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A set of CRISPR–Cas9-based genetic screens in a haploid human cell line identifies more than 200 gene–drug associations involving solute carriers (SLCs), transporters important for the uptake and activity of cytotoxic drugs.
A small-molecule ligand of the APC/C activator Cdc20, which prolongs mitosis in unperturbed cells, instead shortens mitosis when the spindle checkpoint is activated, producing an opposite effect in a different regulatory context.
A pair of fluorescent DNA-based probes for nitric oxide reveals that nitric oxide synthase 3 activity in the trans-Golgi network is essential for Golgi structural integrity, despite being tenfold less active there than at the plasma membrane.
Small-molecule inhibitors of HIV-1 membrane fusion and infectivity act by partially inserting into a hydrophobic binding pocket formed by the membrane-proximal external region of Env spikes, blocking conformational changes of Env required for fusion.
Structural characterization of WbbM, an enzyme involved in O2a-antigen biosynthesis in Klebsiella pneumoniae, reveals two unique active sites with galactopyranosyl- or galactofuranosyl-transferase activities for oligosaccharide polymerization.
Tuning CRISPR–Cas9 nuclease specificity enables precision genome engineering. Identifying arginine residues along the bridge helix of SpCas9 that mediate Cas9 mismatch sensitivity enabled engineering of Cas9 with increased specificity in human cells.
HIDE probes were developed for long time-lapse imaging of endolysosomes and their dynamics at super-resolution. These probes enabled analyses of endosome motility in primary fibroblasts from patients with Niemann–Pick C with distinct mutations in NPC1.
A high-throughput small-molecule drug screening platform enabled the detection of compounds targeting the functional interactions of receptor tyrosine kinases and identifies four new EGFR triple-mutant inhibitors.
Use of receptor variants in knock-in mice to dissect phosphorylation-dependent signaling from G protein-dependent signaling mediated by acetylcholine receptor M1 mAChR defines the ability of receptor ligands to modulate anxiety and locomotion behaviors.
Using genome-wide CRISPR–Cas9-mediated
suppressor screens, cytochrome P450 oxidoreductase was identified as
a contributor to ferroptotic cell death by promoting phospholipid
peroxidation in various cellular lineages.
In place of the expected flavin-C4a-(hydro)peroxide intermediate, certain flavin monooxygenases such as RutA instead use a flavin-N5-peroxide intermediate as a catalytic nucleophile, enabling chemistry not accessible to canonical monooxygenases.
The ER exit site component Sec16A was identified as the target of Retro-2, a small-molecule inhibitor of protein toxins and pathogens. Retro-2 treatment alters retrograde early/maturing endosomes-to-Golgi trafficking of Shiga toxin.
Susceptibility to ferroptosis can be modulated by nitric oxide (NO•) and NO synthase iNOS and through enrichment of activated M1 macrophages. NO inhibits the lipoxygenase 15-LOX that drives production of pro-ferroptotic lipids in macrophages.
Patrick et al. used single-molecule optical tweezers to study the enzymatic activity and dynamics of product release of telomerase and provide direct evidence for the presence of an anchor site in elongating telomerase.
Redesigning the central carbon metabolism of Escherichia coli with the reductive glycine pathway enables growth on the one-carbon compounds formate and CO2, and the addition of methanol dehydrogenase further enables growth on methanol and CO2.
Certain cyanobacteria use an alternative biotin biosynthetic pathway that replaces BioA with the dehydrogenase BioU, a suicide enzyme that catalyzes its reaction via conjugation to Lys124 and loses the amino group of this residue in the process.
A covalent pan-inhibitor of bacterial bile salt hydrolases developed by adding a chenodeoxycholic acid moiety to the warhead is not bactericidal and is therefore useful for studying the effects of bile acids on host physiology.
Crystal structures of phospholipase hPLD1 and hPLD2 catalytic domains and an analysis of the binding modes of dual and isoform-selective inhibitors define mechanisms of PLD regulation and catalytic activity.
NMR structural analysis of an active state of the β2-adrenergic receptor defines a unique orientation for the intracellular half of TM6, responsible for G-protein binding, including an equilibrium among three conformations of a key microswitch.
X-ray crystallography, solution NMR and biochemical and cell-based analyses reveal a model where catalytically repressed receptor tyrosine kinases accomplish activation loop (A-loop) tyrosine transphosphorylation.