A chemical screen identifies BET bromodomain inhibitors as inducers of an activated skin keratinocyte state that promotes the wound-healing capabilities of these cells. The study implicates epigenetic modifiers as potential targets for non-healing, chronic wounds.

Directed evolution on the yeast cell surface enables the discovery of sortase variants with altered specificity capable of modifying Aβ peptides under physiologically relevant conditions.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A Correction to this paper has been published: https://doi.org/10.1038/s41589-020-00722-1.

We asked a collection of chemical biologists, “What is the most exciting frontier area in chemical biology and what key technology is needed to advance knowledge and applications in this area?” and reveal some of the perspectives we received.

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.

This themed issue features a collection of articles that explore long-standing questions in the study of lipids and membranes.

We live in the era of antibiotic resistance, and this problem will progressively worsen if no new solutions emerge. In particular, Gram-negative pathogens present both biological and chemical challenges that hinder the discovery of new antibacterial drugs. First, these bacteria are protected from a variety of structurally diverse drugs by a low-permeability barrier composed of two membranes with distinct

Ion channels play critical roles in cellular function by facilitating the flow of ions across the membrane in response to chemical or mechanical stimuli. Ion channels operate in a lipid bilayer, which can modulate or define their function. Recent technical advancements have led to the solution of numerous ion channel structures solubilized in detergent and/or reconstituted into lipid bilayers, thus

The Hedgehog (Hh) signaling pathway coordinates cell–cell communication in development and regeneration. Defects in this pathway underlie diseases ranging from birth defects to cancer. Hh signals are transmitted across the plasma membrane by two proteins, Patched 1 (PTCH1) and Smoothened (SMO). PTCH1, a transporter-like tumor-suppressor protein, binds to Hh ligands, but SMO, a G-protein-coupled-receptor

Maintenance of lipid asymmetry across the two leaflets of the plasma membrane (PM) bilayer is a ubiquitous feature of eukaryotic cells. Loss of this asymmetry has been widely associated with cell death. However, increasing evidence points to the physiological importance of non-apoptotic, transient changes in PM asymmetry. Such transient scrambling events are associated with a range of biological functions

Within cell membranes numerous protein assemblies reside. Among their many functions, these assemblies regulate the movement of molecules between membranes, facilitate signaling into and out of cells, allow movement of cells by cell-matrix attachment, and regulate the electric potential of the membrane. With such critical roles, membrane protein complexes are of considerable interest for human health

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.

Targeted protein degradation provides a powerful complement to small-molecule inhibition in modulating protein activity and allows access to otherwise intractable drug targets.

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 repertoire of nucleobase methylation in DNA and RNA, introduced by chemical agents or enzymes, is large. Most methylation can be reversed either directly by restoration of the original nucleobase or indirectly by replacement of the methylated nucleobase with an unmodified nucleobase. In many direct and indirect demethylation reactions, ALKBH (AlkB homolog) and TET (ten eleven translocation) hydroxylases

Eukaryotic cells compartmentalize metabolic pathways in organelles to achieve optimal reaction conditions and avoid crosstalk with cytosolic factors. We found that cytosolic expression of norcoclaurine synthase (NCS), the enzyme that catalyzes the first committed reaction in benzylisoquinoline alkaloid biosynthesis, is toxic in Saccharomyces cerevisiae and, consequently, restricts (S)-reticuline production

Despite the central role of iron in biology, our understanding of how cells sense iron is limited to protein-dependent mechanisms. Here, we report the discovery of iron-sensing riboswitches (named Sensei). Present across bacterial phyla, these RNAs reside in the 5′ untranslated regions or within coding regions of messenger RNAs (mRNAs) encoding iron-related proteins. These riboswitches bind the reduced

The angiopoietin (Ang)–Tie pathway is essential for the proper maturation and remodeling of the vasculature. Despite its importance in disease, the mechanisms that control signal transduction through this pathway are poorly understood. Here, we demonstrate that heparan sulfate glycosaminoglycans (HS GAGs) regulate Ang–Tie signaling through direct interactions with both Ang ligands and Tie1 receptors

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 MerR-family transcription factors (TFs) are a large group of bacterial proteins responding to cellular metal ions and multiple antibiotics by binding within central RNA polymerase-binding regions of a promoter. While most TFs alter transcription through protein–protein interactions, MerR TFs are capable of reshaping promoter DNA. To address the question of which mechanism prevails, we determined

The metabolic adaptations by which phloem-feeding insects counteract plant defense compounds are poorly known. Two-component plant defenses, such as glucosinolates, consist of a glucosylated protoxin that is activated by a glycoside hydrolase upon plant damage. Phloem-feeding herbivores are not generally believed to be negatively impacted by two-component defenses due to their slender piercing-sucking

Protein kinases control nearly every facet of cellular function. These key signaling nodes integrate diverse pathway inputs to regulate complex physiological processes, and aberrant kinase signaling is linked to numerous pathologies. While fluorescent protein-based biosensors have revolutionized the study of kinase signaling by allowing direct, spatiotemporally precise kinase activity measurements

TRAAK is an ion channel from the two-pore domain potassium (K2P) channel family with roles in maintaining the resting membrane potential and fast action potential conduction. Regulated by a wide range of physical and chemical stimuli, the affinity and selectivity of K2P4.1 toward lipids remains poorly understood. Here we show the two isoforms of K2P4.1 have distinct binding preferences for lipids dependent

The mitotic kinase AURORA-A is essential for cell cycle progression and is considered a priority cancer target. Although the catalytic activity of AURORA-A is essential for its mitotic function, recent reports indicate an additional non-catalytic function, which is difficult to target by conventional small molecules. We therefore developed a series of chemical degraders (PROTACs) by connecting a clinical