m6A reader and explain its RNA consensus sequence selectivity.
Protein engineering strategies introduced mutations into the Axl receptor, which bind and trap the Gas6 ligand with high affinity, preventing the activation of downstream signaling pathways.
The use of an endoplasmic reticulum–localized HaloTag system results in protein destabilization and activation of a transient unfolding protein response (UPR) without causing cell death, allowing the examination of later stage UPR events.
A single-molecule study of the dwell times and other features along the full rotation for the human mitochondrial F1-ATPase positions the catalytic events (ATP binding, Pi release and ATP hydrolysis) and reveals differences from the bacterial system.
Nonheme iron halogenases, or enzymes that perform oxidative halogenations, exist in a variety of biosynthetic pathways and modify substrates attached to carrier proteins. Biochemical evidence defines a chlorinase that breaks this rule, acting on soluble substrates.
Arylquin 1 was identified as a Par-4 secretagogue that binds the cytoskeletal intermediate filament protein vimentin and disrupts Par-4–vimentin interactions. The release of Par-4 promotes the apoptosis of cancer cells.