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Hydrogen peroxide (H2O2) is a key signaling molecule involved in many processes that affect health and contribute to disease, but tracking its real-time dynamics inside living cells remains challenging. A new set of biosensors now enables accurate, multiparametric monitoring of H2O2 levels without interference from changes in pH or oxygen.
A matching pseudouridine in premature termination codons and in the anticodons of cognate tRNAs promotes ribosome readthrough and avoids nonsense-mediated mRNA decay.
This Review discusses recent strategies for integrating microbial metabolism with chemocatalysis, electrocatalysis, photocatalysis and biocatalysis to enable sustainable chemical production. By highlighting examples involving engineered microorganisms, hybrid catalysis and the design of modular pathways, the Review outlines how these platforms address challenges in yield, scalability and process integration.
The discovery of macrocyclic peptide therapeutics has been slow. We introduce RFpeptides, a deep learning method that enables the de novo design of macrocyclic peptide binders to therapeutic targets. The designed macrocycles bind their respective protein targets with high affinity and atomic-level accuracy.
The reliable design of small-molecule binders to target RNAs remains challenging. Recognizing hidden pockets that are transiently occupied by intramolecular nucleobase intercalation brings us closer to achieving this goal.
This Review explores how post-translational modifications orchestrate replication stress responses by regulating checkpoint signaling, DNA repair and fork remodeling, thereby preserving genome stability under genotoxic conditions.
MARUbylation is a hybrid post-translational protein modification in which mono-ADP-ribosylation acts as a scaffold for sequential mono- and polyubiquitylation. Recent studies illuminate its substrates, molecular recognition, and emerging roles in DNA repair.
ELOVL6 is an acyltransferase involved in the synthesis of saturated and monounsaturated fatty acids. New work finds that inhibition of ELOVL6 function results in mislocalization of oncogenic KRAS from the plasma membrane, which in turn abolishes KRAS-G12V oncogenesis.
We present a versatile, chemo-ribosomal approach to generating isolable quantities of protein-derived biopolymers containing site-specific backbone modifications, including β-, γ- and δ-peptide linkages. Two of these extended backbones would be difficult to establish by alternative strategies in folded, full-length proteins generated in cells.
Chemical biology tools are critical to provide new insights into glycobiology. A protein O-glycosyltransferase, Legionella translocated protein M (LtpM), is reported as a glycoengineering tool that requires strict and short consensus sequons to probe β-O-glucosylation and O-GlcNAcylation.
Recent advances in engineering bottom-up synthetic cells have created powerful compartmentalized biochemical reactors with cell-like abilities. To push the boundaries of the collective capabilities of synthetic cells and unlock biomedical applications, biomimicry of signaling and communication is imperative. This Review highlights state-of-the-art communication mechanisms between synthetic cells and discusses potential applications.
An ex vivo proteomic platform with isotope-labeled co-substrates clearly distinguishes arginyltransferase 1 (ATE1)-mediated arginylation from ribosomal arginine incorporation.
Engineering non-natural functions into enzymes has opened unexpected avenues for chemical synthesis. Whereas past efforts in repurposing natural enzymes have predominantly focused on heme- and flavin-dependent enzymes, latest work further highlights the advantages and potential of non-heme iron enzymes for organic synthesis.
Small proteins are challenging targets for structure determination by cryo-electron microscopy. A new mass-enhancement strategy relies on rigid dimerization of a nanobody into a ‘di-gembody’ that increases protein mass by expanding the symmetry of small protein targets.
Cereblon-based molecular glue degraders provide a powerful strategy to target previously intractable proteins. This approach has now enabled selective elimination of a metabolically essential zinc finger transcription factor that drives resistance to KRAS inhibition in pancreatic cancer.
Peroxisomes have emerged as ideal compartments for hosting heterologous biochemical reactions. A study establishes a modular chauffeur strategy for functional expression and trafficking of multi-spanning transporters and integral membrane enzymes into the yeast peroxisomal membrane for metabolic engineering.
The discovery of lipoamide offers a unique approach to modulate stress granule dynamics. It will advance studies of stress granule biology and inform the therapeutic modification of these biomolecular condensates as a potential treatment option for amyotrophic lateral sclerosis.
Self-labeling protein tags (SLPs) have revolutionized bioimaging by enabling precise protein tracking. A next-generation SLP, SNAP-tag2, has now been developed with improved labeling kinetics, fluorescence brightness, and substrate accessibility. These enhancements enable deeper insights into cellular processes in the field of bioimaging.
Promyelocytic leukemia (PML) nuclear bodies (NB) facilitate the proteasomal degradation of protein aggregates through the SUMO-targeted ubiquitin ligase pathway. A study now reveals a non-proteolytic role for PML-NBs in preventing TDP-43 aggregation that still relies on the SUMOylation–ubiquitylation cascade but uses it to direct protein aggregates towards p97 ATPase-mediated disaggregation.
The development of antibody–drug conjugates remains a challenge in part due to the lack of three-dimensional structural information that must account for the inherent flexibility of antibodies and drug payloads. This Perspective discusses computational methods to guide the design of antibody–drug conjugates.
