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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.
A series of positive allosteric modulators of NMDA receptors that can increase agonist potency, increase channel-open probability, and slow receptor deactivation can also decrease single-channel conductance and decrease calcium permeability.
Lasonolide A is hydrolyzed into a cytotoxic metabolite by a lipid droplet-associated orphan serine hydrolase, showing that lipid droplets can promote drug toxicity by both accumulating and metabolizing drugs in cells.
The X325 protein family is highly similar to lytic polysaccharide monooxygenases (LPMOs) in regulation, structure and copper coordination by a histidine brace, yet lacks LPMO activity and suggests the evolution of an alternative function in fungi.
A chemoproteomics and protein engineering strategy to investigate metabolic activity of lipid kinases led to assignment of a key role for atypical C1 domains in directing fatty acyl specificity of diacylglycerol kinase function in live cells.
Polypeptide GalNAc-transferase T3 catalyzes the specific glycosylation of threonine-178 of fibroblast growth factor 23, and structural insights reveal a unique lectin-based mechanism of substrate recognition.
In cotton, a specialized glyoxalase I variant, SPG, has lost its glutathione-binding sites and organelle-targeting signal during its evolution to catalyze the aromatization of cyclic sesquiterpenes as part of the gossypol biosynthetic pathway.
In the fungal pathogen Cryptococcus neoformans, Bim1 is a copper-binding lytic polysaccharide monooxygenase-like protein that participates in copper uptake in concert with the Ctr1 importer to drive virulence mechanisms during fungal meningitis.
Designed heterotrimers of collagen I, locked in three possible chain registers, enable structural and functional characterization of each permutation, leading to identification of the AAB heterotrimer as the most active and therefore likely to occur biologically.
A set of orthogonal coiled-coil peptide heterodimers were developed to enable control of protein localization as well as transcriptional regulation by enhancing effector recruitment to TALE and CRISPR–dCas9 systems in mammalian cells and in vivo.