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Small-molecule-mediated targeted protein degradation (TPD) relies on the recruitment of a target protein of interest to an E3 ligase. A new study indicates how direct target recruitment to the 26S proteasome can bypass this requirement.
Most engineered bacteria are designed to grow and function in a free-swimming state. A new method enables engineered bacteria to reversibly transition into a biofilm state.
A protein–protein interface between a peptide-recognition domain (Fyn-SH3) and catechol O-methyltransferase (COMT) is computationally designed to generate a highly selective peptide-modifying system. Detailed mechanistic analysis sets a gold standard for studying the complex kinetic properties of designer fusion proteins.
Inspired by nature, a synthetic carbon fixation cycle builds complex molecules directly from CO2. Building metabolism from the ground up requires several innovative advancements — now, a strategy to balance carbon demands in a complex metabolic network is explored.
Bacteria utilize stringent factors to metabolize the nucleotide alarmone guanosine tetra-/pentaphosphate, or (p)ppGpp, for stress adaptation. Now, a distinct conformation of these factors explaining their regulation and specialization has been unveiled.
Major hurdles remain in understanding the mechanisms of multidrug resistance (MDR) protein efflux. A new study uses deep mutational scanning of a bacterial MDR protein to determine the nature of its drug-binding cavity and understand its function and plasticity.
High-mannose N-glycans are common post-translational modifications that occur on many proteins. The mechanism by which these high-mannose N-glycans are consumed by species of Bifidobacterium has now been characterized, which is important given their positive role in human gut microbiota and their abundance in breastfed infants.
Clustering and multimerization of cell surface proteins (CSPs) are essential for triggering downstream intracellular signaling events. Membrane-anchored liquid–liquid phase-separation systems have now been developed to manipulate the spatiotemporal distribution and activation of CSPs.
YcaO enzymes are able to catalyze a diverse set of reactions and have found industrial applications. New biochemical data provide the first direct evidence for the unified reaction mechanism proposed a decade ago and will inform future enzyme engineering efforts.
Ferredoxins are universal electron donors. A study focusing on the two human mitochondrial ferredoxins reveals the existence of unique cellular functions and partners for each protein.
Studies of the microbiome–host interaction are uncovering the metabolic mutual crosstalk between host tissues and gut microbiota. Hepatic glutamine synthetase takes part in this interaction by metabolizing a bacterial substance and producing a molecule with interesting clinical potential.
Ferroptosis is a mechanism of cell death that has possible roles in numerous diseases. Two new studies have identified hydropersulfides as potent inhibitors of O2-dependent membrane damage and destruction, and as potential regulators of ferroptosis.
Metabolic rewiring of activated macrophages promotes glycolysis and contributes to bacterial killing. A new study shows that reactive nitrogen species, released during macrophage activation, induce a profound inhibitory signal that facilitates metabolic reprogramming by modification of lipoate.
A combined structural and biochemical analysis reveals that TRIM7 E3 ligase targets viral proteins for degradation by recognizing their C-terminal glutamine (C-Gln) via its PRY-SPRY domain, providing mechanistic insight into the C-degron pathway.
Prostate tumors, resistant to current antiandrogen therapies, represent a serious clinical challenge. A new report identifies androgen-receptor-dependent liquid condensates as being responsible in part for therapeutic resistance, but, encouragingly, also reveals a novel vulnerability amenable to drug targeting.
The fungal sterol receptor and transcription factor Upc2 activates the transcription of ergosterol biosynthesis genes in response to ergosterol depletion in yeast. A structural and biochemical study reveals an Hsp90-dependent translocation activation mechanism of Upc2, with implications for triazole antifungal resistance.
Unbiased metabolomics revealed the conversion of serotonin into N-acetylserotonin-derived glucosides by an intestinal carboxylesterase in Caenorhabditis elegans, which suggests an unappreciated role of the gut in modulating 5-HT signaling.
The gut microbiota has a key role in protecting hosts from pathogens. A new study identified a gut microbiota-derived bile acid (chenodeoxycholic acid) that inhibits bacterial infection by interacting with a regulatory protein necessary for the expression of virulence factors.
Single-molecule methods are a powerful tool to study the kinetics of ATP-powered enzymes. A method that locally controls the generation of ATP significantly increases the throughput of single-molecule approaches and unlocks single-turnover analysis of molecular machines.
Isoform-selective inhibition of JAK kinases is of key interest in drug discovery. A novel pocket in the JAK pseudokinase domain was targeted by an allosteric covalent inhibitor, leading to specific JAK1 inhibition and providing a deeper understanding of cytokine signaling.
