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The use of atomic-level simulations reveals a molecular mechanism by which a ligand can achieve selectivity between nearly identical receptors, enabling the rational design of targeted drugs.
Brain imaging using the compact NanoLuc luciferase has been stymied by the lack of suitable substrates. Su et al. report a brain-optimized substrate, cephalofurimazine, and use it to perform non-invasive calcium imaging of neuronal activity.
Ferroptosis is a lipid-peroxide-driven cell death with promising therapeutic applications. Although peroxidation of various subcellular membranes can initiate ferroptosis, the authors found that the endoplasmic reticulum is an essential site.
Aromatic carbon fluxes for the metabolism of lignin and plastics derivatives in Comamonas testosteroni KF-1 are controlled by pathway-specific regulation at transcript, protein or metabolite levels. The combination of transcriptional activation and metabolic fine-tuning complicates predictions of modulated carbon and energy fluxes during metabolic engineering strategies.
Dai et al. present a streamlined approach for the design and engineering of synthetic biomolecular condensates for controlling different cellular processes, such as gene flow, transcriptional regulation and modulation of protein circuits.
Mercaptopyruvate sulfur transferase (MPST) is revealed as a protein persulfidase that acts directly on numerous and diverse target proteins, revealing potential origins of persulfidation as a common posttranslational modification.
A potent and selective degrader was developed that depletes STAT5 in cells and mouse tissues, exerts cell growth inhibition in cells with activated STAT5 and induces tumor regression in mouse models.
Using single-molecule biophysics methods, Le et al. discovered that etoposide, a chemotherapeutic poison of topoisomerase II (topo II), promotes topo II to compact DNA, trap DNA loops and pause DNA supercoiling relaxation, thus converting topo II into a strong roadblock to DNA processing.
A new biosynthetic core-forming enzyme, arginine cyclodipeptide synthase (RCDPS), was found to produce cyclo-arginine-Xaa dipeptides via a tRNA-dependent mechanism, and further genome mining using RCDPS as a beacon uncovered new natural products.
The multistep incorporation process of the catalytic NiFe(CN)2(CO) cofactor into [NiFe]-hydrogenase was deciphered by isolating key maturation intermediates, which were characterized by biochemical and a variety of spectroscopic techniques.
A bifunctional amino acid, photo-ANA, equipped with a bio-orthogonal handle and a photoreactive warhead, specifically labels Salmonella spp. during infection and enables the profiling of proteome dynamics and host–pathogen protein–protein interactions.
The F420-dependent sulfite reductase protects some methanogenic archaea by converting toxic sulfite. Structural analysis reveals how the two active centers are electro-connected and provides a plausible picture of a primitive sulfite reductase.
Development of two bright light-up RNA systems with strong aptamer–dye interaction, high fluorogenicity, and remarkable photostability, enable single-molecule mRNA tracking in live cells.
The authors present a framework for multiplexed optimization of metabolic pathways based on CRISPR–dCas12a-mediated genetic circuits, which can be generally applied in the construction of microbial cell factories for sustainable bioproduction.
A near-atomic resolution strain-specific cryo-EM structure of infectious prion fibrils from mice was determined, revealing a structural definition for intra-species prion strain-specific conformations.
Coupling selectivity was found to be partly lost with G proteins that bypass conformations that exist before GDP release, suggesting that selectivity is closely linked to the process of nucleotide release.
Docking virtual libraries against protein structures has identified potent ligands for multiple targets. A comprehensive analysis reveals that the increased size of virtual libraries improves receptor fit but diverges from bio-like molecules.
Development of a chemoproteomic platform to globally interrogate Fe–S cluster incorporation in a native proteome enables the elucidation of Fe–S biogenesis components and the identification of unannotated Fe–S proteins.
Development of a quantitative approach to determine how far a signal from a cell travels as a diffusible molecule reveals a millimeter-scale quorum sensing mechanism that determines collective growth of differentiating embryonic stem cells.
DNA damage results in the acetylation of the cell-cycle checkpoint kinase WEE1 at Lys177 enabling activation. The deacetylase SIRT1 directly associates with and modifies WEE1 to inactivate it enabling resistance to WEE1 inhibition in cancer cells.
