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A fungal ten-eleven translocation (TET) dioxygenase homolog, CcTet, is found to have both 5-methylcytosine (5mC) and N6-methyladenine (6mA) demethylase activity. Structure-based engineering of CcTet yielded a 6mA-specific demethylase, offering a useful tool for the manipulation and functional study of 6mA.
The discovery of long-existing terpenoid biosynthetic pathways in soft corals changes the way specialized metabolism in animals is thought about, and opens unprecedented access to the largely untapped treasure trove of medicinal marine natural products.
This Review discusses how combining computational modeling with multiparametric profiling of small-molecule effects can accelerate and expand the search for new and unconventional antibacterial strategies.
Controlling kinase inhibitors’ residence time via reversible covalent binding is of high interest in drug discovery. Tuning reversible covalent binding kinetics using a pan-kinase inhibitor that reacts with the catalytic lysine enabled exquisite temporal selectivity in vitro and in vivo.
Protein arginine methyltransferases (PRMTs) are overexpressed in many cancer types, including triple-negative breast cancer (TNBC). A new study shows that a reversible inhibitor of type I PRMTs suppresses TNBC tumor growth by inducing a viral mimicry response with retained introns.
Succinate may have evolved as a signaling modality because its concentration reflects the redox state of the mitochondrial coenzyme Q pool, thus communicating to the rest of the cell and beyond about electron supply, oxygen tension and ATP demand.
New research has revealed a wealth of small molecules that target cancer-specific metabolic vulnerabilities by targeting allosteric sites. Here, a Perspective discusses how their application has provided insights into cancer metabolism and therapy.
Lipid metabolism is a major regulator of T cell biology, and this Review Article highlights mechanisms by which diverse lipids modulate T cell signaling and opportunities for therapeutic intervention on targets within these immunological pathways.
This Perspective discusses the genetically encoded tools for measuring and manipulating metabolism, highlighting the tools that are available, guidelines for their use and key areas for future development.
Natural enzyme complexes can rapidly change configurations to respond to intracellular cues. Now CRISPR enzymes and programmable RNA scaffolds allow synthetic enzyme complexes to be assembled and disassembled on demand.
Microproteins can be generated by a shift in the reading frame during translation. A chemoproteomics approach led to the identification of MINAS-60 as an alternative microprotein that regulates the assembly of the pre-60S ribosome.
The cryo-electron microscopy structure of a fluoroquinolone efflux transporter, NorA, in complex with an antibody fragment provides a new strategy whereby peptide inhibitors derived from antibody loops could be used to block antibiotic efflux in a drug-resistant superbug.
Chemoproteomics reveals a cysteine oxidation event that inhibits the maturation process of a lysosomal protease, enabling its secretion into the extracellular space during infection-induced tumorigenesis. A recent study offers a new mechanistic paradigm for redox-dependent regulation of protein trafficking.
Precision oncology requires an understanding of the genes and pathways that dictate therapeutic response. Through specialized analysis of drug sensitivity patterns across hundreds of genomically annotated cancer cell lines, specific and actionable drivers of intrinsic resistance have been identified.
Despite well-established tumorigenic roles of KRAS mutants, targeting their smooth surfaces was a challenge, which was overcome through the development of G12C-specific covalent inhibitors. A new study shows that optimizing non-covalent interactions with a cryptic pocket produces remarkable potency for another hotspot mutation.
Natural self-cleaving RNAs employ a wide range of catalytic strategies, but it is not known whether artificial ribozymes are capable of the same catalytic diversity. New structures of a methyltransferase ribozyme reveal the potential variety of RNA reactions and mechanisms.
Induced proximity is reshaping drug discovery. A new study debuts deubiquitinase-targeting chimeras (DUBTACs), small bifunctional molecules that co-opt a deubiquitinase to stabilize a target protein.
Pharmacological agents exert their therapeutic effects by altering the biochemical activities of drug targets and, consequently, manipulating cell and organism physiology. A new study combines CRISPR interference with metabolomic profiling to rapidly elucidate drug mechanisms of action.
Just how chaperones clear protein aggregates is a notoriously impenetrable problem. A new study now shows how single-molecule movies of Hsp104 and Hsp70 chaperones acting on amyloid fibers are the key to revealing their underlying cooperation in time and space.
Cell-free biosensing is emerging as an effective and low-cost technology, but interpretation and synthesis of the results remains largely manual. Now, researchers have incorporated a new information-processing layer between biosensors and their outputs using logic gates to integrate complex results.
