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Yeast engineered to produce the six-carbon terpene building block 2-methyl-geranyl diphosphate, coupled with terpene synthases engineered to accept this noncanonical substrate, enables the biosynthesis of a collection of new C11 terpenoid scaffolds.
The freshwater microcrustacean Daphnia pulex forms defensive neckteeth in response to a collection of chemical cues (the kairomone), now identified as certain fatty acids conjugated to glutamine, released during digestion by its predator Chaoborus.
The HIV protease inhibitor ritonavir targets the calcium-inducing domain (CID) of CD95 to block interactions with PLCγ1. Peptidomimetics targeting the CD95 CID prevents accumulation of inflammatory Th17 cells observed in systemic lupus erythematosus.
A structural study supported by molecular dynamics simulations describes the basis of receptor-subtype selectivity of a small-molecule antagonist of the human muscarinic M2 receptor.
Bioinformatic analysis coupled to substrate-reactivity profiling for the glycosyltransferase (GT) enzyme superfamily supports the development of ‘GT-Predict’ as a tool for functional prediction of GT–substrate relationships.
High-throughput screening and activity-based protein profiling find a selective and in vivo–active inhibitor of the membrane-associated serine hydrolase ABHD12 that alters lysophospholipid content and has immunostimulatory effects.
HIP1R directly interacts with PD-L1 and targets PD-L1 for lysosomal degradation. Development of a rationally designed peptide incorporating the PD-L1 binding sequence of HIP1R with a lysosomal targeting sequence promotes PD-L1 degradation.
The use of an allosteric drug-design method resulted in the identification of a first-in-class cellularly active SIRT6 activator that induces cell-cycle arrest in the G0–G1 phase, thus suppressing proliferation in human hepatocellular carcinoma cells.
Structural and biochemical analysis of propionyl-CoA synthase reveals that it forms a reaction chamber containing three active sites, which sequesters the reactive intermediate acrylyl-CoA during the conversion of 3-hydroxypropionate to propionyl-CoA.
An inhibitor of the YEATS domain was developed by targeting a unique π-π-π stacking in the YEATS–Kcr recognition. An ENL YEATS-selective inhibitor, XL-13m, helps probe the YEATS-dependent role of ENL in the leukemogenic transcription program.
Engineering of small-molecule-responsive RNA-binding proteins enables chemical regulation of modified mRNA or RNA replicon expression within mammalian cells for applications in synthetic circuit design and RNA-centered therapeutics.
The active-state structure of a GPCR occupied by a partial agonist, β2AR with salmeterol, together with mutagenesis and biophysical studies, explains this ligand's unusual pharmacological profile.
In response to the deletion of key genes involved in biosynthesis of the essential CoA precursor β-alanine, Escherichia coli overcomes this pathway damage by successively evolving alternative metabolic pathways.
mmBCFAs are endogenous fatty acids synthesized from BCAAs by brown and white adipose tissue via CrAT and FASN promiscuity. BCAA catabolism and mmBCFA lipogenesis are decreased by obesity-induced adipose hypoxia and influenced by the microbiome.
Protonation of periplasmic protein carboxylic groups creates a Donnan equilibrium in the bacterial periplasmic space at low pH, leading to accumulation of Cl− and unfolding and aggregation of periplasmic proteins, which can be rescued by chaperones.
High-throughput screening followed by an examination of structure–activity relationship-based optimization resulted in the identification of potent small-molecule inhibitors of group IIB intron splicing in fungal organisms.
High intracellular concentrations of the α-ketoglutarate analog N-oxalylglycine, owing to MCT2-mediated transport of its newly described prodrug MOG, inhibit multiple enzymes in glutamine metabolism and selectively kill MCT2-expressing cancer cells.
A chemical method for site-selective deuterium exchange at protein backbone α-carbons, involving conversion of cysteine to dehydroalanine and then to deuterated cysteine, is used to explore the mechanism of a model protein bioconjugation reaction.
Structural analysis shows that cross-reactivity of the T cell receptor DMF5 is governed by adaptability of the peptide antigen, which can undergo TCR-binding-induced frameshifting forcing the peptide C terminus to extend from the MHC-binding groove.