News & Views

Small molecules and drugs are not homogenously distributed across cells, and are instead enriched in distinct subcellular compartments and membraneless biomolecular condensates. A new study lays out the path to identifying chemical features or ‘rationales’ that confer condensate-selective partitioning of small molecules.

Terpenoids bearing carbon skeletons derived from nonisoprene units are rare and considered noncanonical. Now, a genome-mining study has uncovered previously unknown noncanonical C₁₆ terpenes and their biosynthetic pathways from bacteria. The findings suggest that noncanonical terpenoids are diverse and widespread in nature.

The integrated stress response affects cell survival or death under stress conditions, and depends on the activity of the eukaryotic translation initiation factor eIF2B. New research identifies a protein helix that modulates this response by controlling the structural states of eIF2B.

DNA-encoded libraries are a powerful tool to identify novel chemical inducers of proximity such as targeted protein degraders, even without a known binder for the target protein.

Defining subcellular locations and interacting partners for proteins accelerates their functional characterization. A new in vivo tagging approach achieves both for mitochondrial matrix proteins and helps connect a key oxidoreductase to coenzyme Q biosynthesis.

Genetically encoded tools to manipulate redox metabolism are in high demand for investigating the underlying mechanism of cofactor imbalances in mammalian systems. A new tool enables the induction and interrogation of NADH reductive stress.

Traditional production of therapeutic secretory proteins often experiences delays between protein synthesis and therapeutic effects. An inducible protease-dependent protein secretion technique allows the immediate secretion of pre-translated biotherapeutic agents after exposure to chemical cues, tumor-specific antigens or photons.

The quality of chemical tools and their appropriate use determine the quality and reliability of scientific data based on their use. Now, two papers extend criteria to new modalities and critically review adherence to established guidelines.

Activation of STING-dependent signal transduction results in adaptive immune responses that promote antitumor immunity. A recent study has identified a small-molecule STING agonist that functions by binding to a newly discovered ligandable site to induce high-order STING oligomerization.

Computational approaches are emerging as powerful tools for the discovery of antibiotics. A study now uses machine learning to discover abaucin, a potent antibiotic that targets the bacterial pathogen Acinetobacter baumannii.

Protein lipidation is an important post-translational modification that can be difficult to study. New amino acids with side chains that mimic naturally occurring lipid modifications stand to facilitate the study of lipidated proteins.

The susceptibility of nitric oxide (NO) to scavenging and oxidation limits its bioavailability and signaling role. New studies indicate that a NO–ferroheme adduct is resistant to such constraints and may serve as an alternative NO-derived signaling molecule in vasculature.

Newly developed synthetic antibodies offer the means to be used as high-affinity, conformation-specific probes to capture dynamic repertoires of neddylated cullin–RING E3 ligase complexes. This allows nonenzymatic profiling of the diverse signaling networks that are based on these active complexes.

CAG triple-nucleotide repeats in multiple genes have been linked to various human diseases. A recent study unveils the effects of CAG repeat RNA gelation on protein translation, thereby expanding our knowledge of CAG-elicited toxicities.

A universally effective method has been developed to enable cryo-electron microscopy structural determination of G protein–coupled receptors in various states. This method will accelerate structure-based drug discovery and enhance understanding of the activation mechanism for these receptors.

The development of biosensors has been slowed by the optimization required for each new iteration. Now, the ChemoX platform facilitates the expansion of sensor design, resulting in unique Förster resonance energy transfer pairings with versatile applications and optimized readouts.

Cryo-EM structures of chemical-compound-bound α-synuclein amyloid fibrils shed light on the mechanism by which small molecules bind to cross-beta-sheet amyloid structures, opening the gateway to rational drug design for targeting pathological amyloid assemblies.

Modular polyketide synthases are multidomain megasynthases catalyzing polyketide chain elongation, modification and release. New work reveals a full ~360-kDa modular polyketide synthases with just one active domain, ketosynthase, catalyzing an amidation that releases the completed product (a reaction type typically catalyzed by dedicated thioesterases).

A study has now shown that copper ions can drive inflammation via a mitochondrial signaling pathway that regulates epigenetic states of immune cells. This pathway could offer a new route for treating inflammatory diseases.