Reviews & Analysis

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.

Photorhabdus noenieputensis (a gut microbiota symbiont of nematodes) produces a macrocyclic antibiotic, evybactin, that selectively kills Mycobacterium tuberculosis (Mtb). The Mtb membrane transporter BacA imports evybactin into the cell, where it binds to DNA gyrase and causes cell death.

The microtubule-associated protein tau is strongly linked to Alzheimer’s disease, but the physiological functions of tau on microtubules remain unclear. New experiments reveal that tau recognizes and alters the conformation of the underlying microtubule lattice by forming envelopes that surround its surface, suggestive of a novel role for tau in cell physiology.

Loss of myelin causes neurological symptoms for patients with multiple sclerosis. This Perspective details how phenotypic screening has accelerated discovery efforts toward potential ‘remyelinating therapeutics’.

Elucidating the interactions between serum protein-bound nanoparticles and cell-surface receptors typically operates on a per protein–receptor interaction basis. Integration of omic approaches for testing thousands of interactions unbiasedly reveals important interactions that drive cellular uptake of nanoparticles.

Cas12f1 is a member of type V Cas12 family, which has a hypercompact size. A Cas12f1-based adenine base editor has now been developed that is small enough to be loaded into a single AAV vector without compromising editing activity.

Emerging evidence shows that ubiquitination can occur on nonlysine residues and nonproteinaceous substrates. This perspective summarizes the recent discoveries in noncanonical ubiquitination and advocates the development of chemical biology tools for new substrate identification and mechanistic dissection.

In the post-genomic era, many genes and regulatory elements remain uncharacterized, including riboswitches — RNA structures that control gene expression by directly binding metabolites. Here, a new type of metal-responsive riboswitch that senses sodium cations expands the bacterial Na⁺ metabolic repertoire.

Biomolecular condensates form and dissolve in response to a wide range of signals. A new study reports a solubility-based phosphoproteome-profiling approach, which uncovers the extensive role of phosphorylation in regulating protein partitioning into condensates across the human proteome.

Chemical probes are powerful tools for the discovery of ligand-binding and drug-target sites on proteins. A new software helps to profile their performance in chemoproteomic applications.

Mutant-selective KRAS-targeting drugs hold great promise for the treatment of some of the most aggressive forms of cancer. Building on the breakthrough success of KRAS-G12C inhibitors, researchers have now found a way to target another mutant KRAS with serine-modifying covalent inhibitors.

A directed evolution approach delivers ribosomes with highly functional tethered subunits. Combining the decoding and peptidyl transferase activities of the ribosome into a single entity sets the scene for more efficient protein engineering technologies.

The Hippo pathway is a key regulator of tissue homeostasis, organ size and cancer. Identification of microcolin B and its analog molecules as Hippo pathway activators connects PtdIns4P-dependent lipid signaling with the Hippo pathway, suggesting potential targets for cancer therapy.

This Perspective discussed selective partitioning behaviors of biomolecules and small molecules and proposed that understanding the chemical properties that control their interactions within the condensates would promote drug development.

Several venomous predators and pathogens use insulins to capture prey and to manipulate host physiology. This Review provides an overview of the discovery and potential biomedical application of these and other weaponized hormones found in nature.

Antigen loading onto class I major histocompatibility complex (MHC-I) proteins relies on chaperones and protein flexibility. Researchers now provide new insight into the process, especially for the intriguing ‘non-classical’ MHC-I protein MR1, with implications for fundamental immunology and the development of novel immunotherapies.

Carbon dioxide (CO₂) is a product of cellular respiration that can also serve as a post-translational modification (PTM) through covalent protein modification. A new chemoproteomic strategy enables the capture of functional CO₂-dependent carboxylation on lysine residues of proteins.

The rising threat of antifungal resistance means that alternative therapeutics need to be considered. New research explores the biochemical basis of virulence inhibition by mucus glycans against the fungal pathogen Candida albicans.