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Phenylketonuria (PKU) is a metabolic disease characterized by increased phenylalanine in the blood and progressive mental retardation. Now, phenylalanine is shown to self-assemble into toxic amyloid fibrils at concentrations achieved in disease, and these fibrils accumulate in the brains of individuals with PKU and in mouse models of the disease. The image shows the elongated ordered phenylalanine assemblies stained with thioflavin T. Cover art by Erin Dewalt, based on an image from Lihi Adler-Abramovich. Article, p701
G protein–coupled receptors (GPCRs) are versatile molecular machines that regulate the majority of physiological responses to chemically diverse hormones and neurotransmitters. Recent breakthroughs in structural studies have advanced our understanding of GPCR signaling, particularly the selectivity of ligand recognition and receptor activation of G proteins.
Defining G protein–coupled receptor ligand efficacy and biased agonism in precise chemical terms is one challenge posed by the current structural data that exists for this receptor family. Concepts classically used for understanding enzymes and other nonreceptor proteins may lead us in the right direction.
Siderophores are small molecules allowing microorganisms to competitively acquire iron from soils, aquatic systems or host proteins. New research shows that a siderophore secreted by some bacterial pathogens also binds copper and protects against host-derived copper toxicity during infection.
Bacterial pili are surface fibers that must resist high shearing forces to remain associated with their target. The Escherichia coli type 1 pilus chaperone FimC serves as a 'sensor', ensuring that only stable pilins become incorporated into the growing fiber.
Dissecting the often subtle or time-sensitive roles of glycans in biology demands an increased availability of high-quality inhibitors for carbohydrate-processing enzymes. A review of lessons learned from other fields and considerations unique to glycobiology provides guidelines for development of these critical chemical tools.
Elongation factor P is a conserved translational regulatory protein that has an unusual post-translational modification, in which Lys34 forms an amide linkage to (R)-β-lysine. Further characterization reveals that Lys34 is also hydroxylated, drawing parallels to a functional modification of eukaryotic initiation factor 5A.
Bacterial resistance is propagated in part by metallo-β-lactamases, which hydrolyze and inactivate β-lactam antibiotics. An unusual cysteine residue in the active site is now shown to be critical for retaining the second metal ion, and thus enzyme activity, at low zinc concentrations.
Phenylketonuria (PKU) is characterized by increased levels of phenylalanine in the blood and progressive mental retardation. Now, phenylalanine is shown to form toxic amyloid fibrils at high concentrations, which accumulate in the brains of PKU patients and mouse models.
The chaperone FimC only selects unfolded, disulfide-intact pilus subunits and accelerates protein folding by lowering topological complexity, thereby ensuring quality control in pilus assembly.
Different key residues mediate melanocortin-4 receptor activation via the agonist αMSH or constitutive activation via interaction of the transmembrane domain with the N-terminal domain, and these modes are further distinguishable by the different effects of the physiological antagonist.
Bacterial siderophores are known to bind various metals in vitro but are generally thought of as iron chelators in vivo. MS now demonstrates that yersiniabactin binds copper in vivo, with yersiniabactin expression correlated to bacterial fitness.