Small-molecule modulators of protein synthesis are invaluable tools for dissecting the translation apparatus. This Review summarizes the mechanisms of molecules that disrupt translation in an amino ac...

Allenes and alkynes are important functional groups in chemical biology, yet their biosynthesis is poorly understood. Now, Liu et al. reveal that they form via oxidative C(sp2)-demethylation of the pr...

Multidrug efflux pumps expel antibiotics, contributing to antibiotic resistance. Now, high-throughput screening and structural characterization reveal an inhibitor of Staphylococcus aureus efflux pump...

Sun, Wu et al. identify AvaS as a pyridoxal-phosphate-dependent RNA-modifying enzyme, producing the tRNA modification ava2C from k2C in bacteria and plants and linking RNA chemistry to translational r...

Noncanonical redox cofactors (NRCs) are promising alternatives to nicotinamide adenine dinucleotide (phosphate) (NAD(P)+) for biomanufacturing because of expanded capabilities and lower cost; however,...

Cells undergo membrane remodeling in response to the environment to perform specific functions. Now, a cytometry-based method with immune cell biomarker analysis captures variations in plasma membrane...

Large-scale CRISPR dependency mapping reveals 1,000+ genes that modify cellular outcomes to DNA damage response drugs. Loss of PRDX1, acting through a PAX7–MRGBP–IREB2 pathway, broadly sensitized cell...

Macrophages acquire intact surface proteins from cancer cells during live-cell uptake, with these proteins remaining active, revealing a transcriptionally silent process where macrophages can reengine...

Fang, Ren, Zheng, Wang et al. developed Lantern, a variant of miniSOG, through directed evolution for subcellular transcriptomes and proteomes analyses inside living cells, enabling findings that RNA ...

Pretomanid and delamanid are prodrugs reported to target the decaprenylphosphoribose-2′-reductase DprE2, while the noncovalent inhibitor quabodepistat has been reported to target the decaprenylphospho...

Although hypersialylation on cancer cells and its roles in immune evasion and metastasis are well known, the functional roles of cell-surface sialylation on tumor-infiltrating immune cells (TIICs) are...

An enantioselective covalent inhibitor was developed that restrains BAX, protecting mouse liver and human motor neurons from injury and establishing covalent BAX inhibition as a promising strategy to ...

Existing receptor targets to direct delivery of biologics across the blood−brain barrier are ubiquitously expressed in the central nervous system (CNS) and peripheral tissues. Now, carbonic anhydrase ...

The mitochondrial inner membrane complexes TIM23 and TIM22 mediate distinct protein topogenesis functions in polypeptide import. The authors reveal their mechanistic overlap in topogenic sequence reco...

Agentic AI systems are reshaping drug discovery, and the convergence of agentic AI with laboratory automation is enabling the design of self-driving laboratories that transform the design–make–test–an...

Here the authors present a biosensor for measuring endogenous Ras in live cells, based on HaloTag and the fluorogenic JF635 dye, and they use it to report location-specific inhibition profiles of dist...

Electronic circuit boards carry out different operations on the basis of the configuration of their components. Now, equivalent biological circuits are engineered that compute functions on the basis o...

A photoproximity-labeling approach maps cancer-specific partners of the c-Myc oncoprotein, revealing that the kinase SLK binds and stabilizes c-Myc, drives tumor growth and offers a new strategy to ta...

Through chemical complementation, Brønsted-basic small molecules rescue the loss of the catalytic glutamine side chain in KRAS-Q61X mutants, accelerating GTP hydrolysis up to 20-fold.

A chemical screen identified a PRC2–AR–ETV1–PPP axis that regulates β cell identity features in α cells. An intermediate PPP metabolite, methyl esterified 6-phosphogluconate, induced metabolic reprogr...

An electrophile–drug conjugate covalently activates PFKL through K677 engagement and releases a selective CPT2-targeting payload. This strategy exploits metabolic vulnerabilities to suppress tumor gro...

Here, the authors establish and validate two black yeasts as heterologous hosts for fungal polyketide discovery and production, combining the metabolic robustness of filamentous Aspergillus species wi...

This Review examines the chemical complexity of selenium biology and the tools available to study it. Defining current limitations in detecting selenium species outlines pathways toward a more precise...

Small molecules can covalently modify proteins to generate hapten-modified peptides, triggering T cell-mediated immune responses. Now a chemoproteomic platform enables the discovery of covalent neoant...

Dietary fibers are a primary energy source for gut bacteria and shape the composition and function of the microbiome. Now, an active learning approach integrating explainable machine learning, Bayesia...

Here d’Oelsnitz et al. generate enantioselective transcription factors that convert chiral reaction products into fluorescent signals, enabling the rapid evolution of asymmetric enzymes with inverted ...

Cells have evolved defense pathways to maintain homeostasis against external perturbations, but not against new-to-nature nanomaterials, which can irreversibly accumulate and induce cell stress. Now, ...

Host antimicrobial peptides (AMPs) are a frontline defense against infection. Now, it has been shown that maturation of AMP repertoires early in life can predict stable host coexistence with a highly ...

Resolution of protein phosphorylation at specific sites is challenging. Now, synthetic receptors have been developed that enable high-resolution enrichment of ultralow-abundance phosphopeptide positio...

Sequence biases at individual positions can be used to design more stable protein variants, while correlation between pairs of residues has also been shown to be important for specifying protein struc...

Tumor-associated macrophages (TAMs) predominantly adopt an M2-like pro-tumor phenotype, promoting anti-inflammatory signaling and cancer cell metastasis. Now, tumor immune cell targeting chimeras enab...

Cannabinoid cyclases produce bioactive cannabinoids, but their mechanisms are poorly understood. Here the authors solve the substrate-bound structure of a cannabinoid cyclase, show that bacterial and ...

Homoharringtonine (HHT) is a plant-derived anticancer drug approved by the US Food and Drug Administration. Here, the authors elucidate a root-tip-specific biosynthetic pathway to its alkaloid core, i...

eIF2B is a guanine nucleotide exchange factor that catalyzes GDP/GTP exchange on the translation initiation factor eIF2 to regulate protein synthesis. Using cryo-EM structure-guided biochemistry and p...

Image-guided pharmacotherapy holds great promise for personalized medicine through confining drug activity precisely to the disease area using electromagnetic irradiation. This Perspective describes t...

Cytochrome P450s catalyze essential reactions and carry a strictly conserved proximal cysteine ligand. Here, we identify noncanonical P450s that harbor diverse proximal ligands, including serine and s...

Nature Chemical Biology - A ratiometric fluorescent probe that maps absolute mitochondrial Na+ at single-organelle resolution and works independently of membrane potential has now been developed....

The TIM barrel is nature’s most versatile enzyme fold, yet de novo variants lack functional active sites. Minimal de novo TIM barrels have now been converted into enzymes by designing structural lids ...

Protein–ligand binding affinity prediction is important for the development and optimization of molecular probes. PBCNet2.0 predicts relative affinity changes induced by ligand modifications (for exam...

Pei, Wang, Quan and Geng and colleagues reveal how amino acid composition within intrinsically disordered regions influences the miscibility of biomolecular condensates and their function. Serine and ...

This study identifies and characterizes a conserved trypsin–MBL (metallo-β-lactamase) pair in bacterial immunity; upon infection, trypsin is activated through inhibitory ATP hydrolysis, subsequently a...

An enzyme-triggered tetrazine uncaging strategy for cell-selective bioorthogonal chemistry has now been developed. The method called TRACE (tetrazine release and activation by cellular enzymes) enable...

Telomerase, the ribonucleoprotein that maintains telomere ends, is upregulated in most cancer cells, making it a promising oncology target. Cryo-electron microscopy structures of telomerase with allos...