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Drugs and antibiotics induce oxidation and mobilization of membrane-bound copper(I) ions to copper(II) species within the E. coli cytosol, causing oxidation of a single cysteine residue of the multiple antibiotic-resistance regulator MarR, that leads to formation of disulfide-bonded MarR tetramers and release of dimers from sites of transcriptional activity.
High-throughput screening systems that better mimic the physiological complexity of diseased tissues may aid the discovery of more efficacious compounds. A co-culture system that mimics the microenvironment of leukemia stem cells (LSCs) in bone marrow enables the discovery of compounds, including lovastatin, that selectively kill LSCs.
Cyclic diadenosine monophosphate (c-di-AMP) is a newly identified nucleotide second messenger in bacteria. Though protein receptors for c-di-AMP are known, the ydaO riboswitch has now been validated as a physiological sensor of cellular c-di-AMP levels.
The Doc-Phd toxin-antitoxin system inhibits bacterial translation via an unknown mechanism. Functional and structural analyses now show that Doc, which has an active site like AMPylating Fic proteins, actually works as a kinase, phosphorylating EF-Tu to block translation.
Identification of antibacterials and then their mechanism of action using metabolic suppression profiling uncovers inhibitors targeting glycine metabolism, PABA and biotin biosynthesis.
Assembled helical maquettes have been used to mimic basic oxidoreductase activities, but the requisite design symmetry limited advanced functions. Construction of a single-chain protein now enables intra- and interprotein electron transfer and complex cofactor interactions at rates comparable to those of natural proteins.
Spiran rings appear in numerous natural products, but the mechanism of their formation is not always clear. Reconstitution of the spirotryprostatin pathway now reveals that distinct biochemical mechanisms, one catalyzed by an enzyme from an unrelated pathway, lead to related spiran-containing structures.
The bacterial glmS riboswitch is unique in that the bound glucosamine-6-phosphate ligand acts as a cofactor for ribozyme-mediated RNA cleavage. In vitro selection and crystallographic analysis reveal that three mutations convert glmS from a cofactor-dependent to a metal ion–dependent ribozyme.
A set of tetravalent antigens reveals that low-affinity interactions between an allergen epitope and IgE antibodies contribute to allergic responses through FcɛRI receptors on mast cells, and inhibiting these low-affinity epitopes prevents degranulation.
Aspartate is a primary nitrogen source for Mycobacterium tuberculosis during infection, being required for virulence after entering cells via the amino acid transporter AnsP1.
Nematodes define a new role for sirtuins in lifespan extension, in which the sirtuin product nicotinamide is converted to a substrate for aldehyde oxidase; turnover of this enzyme generates hydrogen peroxide, causing upregulation of defense mechanisms that promote longevity.
Phenotypic screening using a reporter for Notch trafficking and processing leads to the identification of five compounds that affect this pathway, including one that acts at a pre-ER exit step in a manner distinct from known molecules.
The anesthetic propofol binds in a cavity on the β subunit of the GABAA receptor between the transmembrane and extracellular domains, near other residues that have been shown to be important for determining anesthetic sensitivity.
Polyketide synthases infrequently insert β-branched monomers into their growing polyketide chains, the details of which are not well established. Bioinformatic, structural and mutational analyses now define a core motif and surface residues in acyl carrier proteins that govern insertion of β-branched units.
Isolation and characterization of the first hydroxyproline O-arabinosyltransferases demonstrates overlapping and distinct functions in glycosylating protein substrates and controlling plant development.
A 'lockdown' mechanism explains why the CLC-ec1 Cl−/H+ antiporter is selective against F− ions, whereas Cl− and other inorganic ions are moved indiscriminately.
Crystal structures of α-L-iduronidase, the enzyme linked to MPS I, now provide snapshots of the catalytic pathway and rationalize the role of 100 disease-related mutations, while biochemical analysis of deglycosylated and mutated enzymes define roles for non–active site residues in controlling function.
IC50 values are widely used measures of compound potency. A multiparametric analysis of dose-response curves derived from a panel of cell lines treated with anticancer drugs reveals that there can be systematic variability in dose-response parameters across drug classes and cell types, effects that are not apparent by inspection of IC50 values.