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The role of RAS dimerization in tumor biology is an emerging area of preclinical cancer research. Characterization of a RAS monobody indicates that dimer formation is required for RAS signaling, revealing the dimer interface as a potential drug target.
The Global Natural Products Social Molecular Networking (GNPS) resource and the DEREPLICATOR algorithm provide new tools for analyzing mass spectral data and enabling natural products discovery.
Three newly identified endogenous ligands of the nuclear receptor PPARα—hydroxydimethylbutyrate, hexadecanamide and octadecenamide—are implicated in the noncanonical activity of PPARα in synaptic function and hippocampal plasticity.
Interfacing photosynthetic proteins and electrodes for investigating light-induced charge separation remains challenging. The discovery of a competing charge transfer pathway through the light-harvesting antenna defines new design requirements for electrode modification.
Through simultaneous binding to more than one site in a single protein, multivalent small molecules can achieve huge increases in potency. This 'avidity effect' has been demonstrated in BET bromodomain-containing proteins with bivalent probes that represent some of the most potent BET inhibitors to date.
Ferroptosis is characterized by accumulation of lipid peroxidation products and lethal ROS, but the source and identity of lipid death signals that cause toxicity are poorly defined. New studies reveal that ACSL4 controls sensitivity to ferroptosis and that oxidized phosphatidylethanolamines are critical for ferroptosis execution.
New approaches allow tight control over Cas9 activity using chemical induction. These studies expand the ability to rapidly induce and suppress Cas9-mediated nuclease activity and conditionally modulate the multiplex regulation of endogenous gene expression.
The mechanisms by which proteins evolve new functions can be slow and mysterious. Comprehensive structural analysis of enzyme variants reveal how gradual enrichments of pre-existing populations with the right productive dynamics for new functions can accomplish this aim.
A novel approach recruits the largest prokaryotic family of ligand-induced transcriptional regulators to develop a new class of biosensors in yeast based on transcriptional activation, vastly expanding the repertoire of biosensors that could function in eukaryotic hosts.
Proteolytic maturation of an important transcriptional regulator is performed by a glycosyltransferase. The reaction involves glycosylation of a glutamate residue and conversion of the γ-glycosyl ester product into an N-acyl pyroglutamate, which undergoes spontaneous hydrolysis to effect peptide backbone fission.
The rapid spread of antibiotic-resistant bacteria demands novel treatment approaches that delay or even reverse the evolution of resistance. A new screening strategy identifies two compounds that select against a common tetracycline-resistance gene in Escherichia coli.
A new study reports THZ531 as a covalent CDK12/CDK13 inhibitor affecting transcription. Application of the compound in cells decreases transcription elongation of DNA damage response genes and key super-enhancer-associated transcription factor genes, with important implications for targeted cancer therapy.
Scientists find that oxidation of methionine induces favorable interactions with aromatic groups in proteins, contrary to conventional wisdom, providing new molecular insight into the structural and biological impact of methionine oxidation.
Stapled helices are promising compounds for inhibiting intracellular protein–protein interactions, but the discovery of peptides with the key property of cellular uptake has taken place largely through trial and error. A new study defines physicochemical parameters for designing hydrocarbon-stapled helices with a greater likelihood of cellular uptake.
Chemical probes and drugs often bind to functional domains on disease-relevant proteins. A study suggests a chemical genetic approach to establish on-target effects by swapping the targeted domain, affording resistance to pharmacological inhibition while retaining functionality.
Crystal structures of both catalytic domains of HDAC6 provide insights into the mechanisms of deacetylation for their specific substrates and a structural basis for understanding selective inhibition of HDAC6.
A high-throughput screen in the model plant Arabidopsis unveils leads for potential agents to combat Striga, a devastating root parasitic weed that affects food crops in Sub-Saharan Africa.
Glucose metabolism has long been thought to operate with exquisite specificity and near-optimal efficiency. New findings show, however, that two glycolytic enzymes produce minor products that inhibit other enzymes involved in central carbon metabolism unless they are further metabolized by a novel enzyme.
Hsp90 is an energy-consuming molecular chaperone that activates oncogenic proteins in a complicated multi-step reaction. Photoinduced electron transfer (PET) quenching experiments with a fluorescent reporter have now identified molecular transitions at multiple timescales in the chaperone cycle of Hsp90.
