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The cover depicts numerous extracellular membrane vesicles associated with a long cellular process on a neural stem cell, imaged by a scanning electron microscope. Isolated extracellular vesicles were found to be metabolically active, and metabolomics analysis revealed the presence of asparaginase activity attributed to the enzyme asparaginase-like 1. Cover design by Erin Dewalt, based on an image generated by Jose Manuel Garcia-Verdugo and Clara Alfaro-Cervello. Article, p951; News & Views, p924
Extracellular vesicles (EVs) are a class of secreted membrane particles capable of transferring biological molecules between cells. Metabolomics measurements indicate that isolated EVs also have autonomous metabolic enzyme activities, including the unexpected identification of endogenous human asparaginase activity.
An allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase—an enzyme that is nonessential for in vitro growth—has potent antimicrobial activity, revealing a potentially expanded target list for antimicrobials and greater chemical space for new inhibitors.
The ability to solubilize membrane proteins while retaining their native function is a persistent challenge. Re-engineering of the membrane protein DsbB into a soluble cytoplasmic version maintained its activity and enabled recompartmentalization of the periplasmic DsbAB disulfide bond–forming system.
Allosteric modulation and biased agonism at GPCRs could be manifestations of the same underlying 'conformational selection' mechanism, and these can be harmonized by considering the influence of ligand–receptor residence time and kinetic context.
An enzymatic rheostat controls ATP levels by regulating flux through two pathways depending on free phosphate levels. Incorporation of this rheostat overcomes ATPase contamination and improves isobutanol production from glucose in a cell-free system.
High-throughput screening identifies an inhibitor of the interaction between α- and β-subunits of the Mycobacterium tuberculosis (Mtb) tryptophan synthase, TrpAB, that allows for defining TrpAB as essential for Mtb infection, independent of a T cell response.
The structure of vanadium nitrogenase reveals key differences from its counterpart molybdenum nitrogenase, particularly in the way it ligands its FeV cofactor, that help to explain the basis for the unique properties of these two nitrogenases.
An NMR fragment screen identified a small molecule that binds to an allosteric site on the proapoptotic protein BAX and synergizes with the BIM BH3 domain to conformationally activate BAX and enhance BAX-mediated membrane poration.
The use of chemical exchange saturation transfer NMR reveals a previously hidden excited conformational state of the fluoride riboswitch, providing a model in which ligand binding allosterically suppresses a linchpin base pair to activate transcription.
Structural characterization of carboxylic acid reductase in multiple didomain configurations, coupled with mutagenesis, reveals how the enzyme transitions into a catalytically competent orientation and prevents over-reduction of its aldehyde product.
Profiling of over 13,000 compounds against yeast gene deletion mutants, defining the differential responses on cells, reveals chemical-genetic interactions that can be used to predict compound function and their target pathways.
Adenomatous polyposis coli (APC) is shown to promote colorectal cancer cell migration by activating the guanine nucleotide exchange factor Asef. Structure-based design resulted in the development of peptidomimetic inhibitors that disrupted APC–Asef interactions.
Biophysical and structural analyses reveal how the glycosylase AlkD utilizes a mechanism of excision that does not involve base flipping to enable an alternative repair pathway for large yatakemycin–DNA adducts.
FRET sensors based on the adenylation and peptidyl carrier protein domains of a nonribosomal peptide synthetase illuminate the relationships between conformational dynamics and the catalytic cycle of this multidomain assembly line enzyme.
Under high-copper conditions, yersiniabactin (Ybt) binds copper (Cu) to prevent toxicity. Ybt is now shown to mediate Cu import under low-Cu conditions through formation of a Cu(II)-Ybt complex resulting in metalation of a Cu-requiring enzyme.
The design of a water-soluble variant of the integral membrane protein DsbB and its coexpression with an export-defective copy of DsbA facilitates disulfide-bond formation in the Escherichia coli cytoplasm in a quinone-dependent fashion.
Structural, biochemical, and phylogenetic analyses of plant prephenate and arogenate dehydrogenases reveal a single residue that defines substrate specificity and sensitivity to product inhibition in two divergent tyrosine biosynthetic pathways.
2′-Deoxy-ADPR, formed from the combined action of NMNAT and CD38 in response to H2O2 signaling, activates TRPM2 ion channel currents more potently than the known agonist ADPR via a deceleration of channel inactivation and a higher average open probability.
A fluorescent biosensor to monitor thioredoxin (Trx) redox activity called TrxRFP1 was developed by genetically linking Trx1 to the redox-sensitive red fluorescent protein rxRFP1. TrxRFP1 was used to detect redox dynamics induced by various chemicals, serum, or epidermal growth factor.