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Cell-wall biogenesis in bacteria involves multiple intersecting gene networks. A powerful approach that allies synthetic lethality with small-molecule discovery has now been used to probe these networks and has revealed that the pathway for D-alanylation of teichoic acids in Staphylococcus aureus is a viable target for new antibacterials.
Two new studies describe potent and selective inhibitors of CDK8/CDK19. Application of these high-quality probes to several cancer models provides new mechanistic insight and reveals functional dichotomy with respect to Mediator kinases in signal-dependent gene regulation, with important implications for targeted cancer therapy.
Natural (βα)8-barrel proteins support diverse catalytic functions and are fertile scaffolds for engineering synthetic enzymes. The atomic-resolution structure determination of a computationally guided, de novo–designed symmetric barrel is a long-awaited advance that opens up new opportunities for enzyme design.
Recently developed advanced microfluidics-based systems have outperformed known screening tools with respect to throughput, flexibility, sensitivity and tricks for hit recovery. This has enabled the discovery of novel and improved proteins from random mutagenesis libraries or metagenome-based sources.
25-Hydroxycholesterol induces miR-185 to suppress lipid and cholesterol synthesis pathways and inhibit viruses such as hepatitis C virus (HCV), that use host membranes to propagate. HCV counteracts this by suppressing miR-185 expression to drive increased cellular lipid content.
A new high-resolution crystal structure of the subdomain from a catalytically active group II intron reveals important conformational rearrangements necessary to achieve the fully formed catalyst. This structure provides the first atomic-resolution structure of an RNA folding intermediate.
Meropenem/piperacillin/tazobactam is a triple β-lactam combination that kills MRSA in vitro and in a mouse model through a novel synergistic mechanism of action. Similar activity for other carbapenem/β-lactam combinations suggests that MRSA infections might be treatable with combinations of established β-lactams currently classified as ineffective against MRSA.
Multiple mitochondrial components generate reactive oxygen species (ROS), but separating the consequences of each ROS-generating source from overall mitochondrial health is challenging. A new class of small-molecule inhibitors that selectively block ROS generation from one of the most active sources may provide a new approach toward achieving that goal.
Selecting compounds for the chemical library is the foundation of high-throughput screening (HTS). After some years and multiple HTS campaigns, many molecules in the Novartis and NIH Molecular Libraries Program screening collections have never been found to be active. An in-depth exploration of the bioactivity of this 'dark matter' does in fact reveal some compounds of interest.
The long-awaited crystal structure of the Varkud satellite (VS) ribozyme dimer provides atomic-level insights into how the VS ribozyme folds and catalyzes RNA circularization during rolling circle replication, as well as revealing convergent evolution used by RNAs to catalyze an SN2 reaction.
The essential metabolic cofactor coenzyme A was believed to be produced by biosynthesis from pantothenate in all eukaryotic cells. Rescue experiments in systems depleted of CoA have shown that a phosphorylated CoA biosynthetic intermediate can pass through eukaryotic membranes to serve as an alternative source.
The four-helix bundle is a simple structural motif, widespread in nature, that is involved in numerous and fundamental processes. This portfolio is now expanded by the report of a four-helix bundle protein able to store copper for particulate methane monooxygenase, an enzyme that catalyzes methane oxidation.
A new small-molecule inhibitor of the autophagy-initiating kinase ULK1 serves to block a critical survival mechanism activated upon inhibition of mTORC1, potentially enhancing treatment efficacy for mTOR inhibitors currently in clinical trials for cancer treatment.
Iron availability plays a decisive role in host-pathogen interaction, and limitation of iron availability to microbes has been characterized as an effective host defense strategy. The identification of the iron-scavenging property of the neutrophil protein calprotectin adds an important new piece to this concept of nutritional immunity.
PROTACs are heterobifunctional small molecules that simultaneously bind a target protein and a ubiquitin ligase, enabling ubiquitination and degradation of the target. Major progress in developing potent and specific PROTACs has recently been reported, invigorating prospects for novel PROTAC-based therapies.
There are many techniques that can be employed to control gene expression at the post-translational level. However, a novel system called SMASh (small molecule–assisted shutoff), which allows for chemically-induced degradation of target proteins, presents some distinct advantages.
The complex flavonoid montbretin A (MbA) is a powerful inhibitor of human pancreatic amylase (HPA) and a potential tool in the treatment of type 2 diabetes. The X-ray structure of the MbA–HPA complex now shows that a hydrophobic collapse of two phenol fragments in the structure of MbA is key to its activity.
Many peptide-based natural products require a leader peptide to reach their final modified form, but the identification of general rules for leader peptide interactions have been stymied by the diversity of these molecules. Two papers reporting crystallographic and bioinformatic analysis of these systems now reveal a structurally conserved domain that mediates leader peptide binding.
A small molecule targeting the protein-protein interaction between a chromatin binding protein and an oncogenic transcription factor shows therapeutic potential in a subtype of acute myeloid leukemia.
A powerful, high-throughput single-molecule approach to probe the nanoscale mechanical properties of the Tus–Ter protein–DNA complex reveals that the Tus–Ter-induced lock in unzipping at the nonpermissive face requires only DNA strand separation and involves a progressive strengthening of the Tus–Ter complex.
