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Tricyclic peptides have reduced conformational flexibility, making them well suited for ligand development. Researchers have now generated large combinatorial libraries of tricyclic peptides using a disulfide-directing motif. Screening these libraries discovered binders to challenging protein targets.
Anaerobes have developed unique metabolic pathways and strategies, some of which are still not well understood. Now, a study that integrates spectroscopy with dynamic metabolic modeling reveals the metabolism of the anaerobic pathogen Clostridioides difficile.
The mechanisms responsible for replicative misincorporation of an adenine into DNA opposite 8-oxoguanine (8OG) remain obscure. A new study suggests that 8OG redistributes the balance between several mispair conformations, enabling the high rates of misincorporation of adenine paired with 8OG by DNA polymerases.
Bacterial biofilms are resilient multicellular communities with spatially complex localized interactions that remain largely uncharacterized. A new approach called RainbowSeq enables transcriptional profiling in biofilms with increased spatial resolution.
This Perspective details how genome-wide association studies and metabolomics enabled the discovery of structures, bioactivities and pathways of modular metabolite biosynthesis originates from the ‘hijacking’ of conserved detoxification mechanisms by nematodes.
The role of lipid membrane domains in the activation of immune cells remains elusive. New microscopy data on B cell signaling support a mechanism in which lipid membrane domains consolidate upon B cell receptor clustering.
A study of drug-resistant lymphomas with hypermorphic mutations in PRC2 has identified a ‘methylation index’ by which cancer cells maintain optimal H3K27me3 levels for survival, emphasizing the importance of understanding how tumors adapt to changes in chromatin and to drug-resistance mutations.
The NADP+/NADPH coenzyme couple powers cellular biosynthesis and oxidative defense. A new study tracing glucose-derived deuterium during proline biosynthesis analyzes subcellular perturbations in NADPH utilization, revealing that NADP+/NADPH coenzyme pools in the cytosol and mitochondria are regulated independently.
Identifying new proteoforms — structural variants of proteins — is frequently challenging, particularly on the proteome-wide scale. A new study leverages their differential thermal stabilities to identify proteoform functional groups by deep thermal proteome profiling.
A new review article details how new structural insight regarding modular polyketide synthases (PKSs) helps us better understand the organization of catalytic events within a PKS module. The plausible models discussed will likely influence future PKS engineering efforts.
Engineering synthetic tools that facilitate decision-making in mammalian cells could enable myriad biomedical applications. Researchers have now developed a new system of inducer-controlled transcription factors to facilitate synthetic decision-making (LOGIC) in human cells based on modular protein-fusion cascades.
We identified small molecules that rewire the transcriptional state of cancer cells by covalently targeting the RNA-binding protein NONO. These small molecules stabilize the interactions of NONO with its target mRNAs, thereby overriding the compensatory action of paralog proteins and revealing a pharmacological strategy for disrupting previously undruggable oncogenic pathways.
Creatine kinases (CKs) have emerged as a metabolic liability in many rapidly proliferating cancers. We have developed a class of covalent inhibitors that impair creatine phosphagen energetics by targeting a redox-regulated cysteine residue in the active site of CKs.
Substrate–inhibitor conjugation facilitates structural determination of the KDM2A/B-nucleosome complexes, which provides mechanistic insights into the nucleosomal H3K36 demethylation by KDM2A/B and reveals a paralog-specific nucleosome acidic patch recognition mechanism mediated by the N terminus of KDM2A but not KDM2B.
A crucial step in the cell-death process of ferroptosis is the incorporation of free polyunsaturated fatty acids (PUFAs) into membrane phospholipids. An enzyme has now been identified that contributes to ferroptosis by directly transferring PUFAs from phospholipids to ether lysophospholipids to form ether phospholipids.
Comamonas testosteroni utilizes aromatic compounds such as monomers from lignin and plastics, but the underlying metabolic pathways were elusive. Multi-omics analysis now clarifies the multifaceted regulation of its metabolism, facilitating strain engineering to convert substrates from lignin and plastics into valuable bioproducts.
A modular platform was developed to generate designer condensates with tunable material properties for selective partitioning. These programmable assemblies can regulate bacterial plasmid expression and inheritance but will find a broad array of applications, including in eukaryote systems.
Ferroptosis can be induced by lipid peroxidation in various subcellular membranes, including the endoplasmic reticulum (ER), mitochondria and lysosomes. By studying the subcellular distribution of ferroptosis-modulating fatty acids, we observed that the ER is a key initial site of peroxidation, followed by the plasma membrane, whereas other organelles are not as critical for ferroptosis.
Etoposide, a chemotherapeutic poison of type IIA eukaryotic topoisomerases (topo IIs), promotes topo II to compact DNA by trapping DNA loops, creates DNA double-strand breaks, causes topo II to resist relocation, and pauses the ability of topoisomerases to relax DNA supercoiling. Through these mechanisms, etoposide converts topo II into a roadblock to DNA processing.
