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Non-natural amino acids with different electrostatic surface potentials (as depicted on the cover as a color gradient) into the Shaker voltage-sensing potassium channel were introduced by nonsense suppression mutagenesis by Pless et al. to find that salt bridges are not necessary during channel gating, but rather, two of the acidic residues may occupy a hydrophilic water-filled vestibule that creates an energetically favorable environment for movement of positive charges during channel gating. Cover art by Erin Dewalt, based on images from Christopher Ahern.
Defining the scope and venue of a scientific paper requires a balance between the authors' goals for the study and reasonable feedback gleaned through peer review.
Homo- and heterodimerization of G protein–coupled receptors (GPCRs) have been described for numerous receptors, but their functional role has remained elusive. With a new spectroscopic assay based on protein fragment complementation, GPCR heterodimerization was demonstrated to contribute to a phenomenon called 'functional selectivity'.
Man-made adhesives cannot match the ability of a marine mussel to affix itself to a wet rock. New insights help to describe the protein-surface bonding central to this feat of biological materials engineering.
Protein misfolding, oligomerization and aggregation are implicated in a variety of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. New research sheds light on the process of amyloid-β aggregation in vitro, identifying nucleated conformational conversion of oligomers as the mechanism for generating amyloid fibrils.
Nature's approach to biosynthesis often involves the rapid generation of advanced, enantiopure intermediates from simple starting materials. A new, highly efficient strategy adapts this approach, using organocascade catalysis to quickly construct a key intermediate that can be converted into several complex natural products.
A stabilized helical peptide mimic of a key helix from the guanine nucleotide exchange factor Sos interferes with Ras-Sos interaction and inhibits Ras signaling in response to receptor tyrosine kinase activation.
Mussel adhesion depends on secreted dopa-modified proteins, but the dopa groups are prone to oxidation, which decreases their stickiness. A second mussel protein is now shown to regulate the redox state of these adhesive groups by coupling thiol oxidation to dopa reduction.
Phytophthora use mating hormones to mediate reproduction between two distinct strains, but only one of the hormones has been structurally characterized. The isolation and analysis of the elusive second hormone demonstrates that the two hormones are biosynthetically linked and universally used across Phytophthora species.
Polo-like kinase 1 (Plk1) regulates multiple processes that are important for cell proliferation, and it is a promising anticancer drug target. Efforts to inhibit Plk1 function by disrupting interactions that are essential for its proper localization identify a high-affinity alkylated phosphopeptide ligand specific for Plk1.
FlAsH fluorescence and thioflavin-to-FlAsH FRET are used to distinguish amyloid-β oligomer formation from fibril formation, supporting rapid oligomer formation prior to fibril formation—consistent with a nucleated conformational conversion mechanism—that can be modulated by certain Alzheimer's disease–linked mutations or lipids.
Overabundance of the eIF2–GTP–Met-tRNAi translational initiation complex has been linked to malignant transformation. N,N'-diarylurea chemical probes that block ternary complex assembly through heme-regulated inhibitor kinase activation validate translational initiation pathways as a potential anti-cancer targets.
Salt bridges between positively charged residues within the S4 transmembrane segment of the voltage-sensing potassium channel, Shaker, and acidic residues in S2 and S3 segments are not necessary during channel gating; rather, two of the acidic residues may occupy a hydrophilic water-filled vestibule that creates an energetically favorable environment for S4 movement during channel gating.
Based on a BRET readout, dopamine D2 receptor agonist NPA is more potent at activating Gαi when the D2 receptor forms a heteromer with the related D1 receptor than if it forms D2 receptor homomers, suggesting that GPCR heteromerization can result in functional selectivity.
The combination of several biochemical analyses, including determination of kinetic isotope effects and linear free energy relationships, offer the first detailed insights into a natural SNi-like reaction mechanism and provide compelling evidence for a frontal nucleophilic substitution in a retaining glycosyltransferase.
The identification of cellular targets for natural products that potently inhibit the growth of cancer cell lines implicates oxysterol-binding proteins in the growth of cancer cells. These natural products, termed ORPphilins, also affect sphingomyelin biosynthesis.