Reviews & Analysis

A genetically encodable and targetable protein fragment derived from PRAS40 inhibits mTOR complex 1 (mTORC1) signaling in a compartment-specific manner. This innovative tool will enable researchers to address if different subcellular pools of mTORC1 control distinct cellular processes.

For centuries, cinchona alkaloids such as quinine have shaped the history of both medicine and organic chemistry; yet, how plants assemble the molecule’s distinctive quinoline–quinuclidine scaffold has remained a mystery. A report in Nature reveals the biosynthetic pathway responsible for this iconic molecular architecture.

A study reveals that the conformational state of the RAF protein governs sensitivity to a next-generation class of RAF inhibitors. Disrupting a molecular partnership between RAF and its partner MEK can dramatically enhance the anticancer potency of these inhibitors.

Hypocrealean fungi are the most important source of fungal and insect pest biocontrol agents. By integrating phylogenomics, metabolomics and synthetic biology, we surveyed the biosynthetic capabilities of hypocrealeans to produce a catalog of pest-controlling molecules for sustainable agriculture.

This Perspective introduces the recent development of RNA modifications on chromatin-associated RNAs, discusses how they engage chromatin regulators to modulate chromatin states and direct cellular function and proposes future directions for studying RNA regulatory elements to control gene expression.

New work using high-resolution cryogenic electron microscopy and biochemistry reveals, at near-atomic resolution, the mechanism whereby a cancer-associated β3-tubulin mutation enhances paclitaxel binding, stabilizes the microtubule lattice and sensitizes cancer cells to paclitaxel.

Group I introns are catalytic RNAs able to perform self-splicing and generate circular RNAs. The cryo-electron microscopy structures of the full-length group I intron of Anabaena now reveal how RNA rearrangements coordinate self-splicing and circularization, thereby enabling structure-guided optimization of circular RNA production.

Lipid phosphate phosphatases differentially regulate signaling by bioactive lipid phosphates, but the mechanisms are unclear. Research highlights the roles of phosphatidate and phosphatidylinositol 4,5-bisphosphate in tetramer stabilization and their importance in this regulation.

Temperature-sensitive proteins promise precise, remote and penetrant control of cells, but few such proteins are currently available. A study finds that certain existing protein switches can moonlight as thermosensors, immediately expanding the landscape of temperature-sensitive probes.

The universal sulfate donor 3′-phosphoadenosine-5′-phosphosulfate (PAPS) supports diverse processes, including bone metabolism and neural function. We identify MESH1 as the long-sought phosphatase that hydrolyzes PAPS to adenosine-5′-phosphosulfate, thereby actively regulating cellular PAPS levels and glycosaminoglycan sulfation. Depletion of MESH1 in animal models demonstrates a key role for MESH1 in regulating sulfation, with implications for bone metabolism and neurotoxicity.

CenSpark, a dual-ligand fluorescent probe, enables selective live-cell imaging of centriolar and ciliary microtubule doublets and triplets across eukaryotes. By sensing higher-order architecture rather than tubulin alone, it establishes a new paradigm for labeling specialized cytoskeletal assemblies in cells.

Molecular glues offer a promising avenue for novel therapeutic development. The discovery of CLEO4-88 reveals a non-degradative molecular glue that promotes interaction between the CTLH substrate receptor GID4 and the peroxisomal thiolase ACAA1, inhibiting the enzymatic activity of ACAA1.

A study established a photocatalytic proximity interactomic platform tailored to lipid droplets. This platform uses custom photosensitizers to enable in situ labeling, allowing researchers to identify contact sites of lipid droplets with other organelles in living cells without the need for genetic engineering.

Two new studies introduce a high-throughput SuFEx platform and a covalent prodrug strategy that converts target ligands into molecular glues, revealing new E3 ligase candidates for targeted protein degradation.

By combining targetable, cell-permeable photosensitizers with amine-based electrophilic trapping chemistry, a technology termed singlet-oxygen-based photocatalytic proximity labeling (POCA) provides a general strategy for profiling the protein interactomes of diverse molecular baits, including cholesterol, in their native cellular environments.

Biomolecular condensates composed of intrinsically disordered proteins with no inherent catalytic activity promote the reductive amination of diverse metabolites. The proposed electrostatic catalytic mechanism shares features with that used in the active site of enzymes.

How microorganisms build the catalytic heart of the nitrogenase enzyme has remained unknown. Two studies now show how these enzymes repurpose a nitrogenase-like scaffold to assemble the nitrogenase cofactor.

NRF2 enables tumor cells to tolerate oxidative and metabolic stress. A covalent molecular glue restores degradation of NRF2 by stabilizing the KEAP1–ubiquitin ligase complex.

Bowl-shaped mechanosensitive PIEZO channels sense membrane tension by flattening curved transmembrane domains, but how these mechanosensory motions couple with and open the channel pore is unclear. Now, multi-scale molecular dynamics simulations provide insight into this mechano-electrical coupling in PIEZO2, uncovering clockwork-like gating motions of the central pore.

Although long considered to be structured as oligomers comprising a single species, recent work highlights the ability of eukaryotic type 1 peroxiredoxin isoforms to assemble as heterodimers and heterodecamers in vivo. This key property redefines the current understanding of the biological scope of peroxiredoxins.