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Insects have many ways of disabling plant chemical defenses during feeding. Plant phloem feeders use surplus ingested sugar to block the activation of glucosinolate toxins, providing a target for precise resistance breeding.
Metabolic engineering offers the flexibility to meet market demand for bioactive natural products but can be hampered when a necessary protein or intermediate is toxic. In yeast, modifying the subcellular localization of biosynthetic enzymes can alleviate toxicity and increase production titer.
Transfer of ubiquitin onto target proteins requires controlled interplay between E2 conjugating enzymes and E3 ligases. The structure of a trapped E2~Ub/RCR E3 transfer intermediate provides novel insight into the diversity of mechanisms used to fine tune this relay.
Targeted small-molecule inhibition of BRAFV600E faces seemingly insurmountable obstacles in the clinic, such as rapid emergence of drug resistance. A recent study illustrates the potential of an alternative therapeutic strategy via PROTAC-mediated degradation of the oncogenic BRAF.
The ADGRL3 receptor, a member of the adhesion G-protein-coupled receptor family, is implicated in many neurological diseases. Using a novel technique involving controlled proteolysis of the receptor’s extracellular domain, this study demonstrated that ADGRL3 signals via G12/13 G proteins.
The electrogenic bacterium Geobacter synthesizes conductive extracellular nanowires to facilitate electron transfer that powers respiration. A highly conductive form of these nanowires is now revealed to be composed of oligomers of an 8-heme cytochrome, OmcZ.
Coherent Raman imaging enables mapping of chemical features at subcellular resolution, setting the stage for tracking lipids and other metabolites in intact living systems.
Bariatric surgery causes high rates of remission of type 2 diabetes; however, the mechanisms remain unresolved. A new study identifies cholic-acid-7-sulfate as a novel contributor to the metabolic benefits of bariatric surgery and an attractive target for treatment of type 2 diabetes.
It is generally believed that large protein complexes provide a catalytic advantage due to substrate channeling between enzymatic domains. However, the structure and function of the pentafunctional AROM complex suggests a noteworthy exception.
Reprogramming requires resetting the epigenome toward a pluripotent chromatin state. A new chemical screen identifies epigenetic and signaling roadblocks for reprogramming of human somatic cells, with the inhibition of these roadblocks resulting in a more permissive epigenome for reprogramming.
Altered glycosylation helps cancer cells evade immune destruction, and targeted remodeling of glycans in vivo offers the ability to reprogram immune responses. A stable chemical linkage between an antibody and neuraminidase enables the targeted destruction of self-associated sialic acids to enhance antitumor immunity.
Two recent studies identified CDK12 inhibitors that bind to CDK12–cyclin K complexes and act as molecular glues to stabilize an interaction with the ubiquitin ligase CUL4–DDB1, leading to cyclin K degradation.
Thermodynamic principles are used to map the phase behavior of a tunable protein-binding system under crowded cellular conditions. This study marks a substantial step forward in relating molecular interactions to material properties and cellular processes involving protein self-assembly.
A new molecule that specifically activates a key protein homeostasis pathway has been identified. The ability to initiate the IRE1–XBP1s branch of the unfolded protein response opens up new avenues for basic research and treatment of disease.
Rho family GTPases regulate cell behaviors through complex signaling networks that act on rapid timescales in subcellular spatial domains. New live-cell biosensors and analytical methods now provide critical tools to dissect Rho GTPase regulation and to better understand cellular information processing.
An NMR method to monitor conformational states of challenging large protein targets is described. The method, which can be used to evaluate distances between two labels and to measure conformational exchange rates, revealed an unanticipated outward-facing state in a glutamate transporter.
Molecular glues induce novel protein–protein interactions to modulate protein function and downstream biology. A recent study unveils manumycin polyketides with multiple electrophilic centers as covalent molecular glues between UBR7 and TP53.
The enzyme 5-lipoxygenase (5-LOX) initiates the biosynthesis of leukotrienes (LT), potent mediators of the inflammatory response. The first crystal structures of two complexes of inhibitor bound to 5-LOX reveal the functional consequences of the binding, including a change in the regiospecificity toward a 12/15-lipoxygenating enzyme.
Glucose 6-phosphate dehydrogenase (G6PD) stands at the head of the pentose phosphate pathway, which is responsible for nucleotide synthesis. The identification and thorough validation of an improved G6PD inhibitor provide a valuable new tool compound for studying metabolism.
A suite of new enzymes reveals more on how Nature breaks down plant-based polysaccharides and how these enzymes might be harnessed in the utilization of plant-based biomass.
