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Bioymifi, a small-molecule death receptor 5 (DR5) agonist, induces selective cancer cell apoptosis as a single agent or in synergy with small-molecule Smac mimetics.
Cholic acid and 24(S),25-epoxycholesterol are endogenous midbrain LXR ligands that are neurogenic for red nucleus or dopaminergic neurons, respectively.
N6-Threonylcarbamoyladenosine (t6A), a modified nucleotide found in certain tRNAs, has an essential role in translational fidelity. New analytical data reveal that t6A adopts a cyclic form (ct6A) in cells and has led to the identification of the enzymes that convert t6A to ct6A.
Quantification of cytosolic glutathione redox potential leads to the discovery that the ABC-C transporter Ycf1 rapidly transports oxidized glutathione (GSSG) into vacuoles and whole-cell GSSG should not be used as a proxy for cytosolic GSSG.
An allosteric activator of Hsp70 mimics Hip and reduces neurotoxicity in a model for spinobulbar muscular atrophy by promoting ubiquitination and degradation of oligomeric polyglutamine-containing clients.
Structural characterization of an artificial zinc-dependent enzyme created by in vitro evolution yields a new, flexible fold that challenges straightforward definitions of active site residues and raises questions about protein evolution.
Allosteric conformations and proteolytic activities of each subunit of the trimeric E. coli DegS protease share a cooperatively coupled energy landscape that allows regulation via the binding of substrate and OMP peptides.
Maintaining energy homeostasis requires complex feedback across organs that is difficult to study in isolated systems. New research uses whole-organism screening to identify key regulators of fasting metabolism in zebrafish, including ligands for the mitochondrial transporter protein TSPO.
Selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) is a proven methodology for in vitro RNA secondary structure analysis. The identification of a new acylating agent permits the use of SHAPE to probe folded RNAs within living cells.
Stabilization of ubiquitin's β1-β2 region by computational design and phage display, targeting both buried and surface residues, yields a ubiquitin variant that specifically inhibits the deubiquitinase USP7 in vitro and in cells.
The human genome contains stretches of DNA sequence with unknown function. Peptidomics coupled to RNA-Seq now reveals a class of short open reading frames in human genomes that are translated into small peptides.
Medium-sized ring structures can provide unique entry points into natural product–like chemical space but are synthetically challenging to access. A biologically inspired method eases these challenges, employing a dearomatization-rearomatization sequence to form a diverse library of rings from tailored bicyclic compounds.
Biotechnological applications of hydrogenases are limited by their susceptibility to inactivation by oxygen, thought to proceed by trapping a reduced O2 in the active site. Electrochemical and spectroscopic studies using various electron acceptors now show that oxygen inactivation is not linked to oxygen atom donation.
Equilibrium isomerization of retinol is a new activity now attributable to DES1. 11-cis-retinol synthesized by DES1 in Müller cells of the retina can be converted to the visual chromophore for regenerating opsin pigment in cone photoreceptors.
Acanthaporin is identified as a pore-forming protein from the infectious Acanthamoeba culbertsoni with a previously unknown structure. The newly identified structure includes a pH-dependent histidine switch that controls partitioning between the inactive dimer and the active monomer, which assembles into larger species to cause toxicity.
Src family kinase mutants, with altered regulatory domain interactions, were profiled with a photodependent crosslinking strategy to reveal conformation-specific ATP-competitive inhibitors that affect intermolecular binding interactions.
Understanding the reaction mechanism of OGT, responsible for O-GlcNAcylating various protein substrates, has been hampered by a lack of structural information. Snapshots of ternary complexes along the reaction coordinate now provide evidence for substrate participation in an electrophilic migration mechanism.
The identification of Escherichia coli ycfD and human MINA53 and NO66 as ribosomal amino acid hydroxylases defines a role for 2-oxoglutarate/iron-dependent oxygenases in translational regulation.
OGT modifies numerous proteins with O-GlcNAc, but the mechanism for this reaction has been difficult to define. Ternary crystal structures and activity assays with substrate analogs now provide evidence that the α-phosphate of the donor substrate is the catalytic base.
The creation and application of engineered constructs specific for one of two IL-4 coreceptors explain how immune signaling is limited by coreceptor concentration and establish specific roles for type II receptor–specific signaling in dendritic cell differentiation.