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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.
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.
Structural and biochemical studies of an acetyltransferase demonstrate that conformational changes differ depending on the ligand bound, indicating that binding cooperativity is more complex than expected.
Crystallographic analysis depicting the interaction of the kinase inhibitor SCH772984 with ERK1/2 reveals a unique binding pocket distinct from off-targets such as haspin and is associated with slow binding kinetics and prolonged inhibitory activity.
Single-molecule measurements show that HSV-1 DNA changes its stiffness by undergoing a solid-to-fluid transition within the capsid in the ionic environment of host cells and at a temperature that is optimal for viral infection.
HIV-1 binds host CD4+ T cells via its gp120 envelope glycoprotein that undergoes changes to allow ‘opening’ of the envelope trimer, exposure of gp41 and binding to the CCR5 co-receptor. Compound 18A inhibits HIV-1 infection by blocking some of these conformational changes.
Metabolic engineering of yeast to incorporate plant and bacterial enzymes that construct and decorate morphine, along with spatial engineering to enable a spontaneous chemical reaction, provides strains capable of producing up to 130 mg/l of opioids.
Production of eukaryotic proteins in bacteria is limited by the specificity of the bacterial oligosaccharyltransferases that perform N-linked glycosylation. ‘GlycoSNAP’ simplifies the study of these enzymes, leading to mutants with relaxed specificity.
Jasmonate derivatives regulate numerous defense and developmental pathways in plants. A chemical screen in Arabidopsis thaliana identifies jarin-1 as an inhibitor of jasmonate biosynthesis and a potential chemical probe of jasmonate signaling.